Stereotactic vs Hypofractionated Radiotherapy for Inoperable Stage I Non-Small Cell Lung Cancer: The LUSTRE Phase 3 Randomized Clinical Trial.

Importance: Stereotactic body radiotherapy (SBRT) is widely used for stage I medically inoperable non-small cell lung cancer (NSCLC), yet varied results from randomized clinical trials (RCTs) and concerns in treating centrally located tumors persist. Objective: To examine whether SBRT would improve local control (LC) compared with hypofractionated conventional radiotherapy (CRT). Design, Setting, and Participants: This phase 3 RCT was conducted in 16 Canadian centers. Patients with medically inoperable stage I (≤5 cm) NSCLC were randomized 2:1 to SBRT of 48 Gy in 4 fractions (peripheral NSCLC) or 60 Gy in 8 fractions (central NSCLC) vs CRT of 60 Gy in 15 fractions. Data were collected from May 2014 to January 2020, and data were analyzed from July 2022 to July 2023. Interventions: SBRT or CRT. Main Outcomes and Measures: The primary objective was to determine the effectiveness of SBRT compared with CRT based on LC at 3 years. Secondary outcomes included event-free survival, overall survival, and toxic effects. All radiation plans were subject to real-time/final review. Local failures were centrally adjudicated. The study was designed to detect a 3-year LC improvement of SBRT from 75% to 87.5%. The target sample size was 324 patients. Results: Of 233 included patients, 119 (51.1%) were male, and the mean (SD) age was 75.4 (7.7) years; the median (IQR) follow-up was 36.1 (26.4-52.8) months. A total of 154 patients received SBRT and 79 received CRT. The 3-year LC was 87.6% (95% CI, 81.9%-93.4%) for SBRT and 81.2% (95% CI, 71.9%-90.5%) for CRT (hazard ratio [HR], 0.61; 95% CI, 0.31-1.20; P = .15). The HR was 1.02 (95% CI, 0.72-1.45; P = .87) for event-free survival and 1.18 (95% CI, 0.80-1.76; P = .40) for overall survival. Minimal acute toxic effects were observed. Among those randomized to SBRT, late grade 3 or 4 toxic effects occurred in 5 of 45 (11%) with central NSCLC and 2 of 109 (1.8%) with peripheral NSCLC; among those randomized to CRT, in 1 of 19 (5%) with central NSCLC and 1 of 60 (2%) with peripheral NSCLC. One patient who received SBRT for an ultracentral lesion (target overlapping proximal bronchus) experienced a possible treatment-related grade 5 event (hemoptysis). Conclusions and Relevance: This RCT compared lung SBRT with hypofractionated CRT that included central/ultracentral tumors. No difference was detected in LC between groups. Severe toxic effects were limited, including patients with central tumors. The trial provides important prospective data evaluating SBRT; however, further research is necessary to determine if SBRT is more effective than CRT for peripheral and central NSCLC. Trial Registration: ClinicalTrials.gov Identifier: NCT03924869.

Lung SBRT credentialing in the Canadian OCOG-LUSTRE randomized trial.

Purpose: To report on the Stereotactic Body Radiation Therapy (SBRT) credentialing experience during the Phase III Ontario Clinical Oncology Group (OCOG) LUSTRE trial for stage I non-small cell lung cancer. Methods: Three credentialing requirements were required in this process: (a) An institutional technical survey; (b) IROC (Imaging and Radiation Oncology Core) thoracic phantom end-to-end test; and (c) Contouring and completion of standardized test cases using SBRT for one central and one peripheral lung cancer, compared against the host institution as the standard. The main hypotheses were that unacceptable variation would exist particularly in OAR definition across all centres, and that institutions with limited experience in SBRT would be more likely to violate per-protocol guidelines. Results: Fifteen Canadian centres participated of which 8 were new, and 7 were previously established (≥2 years SBRT experience), and all successfully completed surveys and IROC phantom testing. Of 30 SBRT test plans, 10 required replanning due to major deviations, with no differences in violations between new and established centres (p = 0.61). Mean contouring errors were highest for brachial plexus in the central (C) case (12.55 ± 6.62 mm), and vessels in the peripheral (P) case (13.01 ± 12.55 mm), with the proximal bronchial tree (PBT) (2.82 ± 0.78 C, 3.27 ± 1.06 P) as another variable structure. Mean dice coefficients were lowest for plexus (0.37 ± 0.2 C, 0.37 ± 0.14 P), PBT (0.77 ± 0.06 C, 0.75 ± 0.09 P), vessels (0.69 ± 0.29 C, 0.64 ± 0.31 P), and esophagus (0.74 ± 0.04 C, 0.76 ± 0.04 P). All plans passed per-protocol planning target volume (PTV) coverage and maximum/volumetric organs-at-risk constraints, although variations existed in dose gradients within and outside the target. Conclusions: Clear differences exist in both contouring and planning with lung SBRT, regardless of centre experience. Such an exercise is important for studies that rely on high precision radiotherapy, and to ensure that implications on trial quality and outcomes are as optimal as possible.

Responses of the diaphragm to transcranial magnetic stimulation during wake and sleep in humans.

UNLABELLED: The human ventilation depends on bulbospinal and corticospinal commands. This study assessed their interactions in five healthy volunteers (two men, age 25-35) through the description of diaphragm and abductor pollicis brevis (APB) motor potentials (DiMEPs, abpMEPs) evoked by transcranial magnetic stimulation (TMS) during relaxed expiration and tidal inspiration and during wake and sleep. NREM decreased corticospinal excitability and REM further did so, for both the diaphragm and the APB. During wake, inspiration shortened supine DiMEPs latencies (expiration 18.56+/-1.90ms; inspiration 17.37+/-1.48ms, P<0.001). This persisted during sleep in an augmented manner (expiration: 21.05+/-1.39ms; inspiration 18.69+/-1.17ms, P=0.002). Inspiration had no effect on apbMEPs during wake and sleep. IN CONCLUSION: (1) the tidal bulbospinal input to phrenic motoneurones is sufficient to modulate the throughput of the corticospinal pathway to these neurones; (2) this modulation is best seen after the sleep related removal of corticospinal and/or afferent inputs.

Preoperative intensity modulated radiation therapy for retroperitoneal sarcoma.

The use of intensity modulated radiation therapy (IMRT) has allowed for the administration of high doses to retroperitoneal sarcomas (RSTS) while limiting toxicity to adjacent organs. The purpose of our study is to assess the outcome and toxicities of patients with RSTS treated with neo-adjuvant external beam radiation (EBRT) therapy using IMRT. This is a retrospective study of 21 patients treated with preoperative IMRT for primary or recurrent RSTS between 2005 and 2011. Overall survival (OS) and local recurrence free survival (LRFS) were computed using the Kaplan-Meier method (log-rank test). Acute and chronic toxicities were assessed using the CTCAE v. 3 criteria. The actuarial 2 and 3-year OS was 66% for both and the 5-year OS was 51%. As for LRFS it was 57% at 2 and 3-year and 51% for the 5-year LRFS. Factors predictive for local control were microscopically negative margins (p = 0.022), a median tumor diameter <15 cm (p = 0.007) and pathology of liposarcoma (p = 0.021). Furthermore, patients treated for recurrent disease fared worse (p = 0.04) in local control than patients treated for primary disease. As for OS, patients treated for Grade 1 histology had a better outcome (p 5 0.05). EBRT was generally well tolerated. Acute gastrointestinal (GI) Grade 1 or 2 toxicities occurred in 33% of patients and one patient had unexplained post-radiation Grade 2 fever that resolved after tumor resection. As for chronic toxicities 24% of our patients presented Grade 1 GI toxicity and one patient presented Grade 3 small bowel stenosis not clearly due to radiation toxicity. Despite the location and volume of the tumors treated, preoperative IMRT was very well tolerated in our patients with retroperitoneal sarcoma. Unfortunately local recurrences remain common and dose escalation is to be considered.