Search

Abstract Background There are multiple health benefits from participating in physical activity after a cancer diagnosis, but many people living with and beyond cancer (LWBC) are not meeting physical activity guidelines. App-based interventions offer a promising platform for intervention delivery. This trial aims to pilot a theory-driven, app-based intervention that promotes brisk walking among people living with and beyond cancer. The primary aim is to investigate the feasibility and acceptability of study procedures before conducting a larger randomised controlled trial (RCT). Methods This is an individually randomised, two-armed pilot RCT. Patients with localised or metastatic breast, prostate, or colorectal cancer, who are aged 16 years or over, will be recruited from a single hospital site in South Yorkshire in the UK. The intervention includes an app designed to encourage brisk walking (Active 10) supplemented with habit-based behavioural support in the form of two brief telephone/video calls, an information leaflet, and walking planners. The primary outcomes will be feasibility and acceptability of the study procedures. Demographic and medical characteristics will be collected at baseline, through self-report and hospital records. Secondary outcomes for the pilot (assessed at 0 and 3 months) will be accelerometer measured and self-reported physical activity, body mass index (BMI) and waist circumference, and patient-reported outcomes of quality of life, fatigue, sleep, anxiety, depression, self-efficacy, and habit strength for walking. Qualitative interviews will explore experiences of participating or reasons for declining to participate. Parameters for the intended primary outcome measure (accelerometer measured average daily minutes of brisk walking (≥ 100 steps/min)) will inform a sample size calculation for the future RCT and a preliminary economic evaluation will be conducted. Discussion This pilot study will inform the design of a larger RCT to investigate the efficacy and cost-effectiveness of this intervention in people LWBC. Trial registration ISRCTN registry, ISRCTN18063498 . Registered 16 April 2021.

Importance: Advanced clear cell gynecological cancers (CCGCs) have a poor prognosis, with response rates to second-line chemotherapy less than 8%. Preliminary clinical activity with programmed cell death 1 protein (PD-1) inhibitors reported in CCGC merits further investigation., Objective: To assess the clinical benefit of pembrolizumab in patients with previously treated advanced CCGC., Design, Setting, and Participants: The PEACOCC trial is a single-arm multicenter phase 2 trial conducted at 5 UK centers investigating the clinical benefit and safety of pembrolizumab. PD-1 inhibitor-naive patients with histologically confirmed advanced CCGC, radiological disease progression following 1 or more prior courses of chemotherapy, and an Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of 0 to 1 were included. Patients were enrolled from March 2019 to October 2021, with data collected until July 2024., Interventions: Pembrolizumab, 200 mg, intravenously every 21 days up to 2 years until progression, discontinuation due to toxic effects, or patient/clinician decision. Up to 1 year of retreatment on diseases progression, if stable disease, partial response, or complete response at 2 years., Main Outcomes and Measures: The primary end point was progression-free survival (PFS) rate at 12 weeks using Response Evaluation Criteria in Solid Tumors version 1.1 to detect a 12-week PFS rate of 33% or greater and exclude a PFS rate of less than 15%, with 90% power and 1-sided 5% significance level. Secondary end points included objective response rate, duration of response, PFS, overall survival, safety, and quality of life., Results: A total of 48 patients were eligible. The median (range) age was 58.5 (32-77) years, and 26 (54%) had an ECOG PS score of 0 and 22 (46%) had an ECOG PS score of 1; 41 (85%) had ovarian, 6 (13%) had endometrial, and 1 (2%) had cervical advanced CCGC. The median (range) courses prior therapy was 3 (1-6); 19 patients (40%) received prior anti-angiogenic therapy, and 19 (40%) had a platinum-free interval of more than 12 months. Grade 3 treatment-related adverse events were observed in 9 patients (19%), and no patients had grade 4 or 5 adverse events. A total of 45 of 46 patients (98%) had mismatch repair-proficient tumors. The 12-week PFS rate was 42% (95% CI, 28-57), and the best objective response rate was 25% (95% CI, 14-40), with 12 partial responses. After a median follow-up of 46.9 months (95% CI, 43.4-55.0), the median PFS was 2.7 months (95% CI, 1.3-5.4), and the median overall survival was 14.8 months (95% CI, 6.7-28.2)., Conclusions and Relevance: The PEACOCC trial showed clinical benefit with pembrolizumab in patients with previously treated advanced CCGC, of whom all except 1 had MMR-proficient disease. Clinical outcomes were durable with an overall tolerable safety profile, justifying further evaluation of pembrolizumab monotherapy for advanced CCGC in a randomized clinical trial., Trial Registration: ClinicalTrials.gov Identifier: NCT03425565.

Tumour bulk is an established prognostic factor in Hodgkin lymphoma (HL) but most patients with limited-stage (LS) HL do not have 'bulk' by standard binary definitions. In the RAPID trial, maximum tumor diameter (MTD) was associated with risk of relapse for LS-HL patients achieving PET-negativity after ABVD chemotherapy. We aimed to externally validate these findings in the H10 trial. Patients with stage I/IIA HL, without mediastinal bulk, who achieved PET-negativity with ABVD were included. 'PET-negative' patients received 3x ABVD plus radiotherapy (n=208) or 3x ABVD alone (n=211) in RAPID, and 3-4x ABVD plus radiotherapy (n=556) or 4-6x ABVD alone (n=303) in H10. Baseline MTD was measured by CT. MTD was strongly associated with event-free survival (relapse or HL-related death) in H10 (HR=1.22, 95%CI:1.07-1.38, p=0.003), a similar effect to the RAPID trial (HR=1.19, 95%CI:1.02-1.39, p=0.02), giving an estimated 21% increase in HL-risk per centimetre MTD (HRpooled=1.21, 95%CI:1.09-1.33, p<0.001). Findings were consistent when adjusting for baseline risk stratification and chemotherapy cycles. The effect sizes were similar for patients treated with chemotherapy alone (HRpooled=1.19, 95%CI:1.01-1.35, p=0.005) and combined modality treatment (ABVD plus radiotherapy; HRpooled=1.24, 95%CI:1.05-1.46, p=0.009) with no evidence of a differential effect (pinteraction=0.97). Treatment modality and MTD were independent risk factors; patients with higher MTD receiving chemotherapy alone had the greatest risk of relapse. This international validation study confirms that MTD is strongly associated with the risk of relapse for LS-HL patients achieving PET-negativity. These findings refine assessment of risk in LS-HL and can inform clinical discussions for risk-adapted application of radiotherapy. NCT00943423 and NCT00433433., (Copyright © 2025 American Society of Hematology.)

Aims: Patients with endometrial cancer who progress following first line therapy have improved survival outcomes with pembrolizumab and lenvatinib (pem/len) compared with standard of care chemotherapy, as demonstrated in KEYNOTE-775. This was in a group of trial patients with good performance status and excluded those with carcinosarcoma histology. In KEYNOTE-775 pem/len was associated with significant toxicity, leading to dose reductions, treatment cessation, and patient morbidity. We set out to assess the tolerability, toxicity and outcomes following pem/len for patients with recurrent, advanced or metastatic endometrial cancer in a real-world setting., Materials and Methods: UK centres treating patients with pem/len for advanced endometrial cancer within the compassionate access programme were approached. Retrospective data were analysed for those treated between May 2022 and June 2023. Data on patient demographics, treatment, toxicity and outcomes were extracted from medical records. Toxicity and tolerability were compared in those over and under the age of 70., Results: Seven centres returned data for 70 patients. Median age of patients was 68.5 years (range 45-85) with a performance status of 0-1 in 77.1% and of 2 in 22.9%. Histological subtypes included serous (34.3%), endometrioid (32.9%), carcinosarcoma (14.3%), clear cell (7.1%), mixed (2.9%) and other (8.6%). Grade ≥3 toxicity was reported in 55.7% with any-grade toxicity observed in 85.7%. In those aged ≥70 years (n = 30) the rate of grade ≥3 toxicity was 60.0%. Rates of dose reduction of lenvatinib were 64.3%, and toxicity-related treatment interruption was 45.7%. The 6-month progression-free and overall survival rates were 54.0% (95%CI: 39.0-66.8) and 70.1% (95%CI:56.5-80.1) respectively., Conclusion: This real-world, observational study of pem/len showed comparable tolerability, toxicity, and outcomes to previously reported clinical trial data. Our cohort included patients with a poorer PS and a broader range of histological subtypes including carcinosarcoma., (Copyright © 2024 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Introduction: Adaptive ChemoTherapy for Ovarian cancer (ACTOv) is a phase II, multicentre, randomised controlled trial, evaluating an adaptive therapy (AT) regimen with carboplatin in women with relapsed, platinum-sensitive high-grade serous or high-grade endometrioid cancer of the ovary, fallopian tube and peritoneum whose disease has progressed at least 6 months after day 1 of the last cycle of platinum-based chemotherapy. AT is a novel, evolutionarily informed approach to cancer treatment, which aims to exploit intratumoral competition between drug-sensitive and drug-resistant tumour subpopulations by modulating drug dose according to a patient's own response to the last round of treatment. ACTOv is the first clinical trial of AT in this disease setting., Methods and Analysis: 80 patients will be randomised 1:1 to standard therapy (control) or AT (investigational) arms. The starting and maximum carboplatin dose in both arms is area under the curve (AUC) ×5 according to absolute nuclear medicine glomerular filtration rate. The AT regimen will modify the carboplatin dose according to changes in the serum biomarker CA125, a proxy measure of total tumour burden. Patients will receive treatment intravenously every 21 days for a maximum of 6 and 12 cycles in the control and investigational arms, respectively. The primary endpoint is modified progression-free survival (investigator-assessed using RECIST 1.1 (Response Evaluation Criteria in Solid Cancers) compared with the baseline prerandomisation scan rather than the radiological nadir), clinical progression or death from any cause. Secondary endpoints will include acceptability, deliverability, compliance, toxicity, CA125, quality of life and overall survival. ACTOv is open to National Health Service hospitals throughout the UK, recruitment is anticipated to take 36 months across 10 sites and will be managed by the Cancer Research UK and University College London Cancer Trials Centre., Ethics and Dissemination: The trial has been reviewed and received approval from the London-Dulwich Research Ethics Committee (REC). Results of the trial will be disseminated through publication in peer-reviewed journals., Trial Registration Number: NCT05080556., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group.)

There remains a lack of consensus as to the most appropriate primary therapy in Waldenstrőm macroglobulinemia (WM). We evaluated a novel bortezomib-based combination and developed a sensitive WM-specific flow cytometry assay (limit of detection 0.004% of leucocytes) to assess bone marrow (BM) response. Sixty treatment-naïve WM patients were enroled into this phase II trial and randomised (2:1) to receive cyclophosphamide and rituximab with either bortezomib (BRC) or fludarabine (FCR). The primary objective was to assess the overall response rate (ORR) in eligible patients receiving BRC (N = 41). An ORR of 97.6% (95%CI:87.1-99.9) was observed; 27 (65.9%) patients remain alive without progression after 62.6 months median follow-up, with 2-, 3- and 5-year progression-free survival (PFS) rates of 92.7% (95%CI:79.0-97.6), 80.5% (95%CI:64.8-89.7) and 65.5% (95%CI:48.8-77.9). Persistent WM B-cells were demonstrable in 19/38 patients at the end of treatment (median 0.24%, range 0.02-11.2%). PFS was markedly longer in patients with BM B-cell depletion (<0.004%) compared to those who had persistent BM B-cells detectable at end of treatment (HR = 0.06, 95%CI:0.01-0.47, p < 0.001), and remained independently associated after adjusting for baseline risk stratification or investigator-assessed response. BRC is a tolerable, highly efficacious regimen for treatment-naïve WM patients. BM B-cell depletion is independently associated with patient outcomes., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Introduction: Increased moderate to vigorous physical activity (MVPA) can improve clinical and psychosocial outcomes for people living with and beyond cancer (LWBC). This study aimed to assess the feasibility and acceptability of trial procedures in a pilot randomised controlled trial (RCT) of a theory-driven app-based intervention with behavioural support focused on promoting brisk walking (a form of MVPA) in people LWBC (APPROACH)., Methods: Participants diagnosed with breast, prostate or colorectal cancer were recruited from a single UK hospital site. Assessments at baseline and 3 months included online questionnaires, device-measured brisk walking (activPAL accelerometer) and self-reported weight and height. Participants were randomised to intervention or control (care as usual). The intervention comprised a non-cancer-specific app to promote brisk walking (National Health Service 'Active 10') augmented with print information about habit formation, a walking planner and two behavioural support telephone calls. Feasibility and acceptability of trial procedures were explored. Initial estimates for physical activity informed a power calculation for a phase III RCT. A preliminary health economics analysis was conducted., Results: Of those medically eligible, 369/577 (64%) were willing to answer further eligibility questions and 90/148 (61%) of those eligible were enrolled. Feasibility outcomes, including retention (97%), assessment completion rates (>86%) and app download rates in the intervention group (96%), suggest that the trial procedures are acceptable and that the intervention is feasible. The phase III RCT will require 472 participants to be randomised. As expected, the preliminary health economic analyses indicate a high level of uncertainty around the cost-effectiveness of the intervention., Conclusions: This pilot study demonstrates that a large trial of the brisk walking intervention with behavioural support is both feasible and acceptable to people LWBC. The results support progression onto a confirmatory phase III trial to determine the efficacy and cost-effectiveness of the intervention., (© 2024 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Idiopathic brachial neuritis also known as Parsonage-Turner syndrome is a rare neurological disorder characterised by pain and paraesthesia involving the shoulder girdle and upper limb, followed by weakness of the affected area. The cause is not very well understood and is often misdiagnosed leading to delayed treatment and long-term disability. There are many risk factors for the condition, with immunisations being accountable for as many as 15% of cases. In response to the coronavirus disease 2019 (COVID-19) pandemic, many companies have been producing and distributing COVID-19 vaccinations. To our knowledge, there have been 42 cases of brachial neuritis reported following COVID-19 vaccination to date. Here, we report a case of brachial neuritis following a patient's fourth COVID-19 vaccination and present a review of the literature., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Loganathan et al.)

In the H10 and RAPID randomised trials, chemotherapy+radiotherapy (combined modalities treatment, CMT) was compared with chemotherapy (C) in limited-stage Hodgkin lymphoma (HL), with negative early positron emission tomography (ePETneg). We analysed patterns of relapses in the H10 trial, validated findings in the RAPID trial and performed a combined analysis stratified by trial. The impact of radiotherapy (RT) on risk of relapse was studied using adjusted Cox models, with time-varying effects. In H10, 1,059 ePETneg patients were included (465 European Organisation for Research and Treatment of Cancer (EORTC) favourable [F], 594 unfavourable [U]). Among the F patients, 2/227 (1%) relapsed after CMT, 30/238 (13%) after C: of these relapses, 21/30 (70%) occurred in less than 2 years and 25/30 (83%) affected originally involved areas. Among the U group, 16/292 (5%) relapsed after CMT: 8/16 (50%) in less than 2 years, 11/16 (69%) in originally involved areas. After C 30/302 (10%) relapsed: 27/30 (90%) in less than 2 years, and 26/30 (87%) in originally involved areas. Similar results were observed in 419 ePETneg RAPID patients (241 F, 128 U, 50 unclassified): among F patients, 6/118 (5%) relapsed after CMT; 13/123 (11%) after C: 11/13 (85%) in less than 2 years and 11/13 (85%) affecting originally involved areas. In U patients, 3/65 (5%) relapsed after CMT and 5/63 (8%) after C. In both trials, omitting RT in ePETneg HL resulted in more early relapses, mainly affecting originally involved areas. RT significantly reduced risk of early relapses in the combined stratified analysis., (© 2022 British Society for Haematology and John Wiley & Sons Ltd.)

Purpose: To assess the safety and tolerability of a vandetanib-eluting radiopaque embolic (BTG-002814) for transarterial chemoembolization (TACE) in patients with resectable liver malignancies., Materials and Methods: The VEROnA clinical trial was a first-in-human, phase 0, single-arm, window-of-opportunity study. Eligible patients were aged ≥18 years and had resectable hepatocellular carcinoma (HCC) (Child-Pugh A) or metastatic colorectal cancer (mCRC). Patients received 1 mL of BTG-002814 transarterially (containing 100 mg of vandetanib) 7-21 days prior to surgery. The primary objectives were to establish the safety and tolerability of BTG-002814 and determine the concentrations of vandetanib and the N-desmethyl vandetanib metabolite in the plasma and resected liver after treatment. Biomarker studies included circulating proangiogenic factors, perfusion computed tomography, and dynamic contrast-enhanced magnetic resonance imaging., Results: Eight patients were enrolled: 2 with HCC and 6 with mCRC. There was 1 grade 3 adverse event (AE) before surgery and 18 after surgery; 6 AEs were deemed to be related to BTG-002814. Surgical resection was not delayed. Vandetanib was present in the plasma of all patients 12 days after treatment, with a mean maximum concentration of 24.3 ng/mL (standard deviation ± 13.94 ng/mL), and in resected liver tissue up to 32 days after treatment (441-404,000 ng/g). The median percentage of tumor necrosis was 92.5% (range, 5%-100%). There were no significant changes in perfusion imaging parameters after TACE., Conclusions: BTG-002814 has an acceptable safety profile in patients before surgery. The presence of vandetanib in the tumor specimens up to 32 days after treatment suggests sustained anticancer activity, while the low vandetanib levels in the plasma suggest minimal release into the systemic circulation. Further evaluation of this TACE combination is warranted in dose-finding and efficacy studies., (Copyright © 2022. Published by Elsevier Inc.)

Objectives  Sinonasal mucosal melanoma (SNMM) is an extremely rare and challenging sinonasal malignancy with a poor prognosis. Standard treatment involves complete surgical resection, but the role of adjuvant therapy remains unclear. Crucially, our understanding of its clinical presentation, course, and optimal treatment remains limited, and few advancements in improving its management have been made in the recent past. Methods  We conducted an international multicenter retrospective analysis of 505 SNMM cases from 11 institutions across the United States, United Kingdom, Ireland, and continental Europe. Data on clinical presentation, diagnosis, treatment, and clinical outcomes were assessed. Results  One-, three-, and five-year recurrence-free and overall survival were 61.4, 30.6, and 22.0%, and 77.6, 49.2, and 38.3%, respectively. Compared with disease confined to the nasal cavity, sinus involvement confers significantly worse survival; based on this, further stratifying the T3 stage was highly prognostic ( p  < 0.001) with implications for a potential modification to the current TNM staging system. There was a statistically significant survival benefit for patients who received adjuvant radiotherapy, compared with those who underwent surgery alone (hazard ratio [HR] = 0.74, 95% confidence interval [CI]: 0.57-0.96, p  = 0.021). Immune checkpoint blockade for the management of recurrent or persistent disease, with or without distant metastasis, conferred longer survival (HR = 0.50, 95% CI: 0.25-1.00, p  = 0.036). Conclusions  We present findings from the largest cohort of SNMM reported to date. We demonstrate the potential utility of further stratifying the T3 stage by sinus involvement and present promising data on the benefit of immune checkpoint inhibitors for recurrent, persistent, or metastatic disease with implications for future clinical trials in this field., Competing Interests: Conflict of Interest NL receives research funding from Merck Inc., not related to this manuscript and was a consultant for CoolTech Inc. and holds stock in Navigen Pharmaceuticals, both of which are unrelated to this manuscript. All other authors declare no potential relevant conflicts of interest., (Thieme. All rights reserved.)

Aims: Overall survival and progression-free survival with concomitant chemoradiotherapy for locally advanced cervical carcinoma have been described as 66% and 58%, respectively, at 5 years. Para-aortic lymph node involvement significantly increases the risk of relapse and death. The role of additional chemotherapy in these patients is as yet undefined. This aim of the present study was to determine the outcome of a cohort of para-aortic lymph node-positive patients treated with neoadjuvant chemotherapy followed by extended-field chemoradiation compared with patients treated with extended-field chemoradiation without neoadjuvant chemotherapy., Materials and Methods: We reviewed patients with International Federation of Gynaecology and Obstetrics (FIGO) 2014 stage IB1-IVA cervical carcinoma who received extended-field radiotherapy in addition to standard pelvic chemoradiotherapy with or without neoadjuvant chemotherapy, at University College London Hospital (January 2007 to January 2018). Patients in open clinical trials were excluded., Results: Overall, 47 patients (15.8% of 298 eligible patients) with pelvic and/or para-aortic lymph node-positive cervical carcinoma received extended-field radiotherapy. Nineteen patients (40.4%) had both neoadjuvant chemotherapy (all received six cycles) and extended-field radiotherapy (median 44 days); 28 (59.6%) patients received extended-field radiotherapy alone (median 43 days). All patients completed radical radiotherapy within 49 days. We observed evidence that patients receiving neoadjuvant chemotherapy and extended-field radiotherapy had a lower risk of death (median follow-up 4.8 years, three deaths) compared with extended-field radiotherapy alone (median follow-up 3.0 years, 11 deaths; hazard ratio = 0.27, 95% confidence interval 0.08-1.00; P = 0.05). Three-year overall survival rates were 83.3% (95% confidence interval 66.1-100) and 64.6% (95% confidence interval 44.6-84.6), respectively. A PFS benefit was seen (hazard ratio 0.25, 95% confidence interval 0.08-0.77; P = 0.02), with 3-year PFS rates of 77.8% (95% confidence interval 58.6-97.0) and 35.0% (95% confidence interval 14.0-56.0), respectively., Conclusions: Our institutional experience suggests that the use of additional systemic therapy before chemoradiotherapy benefits patients with locoregionally advanced (FIGO 2018 IIIC2) cervical cancer. Neoadjuvant chemotherapy was associated with longer overall survival and PFS, without compromising definitive extended-field chemoradiation., (Copyright © 2021 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Background: Olfactory dysfunction is a cardinal symptom of COVID-19 infection, however, studies assessing long-term olfactory dysfunction are limited and no randomised-controlled trials (RCTs) of early olfactory training have been conducted., Methodology: We conducted a prospective, multi-centre study consisting of baseline psychophysical measurements of smell and taste function. Eligible participants were further recruited into a 12-week RCT of olfactory training versus control (safety information). Patient-reported outcomes were measured using an electronic survey and BSIT at baseline and 12 weeks. An additional 1-year follow-up was open to all participants., Results: 218 individuals with a sudden loss of sense of smell of at least 4-weeks were recruited. Psychophysical smell loss was observed in only 32.1%; 63 participants were recruited into the RCT. The absolute difference in BSIT improvement after 12 weeks was 0.45 higher in the intervention arm. 76 participants completed 1-year follow-up; 10/19 (52.6%) of participants with an abnormal baseline BSIT test scored below the normal threshold at 1-year, and 24/29 (82.8%) had persistent parosmia., Conclusions: Early olfactory training may be helpful, although our findings are inconclusive. Notably, a number of individuals who completed the 1-year assessment had persistent smell loss and parosmia at 1-year. As such, both should be considered important entities of long-Covid and further studies to improve management are highly warranted.

Introduction: Olfactory neuroblastoma (ONB) is a rare cancer of the sinonasal region. We provide a comprehensive analysis of this malignancy with molecular and clinical trial data on a subset of our cohort to report on the potential efficacy of somatostatin receptor 2 (SSTR2)-targeting imaging and therapy., Methods: We conducted a retrospective analysis of 404 primary, locally recurrent, and metastatic olfactory neuroblastoma (ONB) patients from 12 institutions in the United States of America, United Kingdom and Europe. Clinicopathological characteristics and treatment approach were evaluated. SSTR2 expression, SSTR2-targeted imaging and the efficacy of peptide receptor radionuclide therapy [PRRT]( 177 Lu-DOTATATE) were reported in a subset of our cohort (LUTHREE trial; NCT03454763)., Results: Dural infiltration at presentation was a significant predictor of overall survival (OS) and disease-free survival (DFS) in primary cases (n = 278). Kadish-Morita staging and Dulguerov T-stage both had limitations regarding their prognostic value. Multivariable survival analysis demonstrated improved outcomes with lower stage and receipt of adjuvant radiotherapy. Prophylactic neck irradiation significantly reduces the rate of nodal recurrence. 82.4% of the cohort were positive for SSTR2; treatment of three metastatic cases with SSTR2-targeted peptide-radionuclide receptor therapy (PRRT) in the LUTHREE trial was well-tolerated and resulted in stable disease (SD)., Conclusions: This study presents pertinent clinical data from the largest dataset, to date, on ONB. We identify key prognostic markers and integrate these into an updated staging system, highlight the importance of adjuvant radiotherapy across all disease stages, the utility of prophylactic neck irradiation and the potential efficacy of targeting SSTR2 to manage disease., Competing Interests: Conflict of interest statement NL receives research funding from Merck Inc., not related to this manuscript, and was a consultant for CoolTech Inc. and holds stock in Navigen Pharmaceuticals, both of which are unrelated to this manuscript. SW is on the advisory board of ALK, Genentech, OptiNose, SinopSys and a Consultant to NeurENT, Stryker, all of which are unrelated to this manuscript. All other authors declare no potential relevant conflicts of interest., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Introduction: In 'IDEAL-6' patients (N = 78) treated for locally-advanced non-small-cell lung cancer using isotoxically dose-escalated radiotherapy, overall survival (OS) was associated more strongly with V LAwall-64-73-EQD2 , the left atrial (LA) wall volume receiving 64-73 Gy equivalent dose in 2 Gy fractions (EQD2), than with whole-heart irradiation measures. Here we test this in an independent cohort 'OX-RT' (N = 64) treated routinely., Methods: Using Cox regression analysis we assessed how strongly OS was associated with V LAwall-64-73-EQD2 , with whole-heart volumes receiving 64-73 Gy EQD2 or doses above 10-to-70 Gy thresholds, and with principal components of whole-heart dose-distributions. Additionally, we tested associations between OS and volumes of cardiac substructures receiving dose-ranges described by whole-heart principal components significantly associated with OS., Results: In univariable analyses of OX-RT, OS was associated more strongly with V LAwall-64-73-EQD2 than with whole-heart irradiation measures, but more strongly still with V AortV-29-38-EQD2 , the volume of the aortic valve region receiving 29-38 Gy EQD2. The best multivariable OS model included LA wall and aortic valve region mean doses, and the aortic valve volume receiving ≥38 Gy EQD2, V AortV-38-EQD2 . In a subsidiary analysis of IDEAL-6, the best multivariable model included V LAwall-64-73-EQD2 , V AortV-29-38-EQD2 , V AortV-38-EQD2 and mean aortic valve dose., Conclusion: We propose reducing heart mean doses to the lowest levels possible while meeting protocol dose-limits for lung, oesophagus, proximal bronchial tree, cord and brachial plexus. This in turn achieves large reductions in V AortV-29-38-EQD2 and V LAwall-64-73-EQD2 , and we plan to closely monitor patients with values of these measures still >0% (their median value in OX-RT) following reduction., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background Glioblastoma (GBM) is the commonest primary malignant brain tumour in adults and effective treatment options are limited. Combining local chemotherapy with enhanced surgical resection using 5-aminolevulinic acid (5-ALA) could improve outcomes. Here we assess the safety and feasibility of combining BCNU wafers with 5-ALA-guided surgery. Methods We conducted a multicentre feasibility study of 5-ALA with BCNU wafers followed by standard-of-care chemoradiotherapy (chemoRT) in patients with suspected GBM. Patients judged suitable for radical resection were administered 5-ALA pre-operatively and BCNU wafers at the end resection. Post-operative treatment continued as per routine clinical practice. The primary objective was to establish if combining 5-ALA and BCNU wafers is safe without compromising patients from receiving standard chemoRT. Results Seventy-two patients were recruited, sixty-four (88.9%) received BCNU wafer implants, and fifty-nine (81.9%) patients remained eligible following formal histological diagnosis. Seven (11.9%) eligible patients suffered surgical complications but only two (3.4%) were not able to begin chemoRT, four (6.8%) additional patients did not begin chemoRT within 6 weeks of surgery due to surgical complications. Eleven (18.6%) patients did not begin chemoRT for other reasons (other toxicity ( n = 3), death ( n = 3), lost to follow-up/withdrew ( n = 3), clinical decision ( n = 1), poor performance status ( n = 1)). Median progression-free survival was 8.7 months (95% CI: 6.4-9.8) and median overall survival was 14.7 months (95% CI: 11.7-16.8). Conclusions Combining BCNU wafers with 5-ALA-guided surgery in newly diagnosed GBM patients is both feasible and tolerable in terms of surgical morbidity and overall toxicity. Any potential therapeutic benefit for the sequential use of 5-ALA and BCNU with chemoRT requires further investigation with improved local delivery technologies.

We compared the International Prognostic Index (IPI), Revised (R)-IPI and age-adjusted (aa)-IPI as prognostic indices for patients with diffuse large B-cell lymphoma (DLBCL) in the UK National Cancer Research Institute (NCRI) R-CHOP 14 versus 21 trial (N = 1080). The R-IPI and aa-IPI showed no marked improvement compared to the IPI for overall and progression-free survival, in terms of model fit or discrimination. Similar results were observed in exploratory analyses incorporating the Grupo Español de Linfomas/Transplante de Médula Ósea (GELTAMO)-IPI, where baseline β2-microglobulin data were available (N = 655). Although our findings support current use of the IPI, a novel prognostic tool to better delineate a high-risk DLBCL group in the rituximab era is needed., (© 2020 British Society for Haematology and John Wiley & Sons Ltd.)

The UK National Cancer Research Institute initiated a prospective study (UKCRN-ID 1760) to assess the prognostic value of early fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT) in diffuse large B-cell lymphoma (DLBCL). In total, 189 patients with DLBCL treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) had baseline and post-cycle-2 PET (PET2) within a quality assurance framework. Treatment decisions were based on CT; PET2 was archived for central blinded reporting after treatment completion. The association of PET2 response with end-of-treatment CT, progression-free (PFS) and overall survival (OS) was explored. The end-of-treatment complete response rate on CT was 83·9%, 75·0%, 70·5%, 40·4% and 36·4% for Deauville score (DS) 1 (n = 34), 2 (n = 39), 3 (n = 46), 4 (n = 56) and 5 (n = 14) (P < 0·001); and 64·1% and 50·0% for the maximum standardised uptake value (∆SUV max ) of ≥66% (n = 168) and <66% (n = 21), respectively (P = 0·25). After a median 5·4 years of follow-up, the 5-year PFS was 69·4%, 72·8%, 76·7%, 71·2% and 47·6% by DS 1-5 (P = 0·01); and 72·6% and 57·1% by ∆SUV max of ≥66% and <66% (P = 0·03), respectively. The association with DS remained in multivariable analyses, and was consistent for OS. Early complete metabolic response (DS 1-3) at interim PET/CT after two cycles of R-CHOP in DLBCL was associated with a higher end-of-treatment complete and overall response rate; however, only DS-5 patients had inferior PFS and OS., (© 2020 British Society for Haematology and John Wiley & Sons Ltd.)

Background: Two novel biological agents-cediranib targeting angiogenesis, and olaparib targeting DNA repair processes-have individually led to an improvement in ovarian cancer control. The aim of ICON9 is to investigate the combination of cediranib and olaparib maintenance in recurrent ovarian cancer following platinum-based therapy., Primary Objective: To assess the efficacy of maintenance treatment with olaparib in combination with cediranib compared with olaparib alone following a response to platinum-based chemotherapy in women with platinum-sensitive ovarian, fallopian tube or peritoneal cancer during first relapse., Study Hypothesis: Maintenance therapy with cediranib and olaparib in combination is associated with improved patient outcomes compared with olaparib alone., Trial Design: International phase III randomized controlled trial. Following a response to platinum-based chemotherapy patients are randomized 1:1 to either oral olaparib and cediranib (intervention arm) or oral olaparib alone (control arm)., Major Inclusion Criteria: Patients with a known diagnosis of high grade serous or endometrioid carcinoma of the ovary, fallopian tube or peritoneum, progressing more than 6 months after first-line platinum-based chemotherapy, who have responded to second-line platinum-based chemotherapy., Primary Endpoints: Progression-free and overall survival. Co-primary endpoints to be assessed using a fixed-sequence gatekeeping approach: (1) progression-free survival, all patients; (2) progression-free survival, BRCA wild type; (3) overall survival, all patients; (4) overall survival, BRCA wild type., Sample Size: 618 patients will be recruited., Estimated Dates for Completing Accrual and Presenting Results: Accrual is expected to be completed in 2024 with presentation of results in 2025., Trial Registration: ClinicalTrials.gov: NCT03278717., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: The IDEAL-CRT phase 1/2 multicenter trial of isotoxically dose-escalated concurrent chemoradiation for stage II/III non-small cell lung cancer investigated two 30-fraction schedules of 5 and 6 weeks' duration. We report toxicity, tumor response, progression-free survival (PFS), and overall survival (OS) for both schedules, with long-term follow-up for the 6-week schedule., Methods and Materials: Patients received isotoxically individualized tumor radiation doses of 63 to 71 Gy in 5 weeks or 63 to 73 Gy in 6 weeks, delivered concurrently with 2 cycles of cisplatin and vinorelbine. Eligibility criteria were the same for both schedules., Results: One-hundred twenty patients (6% stage IIB, 68% IIIA, 26% IIIB, 1% IV) were recruited from 9 UK centers, 118 starting treatment. Median prescribed doses were 64.5 and 67.6 Gy for the 36 and 82 patients treated using the 5- and 6-week schedules. Grade ≥3 pneumonitis and early esophagitis rates were 3.4% and 5.9% overall and similar for each schedule individually. Late grade 2 esophageal toxicity occurred in 11.1% and 17.1% of 5- and 6-week patients. Grade ≥4 adverse events occurred in 17 (20.7%) 6-week patients but no 5-week patients. Four adverse events were grade 5, with 2 considered radiation therapy related. After median follow-up of 51.8 and 26.4 months for the 6- and 5-week schedules, median OS was 41.2 and 22.1 months, respectively, and median PFS was 21.1 and 8.0 months. In exploratory analyses, OS was significantly associated with schedule (hazard ratio [HR], 0.56; 95% confidence interval [CI], 0.32-0.98; P = .04) and fractional clinical/internal target volume receiving ≥95% of the prescribed dose (HR, 0.88; 95% CI, 0.77-1.00; P = .05). PFS was also significantly associated with schedule (HR, 0.53; 95% CI, 0.33-0.86; P = .01)., Conclusions: Toxicity in IDEAL-CRT was acceptable. Survival was promising for 6-week patients and significantly longer than for 5-week patients. Survival might be further lengthened by following the 6-week schedule with an immune agent, motivating further study of such combined optimized treatments., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Low-dose computed tomography (LDCT) screening detects early-stage lung cancer and reduces mortality. We proposed a sequential approach targeted to a high-risk group as a potentially efficient screening strategy., Methods: LungSEARCH was a national multicentre randomised trial. Current/ex-smokers with mild/moderate chronic obstructive pulmonary disease (COPD) were allocated (1:1) to have 5 years surveillance or not. Screened participants provided annual sputum samples for cytology and cytometry, and if abnormal were offered annual LDCT and autofluorescence bronchoscopy (AFB). Those with normal sputum provided annual samples. The primary end-point was the percentage of lung cancers diagnosed at stage I/II (nonsmall cell) or limited disease (small cell)., Results: 1568 participants were randomised during 2007-2011 from 10 UK centres. 85.2% of those screened provided an adequate baseline sputum sample. There were 42 lung cancers among 785 screened individuals and 36 lung cancers among 783 controls. 54.8% (23 out of 42) of screened individuals versus 45.2% (14 out of 31) of controls with known staging were diagnosed with early-stage disease (one-sided p=0.24). Relative risk was 1.21 (95% CI 0.75-1.95) or 0.82 (95% CI 0.52-1.31) for early-stage or advanced cancers, respectively. Overall sensitivity for sputum (in those randomised to surveillance) was low (40.5%) with a cumulative false-positive rate (FPR) of 32.8%. 55% of cancers had normal sputum results throughout. Among sputum-positive individuals who had AFB, sensitivity was 45.5% and cumulative FPR was 39.5%; the corresponding measures for those who had LDCT were 100% and 16.1%, respectively., Conclusions: Our sequential strategy, using sputum cytology/cytometry to select high-risk individuals for AFB and LDCT, did not lead to a clear stage shift and did not improve the efficiency of lung cancer screening., Competing Interests: Conflict of interest: S.G. Spiro has nothing to disclose. Conflict of interest: P.L. Shah has nothing to disclose. Conflict of interest: R.C. Rintoul has nothing to disclose. Conflict of interest: J. George has nothing to disclose. Conflict of interest: S. Janes reports personal fees for advisory board work from BARD1, Achilles Therapeutics and AstraZeneca, personal fees for conference travel from AstraZeneca, outside the submitted work. Conflict of interest: M. Callister has nothing to disclose. Conflict of interest: M. Novelli has nothing to disclose. Conflict of interest: P. Shaw has nothing to disclose. Conflict of interest: G. Kocjan has nothing to disclose. Conflict of interest: C. Griffiths has nothing to disclose. Conflict of interest: M. Falzon has nothing to disclose. Conflict of interest: R. Booton has nothing to disclose. Conflict of interest: N. Magee has nothing to disclose. Conflict of interest: M. Peake reports personal fees for lectures from Roche Products Ltd, grants and personal fees for lectures from MSD Ltd, personal fees for advisory board work from BMS and Pfizer Ltd, outside the submitted work. Conflict of interest: P. Dhillon has nothing to disclose. Conflict of interest: K. Sridharan has nothing to disclose. Conflict of interest: A.G. Nicholson has nothing to disclose. Conflict of interest: S. Padley has nothing to disclose. Conflict of interest: M.N. Taylor has nothing to disclose. Conflict of interest: A. Ahmed has nothing to disclose. Conflict of interest: J. Allen has nothing to disclose. Conflict of interest: Y. Ngai has nothing to disclose. Conflict of interest: N. Chinyanganya has nothing to disclose. Conflict of interest: V. Ashford-Turner has nothing to disclose. Conflict of interest: S. Lewis has nothing to disclose. Conflict of interest: D. Oukrif has nothing to disclose. Conflict of interest: P. Rabbits has nothing to disclose. Conflict of interest: N. Counsell has nothing to disclose. Conflict of interest: A. Hackshaw has nothing to disclose., (Copyright ©ERS 2019.)

Purpose: Accurate stratification of patients is an important goal in Hodgkin lymphoma (HL), but the role of pretreatment clinical risk stratification in the context of positron emission tomography (PET) -adapted treatment is unclear. We performed a subsidiary analysis of the RAPID trial to assess the prognostic value of pretreatment risk factors and PET score in determining outcomes., Patients and Methods: Patients with stage IA to IIA HL and no mediastinal bulk underwent PET assessment after three cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine; 143 PET-positive patients (PET score, 3 to 5) received a fourth doxorubicin, bleomycin, vinblastine, and dacarbazine cycle and involved-field radiotherapy, and 419 patients in complete metabolic remission were randomly assigned to receive involved-field radiotherapy (n = 208) or no additional treatment (n = 211). Cox regression was used to investigate the association between PET score and pretreatment risk factors with HL-specific event-free survival (EFS)., Results: High PET score was associated with inferior EFS, before ( P < .001) and after adjustment ( P = .01) for baseline risk stratification. Only patients with a postchemotherapy PET score of 5 (uptake ≥ three times maximum liver uptake) had an increased risk of progression or HL-related death (hazard ratio, 9.4 v score of 3; 95% CI, 2.8 to 31.3 and hazard ratio, 6.7 v score of 4; 95% CI, 1.4 to 31.7). Patients with a PET score of 5 also had inferior progression-free and overall survival. There was no association between European Organisation for Research and Treatment of Cancer or German Hodgkin Study Group risk group and EFS, before or after adjusting for PET score (all P > .4)., Conclusion: In RAPID, a positive PET scan did not carry uniform prognostic weight; only a PET score of 5 was associated with inferior outcomes. This suggests that in future trials involving patients without B symptoms or mediastinal bulk, a score of 5 rather than a positive PET result should be used to guide treatment escalation in early-stage HL.

Improving outcomes in multiple myeloma will involve not only development of new therapies but also better use of existing treatments. We performed RNA sequencing on samples from newly diagnosed patients enrolled in the phase 2 PADIMAC (Bortezomib, Adriamycin, and Dexamethasone Therapy for Previously Untreated Patients with Multiple Myeloma: Impact of Minimal Residual Disease in Patients with Deferred ASCT) study. Using synthetic annealing and the large margin nearest neighbor algorithm, we developed and trained a 7-gene signature to predict treatment outcome. We tested the signature in independent cohorts treated with bortezomib- and lenalidomide-based therapies. The signature was capable of distinguishing which patients would respond better to which regimen. In the CoMMpass data set, patients who were treated correctly according to the signature had a better progression-free survival (median, 20.1 months vs not reached; hazard ratio [HR], 0.40; confidence interval [CI], 0.23-0.72; P = .0012) and overall survival (median, 30.7 months vs not reached; HR, 0.41; CI, 0.21-0.80; P = .0049) than those who were not. Indeed, the outcome for these correctly treated patients was noninferior to that for those treated with combined bortezomib, lenalidomide, and dexamethasone, arguably the standard of care in the United States but not widely available elsewhere. The small size of the signature will facilitate clinical translation, thus enabling more targeted drug regimens to be delivered in myeloma., (© 2018 by The American Society of Hematology.)

Background: We previously initiated a randomized controlled trial to test the effectiveness of two self-referral reminders and a theory-based leaflet (sent 12 and 24 months after the initial invitation) to increase participation within the English Bowel Scope Screening program., Purpose: This study reports the results following the second reminder., Methods: Men and women included in the initial sample (n = 1,383) were re-assessed for eligibility 24 months after their invitation (12 months after the first reminder) and excluded if they had attended screening, moved away, or died. Eligible adults received the same treatment they were allocated 12 months previous, that is, no reminder ("control"), or a self-referral reminder with either the standard information booklet ("Reminder and Standard Information Booklet") or theory-based leaflet designed using the Behavior Change Wheel ("Reminder and Theory-Based Leaflet"). The primary outcome was the proportion screened within each group 12 weeks after the second reminder., Results: In total, 1,218 (88.1%) individuals were eligible. Additional uptake following the second reminder was 0.4% (2/460), 4.8% (19/399), and 7.9% (29/366) in the control, Reminder and Standard Information Booklet, and Reminder and Theory-Based Leaflet groups, respectively. When combined with the first reminder, the overall uptake for each group was 0.7% (3/461), 14.5% (67/461), and 21.5% (99/461). Overall uptake was significantly higher in the Reminder and Standard Information Booklet and Reminder and Theory-Based Leaflet groups than in the control (odds ratio [OR] = 26.1, 95% confidence interval [CI] = 8.1-84.0, p < .001 and OR = 46.9, 95% CI = 14.7-149.9, p < .001, respectively), and significantly higher in the Reminder and Theory-Based Leaflet group than in the Reminder and Standard Information Booklet group (OR = 1.8, 95% CI = 1.3-2.6, p < .001)., Conclusion: A second reminder increased uptake among former nonparticipants. The added value of the theory-based leaflet highlights a potential benefit to reviewing the current information booklet., Trials Registry Number: ISRCTN44293755.

Introduction: Following growing evidence to support the safety, local control (LC) and potential improvement in overall survival (OS) in patients with oligometastatic non-small cell lung cancer (NSCLC) that have been treated with local ablative therapy such as stereotactic ablative radiotherapy (SABR) and stereotactic radiosurgery (SRS), we initiate the SARON trial to investigate the impact and feasibility of adding SABR/SRS and radical radiotherapy (RRT) following standard chemotherapy on OS., Methods and Analysis: SARON is a large, randomised controlled, multicentre, phase III trial for patients with oligometastatic EGFR, ALK and ROS1 mutation negative NSCLC (1-3 sites of synchronous metastatic disease, one of which must be extracranial). 340 patients will be recruited over 3 years from approximately 30 UK sites and randomised to receive either standard platinum-doublet chemotherapy only (control arm) or standard chemotherapy followed by RRT/SABR to their primary tumour and then SABR/SRS to all other metastatic sites (investigational arm). The primary endpoint is OS; the study is powered to detect an improvement in median survival from 9.9 months in the control arm to 14.3 months in the investigational arm with 85% power and two-sided 5% significance level. The secondary endpoints are LC, progression-free survival, new distant metastasis-free survival, toxicity and quality of life. An early feasibility review will take place after 50 randomised patients. Patients requiring both conventional thoracic RT to the primary and SABR to a thoracic metastasis will be included in a thoracic SABR safety substudy to assess toxicity and planning issues in this subgroup of patients more thoroughly., Ethics and Dissemination: All participants are given a SARON patient information sheet and required to give written informed consent. Results will be submitted for presentation at local and international conferences and expected to be published in a peer-reviewed journal., Trial Registration Number: NCT02417662., Sponsor Reference: UCL/13/0594., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)