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Summary Background In the ongoing, phase 3 PACIFIC trial, durvalumab improved the primary endpoints of progression-free survival and overall survival compared with that for placebo, with similar safety, in patients with unresectable, stage III non-small-cell lung cancer. In this analysis, we aimed to evaluate one of the secondary endpoints, patient-reported outcomes (PROs). Methods PACIFIC is an ongoing, international, multicentre, double-blind, randomised, controlled, phase 3 trial. Eligible patients were aged at least 18 years, had a WHO performance status of 0 or 1, with histologically or cytologically documented stage III, unresectable non-small-cell lung cancer, for which they had received at least two cycles of platinum-based chemoradiotherapy, with no disease progression after this treatment. We randomly assigned patients (2:1) using an interactive voice response system and a blocked design (block size=3) stratified by age, sex, and smoking history to receive 10 mg/kg intravenous durvalumab or matching placebo 1–42 days after concurrent chemoradiotherapy, then every 2 weeks up to 12 months. The primary endpoints of progression-free survival and overall survival have been reported previously. PROs were a prespecified secondary outcome. We assessed PRO symptoms, functioning, and global health status or quality of life in the intention-to-treat population with the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) version 3 and its lung cancer module, the Quality of Life Questionnaire-Lung Cancer 13 (QLQ-LC13) at the time of random allocation to groups, at weeks 4 and 8, every 8 weeks until week 48, and then every 12 weeks until progression. Changes from baseline to 12 month in key symptoms were analysed with mixed model for repeated measures (MMRM) and time-to-event analyses. A 10-point or greater change from baseline (deterioration or improvement) was deemed clinically relevant. This study is registered with ClinicalTrials.gov , NCT02125461 , and EudraCT, 2014-000336-42. Findings Between May 9, 2014, and April 22, 2016, 476 patients were assigned to receive durvalumab, and 237 patients were assigned to receive placebo. As of March 22, 2018, the median follow-up was 25·2 months (IQR 14·1–29·5). More than 79% of patients given durvalumab and more than 82% of patients given placebo completed questionnaires up to week 48. Between baseline and 12 months, the prespecified longitudinal PROs of interest, cough (MMRM-adjusted mean change 1·8 [95% CI 0·06 to 3·54] in the durvalumab group vs 0·7 [–1·91 to 3·30] in the placebo group), dyspnoea (3·1 [1·75 to 4·36] vs 1·4 [–0·51 to 3·34]), chest pain (−3·1 [–4·57 to −1·60] vs −3·5 [–5·68 to −1·29]), fatigue (−3·0 [–4·53 to −1·50] vs −5·2 [–7·45 to −2·98]), appetite loss (−5·8 [–7·28 to −4·36] vs −7·0 [–9·17 to −4·87]), physical functioning (0·1 [–1·10 to 1·28] vs 2·0 [0·22 to 3·73]), and global health status or quality of life (2·6 [1·21 to 3·94] vs 1·8 [–0·25 to 3·81]) remained stable with both treatments, with no clinically relevant changes from baseline. The between-group differences in changes from baseline to 12 months in cough (difference in adjusted mean changes 1·1, 95% CI −1·89 to 4·11), dyspnoea (1·6, −0·58 to 3·87), chest pain (0·4, −2·13 to 2·93), fatigue (2·2, −0·38 to 4·78), appetite loss (1·2, −1·27 to 3·67), physical functioning (−1·9, −3·91 to 0·15), or global health status or quality of life (0·8, −1·55 to 3·14) were not clinically relevant. Generally, there were no clinically important between-group differences in time to deterioration of prespecified key PRO endpoints. Interpretation Our findings suggest that a clinical benefit with durvalumab can be attained without compromising PROs. This result is of note because the previous standard of care was observation alone, with no presumed detriment to PROs. Funding AstraZeneca.

Background and purpose : This study aims to evaluate the reduction in radiation dose to normal thoracic structures through the use of conformal radiotherapy techniques in the treatment of oesophageal cancer, and to quantify the resultant potential for dose escalation. Materials and methods : Three different CT-derived treatment plans were created and compared for each of ten patients. A two-phase treatment with conventional straight-edged fields and standard blocks (CV2), a two-phase conformal plan (CF2), and a three-phase conformal plan where the third phase was delivered to the gross tumour only (CF3), were considered for each patient. Escalated dose levels were determined for techniques CF2 and CF3, which by virtue of the conformal field shaping, did not increase the mean lung dose. The resulting increase in tumour control probability (TCP) was estimated. Results : A two-phase conformal technique (CF2) reduced the volume of lung irradiated to 18 Gy from 19.7±11.8 (1 SD) to 17.1±12.3% ( P =0.004), and reduced the normal tissue complication probability (NTCP) from 2.4±4.0 to 0.7±1.6% ( P =0.02) for a standard prescribed dose of 55 Gy. Consequently, technique CF2 permitted a target dose of 59.1±3.2 Gy without increasing the mean lung dose. Technique CF3 facilitated a prescribed dose of 60.7±4.3 Gy to the target, the additional 5 Gy increasing the TCP from 53.1±5.5 to 68.9±4.1%. When the spinal cord tolerance was raised from 45 to 48 Gy, technique CF3 allowed 63.6±4.l Gy to be delivered to the target, thereby increasing the TCP to 78.1±3.2%. Conclusions : Conformal radiotherapy techniques offer the potential for a 5–10 Gy escalation in dose delivered to the oesophagus, without increasing the mean lung dose. This is expected to increase local tumour control by 15–25%.

Forty-three cardiac allografts (39 autopsies and 4 surgically resected hearts) showing chronic rejection—defined as greater than 75% narrowing of one or more major coronary arteries (MCA) with or without severe narrowing of intramyocardial coronary arteries (ICA)—were studied histologically. MCA showed purely concentric narrowing in 24 patients (56%), and 19 patients (44%) showed eccentric narrowing in some arteries. Fibrofatty (collipid) plaques were seen in 54%, abundant foam cells sans free lipid in 33%, purely fibrous plaques in 14%, and calcification in 9%. Four pathologic alterations separated graft atherosclerosis from usual atherosclerosis: (i) the presence in the MCA and/or ICA of either active or healed vasculitis, (ii) outer medial defects attributable to mediolysis and/or foam cell transformation in the MCA, (iii) the diffuse nature of the atherosclerotic-like changes, and (iv) obliterative narrowing of the ICA. No difference was found between early and late survivors with regard to features of graft atherosclerosis. The majority of the patients studied had received steroid-based immunosuppression. MCA and/or ICA active vasculitis was observed in the absence of acute myocardial rejection in some patients. ICA showed intimal thickening in 37% of patients, active vasculitis in 21%, healed vasculitis in 7%, and combination of the latter two changes in 12%. Acute myocardial ischemia, present in 33 hearts (77%), had the following distribution: subendocardial in 42%, focal in 36%, and regional transmural in 21%. Myocytolysis (83%), coagulative necrosis (26%), and contraction band necrosis (16%) were noted. Replacement fibrosis of the myocardium was frequently observed (44%), followed by interstitial (33%) and perivascular fibrosis (1%). Patients with chronic rejection showed no difference with regard to the incidence and severity of rejection episodes during life compared with patients without chronic rejection.

TPS9596 Background: Despite therapeutic advances, outcomes in pediatric HGG remain poor. The phase I study (Glade-Bender et al., J Clin Oncol. 2008) indicated that Bv is well tolerated in children with refractory solid tumors and yielded pharmacokinetic (PK) data that support further studies of Bv in childhood cancer. Reports of Bv used in children with solid tumors showed safety profiles consistent with data from adults. Methods: 120 evaluable patients aged 3-18 years with newly diagnosed histologically confirmed WHO grade 3or 4 HGG are randomized to receive standard combined modality therapy as currently adopted worldwide by the pediatric neuro-oncology community with or without Bv. Treatment consists of 6 weeks of concomitant TMZ and local radiotherapy, followed by a 4-week TMZ treatment break and 48 weeks of adjuvant TMZ with or without Bv every other week. Primary endpoint is event-free survival (EFS). Progression is based on RANO criteria. Secondary endpoints are overall survival (OS), safety, feasibility, and tolerability. PK sampling is performed during cycles 1-4 of the adjuvant TMZ phase on all patients randomized to receive Bv. Health-related quality of life, neurocognitive functions, MGMT methylation status, functional changes in tumor based on magnetic resonance diffusion & perfusion imaging and spectroscopy are explored as well as the correlation of biomarkers with clinical activity and adverse events. All randomized patients will be followed for at least 3 years. Analysis of EFS and secondary endpoints will be performed after the 120 patients evaluable for EFS have been followed for 1 year. Multimodal imaging will provide a platform to develop new imaging criteria for pediatric neuro-oncological treatment response. An updated OS and safety analysis will be performed 3 years after the last patient has been randomized. The first patient was randomized in October 2011; completion of the study is expected in 2016.