PURPOSE Whether dosimetric advantages of proton beam therapy (PBT) translate to improved clinical outcomes compared with intensity-modulated radiation therapy (IMRT) remains unclear. This randomized trial compared total toxicity burden (TTB) and progression-free survival (PFS) between these modalities for esophageal cancer. METHODS This phase IIB trial randomly assigned patients to PBT or IMRT (50.4 Gy), stratified for histology, resectability, induction chemotherapy, and stage. The prespecified coprimary end points were TTB and PFS. TTB, a composite score of 11 distinct adverse events (AEs), including common toxicities as well as postoperative complications (POCs) in operated patients, quantified the extent of AE severity experienced over the duration of 1 year following treatment. The trial was conducted using Bayesian group sequential design with three planned interim analyses at 33%, 50%, and 67% of expected accrual (adjusted for follow-up). RESULTS This trial (commenced April 2012) was approved for closure and analysis upon activation of NRG-GI006 in March 2019, which occurred immediately prior to the planned 67% interim analysis. Altogether, 145 patients were randomly assigned (72 IMRT, 73 PBT), and 107 patients (61 IMRT, 46 PBT) were evaluable. Median follow-up was 44.1 months. Fifty-one patients (30 IMRT, 21 PBT) underwent esophagectomy; 80% of PBT was passive scattering. The posterior mean TTB was 2.3 times higher for IMRT (39.9; 95% highest posterior density interval, 26.2-54.9) than PBT (17.4; 10.5-25.0). The mean POC score was 7.6 times higher for IMRT (19.1; 7.3-32.3) versus PBT (2.5; 0.3-5.2). The posterior probability that mean TTB was lower for PBT compared with IMRT was 0.9989, which exceeded the trial’s stopping boundary of 0.9942 at the 67% interim analysis. The 3-year PFS rate (50.8% v 51.2%) and 3-year overall survival rates (44.5% v 44.5%) were similar. CONCLUSION For locally advanced esophageal cancer, PBT reduced the risk and severity of AEs compared with IMRT while maintaining similar PFS.

Purpose To evaluate the efficacy and adverse effects of image-guided stereotactic body radiation therapy (SBRT) in centrally/superiorly located non–small-cell lung cancer (NSCLC). Methods and Materials We delivered SBRT to 27 patients, 13 with stage I and 14 with isolated recurrent NSCLC. A central/superior location was defined as being within 2 cm of the bronchial tree, major vessels, esophagus, heart, trachea, pericardium, brachial plexus or vertebral body but 1 cm away from the spinal canal. All patients underwent four-dimensional CT–based planning, and daily CT-on-rail guided SBRT. The prescribed dose of 40 Gy (n=7) to the planning target volume was escalated to 50 Gy (n=20) in 4 consecutive days. Results With a median follow-up of 17 months (range, 6–40 months), the crude local control at the treated site was 100% using 50 Gy. However, three of seven patients had local recurrences when treated using 40 Gy. Of the patients with stage I disease, one (7.7%) and two (15.4%) developed mediastinal lymph node metastasis and distant metastases, respectively. Of the patients with recurrent disease, three (21.4%) and five (35.7%) developed mediastinal lymph node metastasis and distant metastasis, respectively. Four patients (28.6%) with recurrent disease but none with stage I disease developed grade 2 pneumonitis. Three patients (11.1%) developed grade 2–3 dermatitis and chest wall pain. One patient developed brachial plexus neuropathy. No esophagitis was noted in any patient. Conclusion Image-guided SBRT using 50 Gy delivered in four fractions is feasible and resulted in excellent local control.

IMPORTANCE Consensus is lacking as to the optimal radiotherapy dose and fractionation schedule for treating bone metastases.OBJECTIVE To assess the relative efficacy of high-dose, single-fraction stereotactic body radiotherapy (SBRT) vs standard multifraction radiotherapy (MFRT) for alleviation of pain in patients with mostly nonspine bone metastases. DESIGN, SETTING, AND PARTICIPANTSThis prospective, randomized, single-institution phase 2 noninferiority trial conducted at a tertiary cancer care center enrolled 160 patients with radiologically confirmed painful bone metastases from September 19, 2014, through June 19, 2018. Patients were randomly assigned in a 1:1 ratio to receive either single-fraction SBRT (12 Gy for Ն4-cm lesions or 16 Gy for <4-cm lesions) or MFRT to 30 Gy in 10 fractions. MAIN OUTCOMES AND MEASURESThe primary end point was pain response, defined by international consensus criteria as a combination of pain score and analgesic use (daily morphine-equivalent dose). Pain failure (ie, lack of response) was defined as worsening pain score (Ն2 points on a 0-to-10 scale), an increase in morphine-equivalent opioid dose of 50% or more, reirradiation, or pathologic fracture. We hypothesized that SBRT was noninferior to MFRT. RESULTSIn this phase 2 noninferiority trial of 96 men and 64 women (mean [SD] age, 62.4 [10.4] years), 81 patients received SBRT and 79 received MFRT. Among evaluable patients who received treatment per protocol, the single-fraction group had more pain responders than the MFRT group (complete response + partial response) at 2 weeks (34 of 55 [62%] vs 19 of 52 [36%]) (P = .01), 3 months (31 of 43 [72%] vs 17 of 35 [49%]) (P = .03), and 9 months (17 of 22 [77%] vs 12 of 26 [46%]) (P = .03). No differences were found in treatment-related toxic effects or quality-of-life scores after SBRT vs MFRT; local control rates at 1 and 2 years were higher in patients receiving single-fraction SBRT.CONCLUSIONS AND RELEVANCE Delivering high-dose, single-fraction SBRT seems to be an effective treatment option for patients with painful bone metastases. Among evaluable patients, SBRT had higher rates of pain response (complete response + partial response) than did MFRT and thus should be considered for patients expected to have relatively long survival.

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Background We evaluated the efficacy, pattern of failure, and toxicity of stereotactic ablative radiotherapy (SABR) for medically inoperable clinical stage I non-small cell lung cancer (NSCLC) in a prospective clinical trial with 7 years follow-up. Methods Eligible patients with histologically confirmed NSCLC and PET clinically staged I disease were treated with SABR (50 Gy in 4 fractions). The primary endpoint was progression-free survival (PFS). Patients were followed with CT/PET-CT every 3 months for the first two years, then every 6 months for the next three years and then annually thereafter. Results Sixty-five patients were eligible for analysis. The median age was 71 years, and median follow-up was 7.2 years. A total of 18 (27.7%) patients had disease recurrence at a median of 14.5 months (range 4.3–71.5) after SABR. Estimated incidences of local, regional, and distant recurrence using competing risk analysis were 8.1%, 10.9%, and 11.0% at 5 years, respectively, and 8.1%, 13.6%, and 13.8% at 7 years. Second primary lung carcinoma (SPLC) developed in 12 (18.5%) patients at a median of 35 months (range 5–67) after SABR. Estimated 5- and 7-year PFS rates were 49.5% and 38.2%, respectively; corresponding overall survival rates were 55.7% and 47.5%. Three (4.6%) patients had grade 3 treatment-related adverse events. No patients had grade 4 or 5 events. Conclusion With long-term follow-up, our prospective study demonstrated outstanding local control and low toxicity after SABR in clinical stage I NSCLC. Regional recurrence and distant metastases were the dominant manifestations of failure. Surveillance for SPLC is recommended.