• Dataset for the reporting of carcinoma of the bladder-cystectomy, cystoprostatectomy and diverticulectomy specimens: recommendations from the International Collaboration on Cancer Reporting (ICCR)

      Comperat, E; Srigley, JR; Brimo, F; Delahunt, B; Koch, M; Lopez-Beltran, A; Reuter, V; Samaratunga, H; Shanks, Jonathan H; Tsuzuki, T; et al. (2020)
      The International Collaboration on Cancer Reporting (ICCR) is a not for profit organisation whose goal is to produce standardised internationally agreed and evidence-based datasets for pathology reporting. With input from pathologists worldwide, the datasets are intended to be uniform and structured. They include all items necessary for an objective and accurate pathology report which enables clinicians to apply the best treatment for the patient. This dataset has had input from a multidisciplinary ICCR expert panel. The rationale for some items being required and others recommended is explained, based on the latest literature. The dataset incorporates data from the World Health Organization (WHO) 2016, and also from the latest (8th edition) TNM staging system of the American Joint Committee on Cancer (AJCC). Fifteen required elements and eight recommended items are described. This dataset provides all the details for a precise and valuable pathology report required for patient management and prognostication. This dataset is intended for worldwide use, and should facilitate the collection of standardised comparable data on bladder carcinoma at an international level.
    • Two case reports involving therapeutic monoclonal anti-CD47 (Hu5F9-G4), it's effect on compatibility testing and subsequent selection of components for transfusion

      Reyland, L; Dwight, M; Bullock, T; Latham, T; Lord, K; Wardle, A; Palmer, D; Eggington, J; Callaghan, T; Seals, Deborah; et al. (2020)
    • Patient-reported functional outcomes after hypofractionated or conventionally fractionated radiation for prostate cancer: a national cohort study in England

      Nossiter, J; Sujenthiran, A; Cowling, TE; Parry, MG; Charman, SC; Cathcart, P; Clarke, Noel W; Payne, H; van der Meulen, J; Aggarwal, A; et al. (2020)
      PURPOSE: The aim of the current study was to determine patient-reported functional outcomes in men with prostate cancer (PCa) undergoing moderately hypofractionated (H-RT) or conventionally fractionated radiation therapy (C-RT) in a national cohort study. PATIENDS AND METHODS: All men diagnosed with PCa between April 2014 and September 2016 in the English National Health Service undergoing C-RT or H-RT were identified in the National Prostate Cancer Audit and mailed a questionnaire at least 18 months after diagnosis. We estimated differences in patient-reported urinary, bowel, sexual, and hormonal function-Expanded Prostate Cancer Index Composite short-form 26 domain scores on a 0 to 100 scale-and health-related quality of life-EQ-5D-5L on a 0 to 1 scale-using linear regression with adjustment for patient, tumor, and treatment-related factors in addition to GI and genitourinary baseline function, with higher scores representing better outcomes. RESULTS: Of the 17,058 men in the cohort, 77% responded: 8,432 men received C-RT (64.2%) and 4,699 H-RT (35.8%). Men in the H-RT group were older (age ³ 70 years: 67.5% v 60.9%), fewer men had locally advanced disease (56.5% v 71.3%), were less likely to receive androgen-deprivation therapy (79.5% v 87.8%), and slightly more men had pretreatment genitourinary procedures (24.2% v 21.2%). H-RT was associated with small increases in adjusted mean Expanded Prostate Cancer Index Composite short-form 26 sexual (3.3 points; 95% CI, 2.1 to 4.5; P < .001) and hormonal function scores (3.2 points; 95% CI, 1.8 to 4.6; P < .001). These differences failed to meet established thresholds for a clinically meaningful change. There were no statistically significant differences in urinary or bowel function and quality of life. CONCLUSION: This is the first national cohort study comparing functional outcomes after H-RT and C-RT reported by patients. These real-world results further support the use of H-RT as the standard for radiation therapy in men with nonmetastatic PCa.
    • Retrospective analyses of registry data for technical radiation oncology questions: apples versus pears or solid evidence?

      Nestle, U; Adebahr, S; van Herk, Marcel; Department of Radiation Oncology, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany; (2020)
    • Determinants of variation in the use of adjuvant chemotherapy for stage III colon cancer in England

      Boyle, JM; Kuryba, A; Cowling, TE; Aggarwal, A; Hill, J; van der Meulen, J; Walker, K; Braun, Michael S; Department of Health Services Research and Policy, London School of Hygiene and Tropical Medicine, London, UK (2020)
      AIMS: Adjuvant chemotherapy (ACT) for stage III colon cancer is well-established. This study aimed to explore the determinants of ACT use and between-hospital variation within the English National Health Service (NHS). MATERIALS AND METHODS: In total, 11 932 patients (diagnosed 2014-2017) with pathological stage III colon cancer in the English NHS were identified from the National Bowel Cancer Audit. Records were linked to Systemic Anti-Cancer Therapy and Hospital Episode Statistics databases. Multi-level logistic regression analyses were carried out to estimate independent factors for ACT use, including age, sex, deprivation, comorbidities, performance status, American Society of Anaesthesiologists (ASA) grade, surgical urgency, surgical access, TNM staging, readmission and hospital-level factors (university teaching hospital, on-site chemotherapy and high-volume centre). A random intercept was modelled for each English NHS hospital (n = 142). Between-hospital variation was explored using funnel plot methodology. Fully adjusted random-intercept models were fitted separately in young (<70 years) and elderly (³70 years) patients and intra-class correlation coefficients estimated. RESULTS: 60.7% of patients received ACT. Age was the strongest determinant. Compared with patients aged <60 years, those aged 60-64 (adjusted odds ratio [aOR] 0.76, 95% confidence interval 0.63-0.93), 65-69 (aOR 0.63, 95% confidence interval 0.54-0.74), 70-74 (aOR 0.53, 95% confidence interval 0.44-0.62), 75-79 (aOR 0.23, 95% confidence interval 0.19-0.27) and ³80 years (aOR 0.05, 95% confidence interval 0.04-0.06) were significantly less likely to receive ACT. With adjustment for other factors, ACT use was more likely in patients with higher socioeconomic status, fewer comorbidities, better performance status, lower ASA grade, advanced disease, elective resections, laparoscopic procedures and no unplanned readmissions. Hospital-level factors were non-significant. The observed proportions of ACT administration in the young and elderly were 46-100% (80% of hospitals 74-90%) and 10-81% (80% of hospitals 33-65%), respectively. Risk adjustment did not reduce between-hospital variation. Despite adjustment, age accounted for 9.9% (7.2-13.4%) of between-hospital variation in the elderly compared with 2.7% (1.2-5.7%) in the young. CONCLUSIONS: There is significant between-hospital variation in ACT use for stage III colon cancer, especially for older patients. Advanced age alone seems to be a greater barrier to ACT use in some hospitals.
    • Distributed learning on 20 000+ lung cancer patients - The Personal Health Train

      Deist, TM; Dankers, FJWM; Ojha, P; Scott, MM; Janssen, T; Faivre-Finn, Corinne; Masciocchi, C; Valentini, V; Wang, J; Chen, J; et al. (2020)
      BACKGROUND AND PURPOSE: Access to healthcare data is indispensable for scientific progress and innovation. Sharing healthcare data is time-consuming and notoriously difficult due to privacy and regulatory concerns. The Personal Health Train (PHT) provides a privacy-by-design infrastructure connecting FAIR (Findable, Accessible, Interoperable, Reusable) data sources and allows distributed data analysis and machine learning. Patient data never leaves a healthcare institute. MATERIALS AND METHODS: Lung cancer patient-specific databases (tumor staging and post-treatment survival information) of oncology departments were translated according to a FAIR data model and stored locally in a graph database. Software was installed locally to enable deployment of distributed machine learning algorithms via a central server. Algorithms (MATLAB, code and documentation publicly available) are patient privacy-preserving as only summary statistics and regression coefficients are exchanged with the central server. A logistic regression model to predict post-treatment two-year survival was trained and evaluated by receiver operating characteristic curves (ROC), root mean square prediction error (RMSE) and calibration plots. RESULTS: In 4 months, we connected databases with 23 203 patient cases across 8 healthcare institutes in 5 countries (Amsterdam, Cardiff, Maastricht, Manchester, Nijmegen, Rome, Rotterdam, Shanghai) using the PHT. Summary statistics were computed across databases. A distributed logistic regression model predicting post-treatment two-year survival was trained on 14 810 patients treated between 1978 and 2011 and validated on 8 393 patients treated between 2012 and 2015. CONCLUSION: The PHT infrastructure demonstrably overcomes patient privacy barriers to healthcare data sharing and enables fast data analyses across multiple institutes from different countries with different regulatory regimens. This infrastructure promotes global evidence-based medicine while prioritizing patient privacy.
    • Recommendation for supportive care in patients receiving concurrent chemotherapy and radiotherapy for lung cancer

      de, Ruysscher D; Faivre-Finn, Corinne; Nackaerts, K; Jordan, K; Arends, J; Douillard, JY; Ricardi, U; Peters, S; Maastricht University Medical Center, Department of Radiation Oncology (Maastro), GROW School for Oncology and Developmental Biology, Maastricht, The Netherlands (2020)
      Concurrent chemotherapy and radiotherapy (CCRT) followed by durvalumab immune therapy in appropriate patients is considered to be the standard of care in most fit stage III non-small-cell lung cancer (NSCLC) patients. However, CCRT is a toxic treatment that affects all organ systems and may cause acute and permanent side effects, some of which may be lethal. Supportive care is therefore of utmost importance in this clinical setting. A group of experts from the European Society for Therapeutic Radiology and Oncology (ESTRO) and the European Society of Medical Oncology (ESMO) identified the following items of importance for further improvement of supportive care: smoking cessation; nutrition before and during CCRT (including treatment and prevention of anorexia); physical exercise before and during CCRT; prevention and treatment of acute esophagitis and dysphagia; treatment of cough and dyspnea; treatment of skin reactions; treatment of fatigue; prophylaxis of nausea and emesis; prevention, diagnosis, and treatment of cardiac disease and damage; and optimization of radiotherapy techniques and chemotherapy adjustments to reduce toxicity in the era of immune therapy. The resulting recommendations are summarized in this manuscript and knowledge gaps identified, in which future investments are needed to improve supportive care and hence quality of life and survival for our stage III NSCLC patients.
    • Nursing research priorities in critical care, pulmonary, and sleep: International Delphi survey of nurses, patients, and caregivers an official American Thoracic Society workshop report

      George, M; Hernandez, C; Smith, S; Narsavage, G; Kapella, MC; Carno, M; Guttormson, J; Disler, RT; Hart, DE; Chlan, LL; et al. (2020)
      The objective of this workshop was to determine current nursing research priorities in critical care, adult pulmonary, and sleep conditions through input from consumer (patient, family, and formal and informal caregivers) and nursing experts around the world. Working groups composed of nurses and patients selected potential research priorities based on patient insight and a literature review of patient-reported outcomes, patient-reported experiences, and processes and clinical outcomes in the focal areas. A Delphi consensus approach, using a qualitative survey method to elicit expert opinion from nurses and consumers was conducted. Two rounds of online surveys available in English, Spanish, and Chinese were completed. A 75% or greater threshold for endorsement (combined responses from nursing and consumer participants) was determined a priori to retain survey items. A total of 837 participants (649 nurses and 188 patients, family, and/or caregivers) from 45 countries responded. Survey data were analyzed and nursing research priorities that comprise 23 critical care, 45 adult pulmonary, and 16 sleep items were identified. This project was successful in engaging a wide variety of nursing and consumer experts, applying a patient-reported outcome/patient-reported experience framework for organizing and understanding research priorities. The project outcome was a research agenda to inform, guide, and aid nurse scientists, educators, and providers, and to advise agencies that provide research and program funding in these fields.
    • A cross sectional study to determine the prevalence of cough and its impact in patients with lung cancer: a patient unmet need

      Harle, Amelie S; Molassiotis, A; Buffin, O; Burnham, J; Smith, J; Yorke, Janelle; Blackhall, Fiona H; Dorset Cancer Centre, Poole NHS Foundation Trust, Longfleet Road, Poole, BH15 2LB, UK. (2020)
      BACKGROUND: There is absence of literature related to cough prevalence and its characteristics in lung cancer patients, with information deriving only from broader symptoms occurrence studies. The aims of this study were to provide a snapshot of the prevalence of all-cause-cough in lung cancer patients and to characterise cough in terms of its impact and severity. METHODS: A cross-sectional study recruiting consecutive lung cancer patients over a pre-defined period of time and using cough-specific validated tools in a tertiary referral centre in the UK, including a cough severity VAS and the Manchester Cough in Lung Cancer scale (MCLCS). RESULTS: Data was collected from 202 patients. All-cause cough prevalence was 57% (through VAS) both in the screened (N =?223) and research (N =?202) population or 67% (through the MCLCS), and cough severity was moderate at a mean of 32?mm (in a 100?mm VAS). Age, sex, smoking status, lung cancer histology, stage and comorbidities were not associated with cough prevalence. The only variable associated with lower cough reports was being 'on anticancer treatment'; fewer patients on treatment reported a cough (40%) compared to those off treatment (54%) (p =?0.04). The impact of cough (as measured by MCLCS) was also significant (mean score?=?22). About 18% of patients felt moderate/severe distress from their cough and about 15% often or always reported disturbed sleep due to coughing. Half the patients felt their cough warranted treatment. CONCLUSIONS: Cough is a common symptom in lung cancer with considerable impact on patients' lives. Cough presence and severity should regularly be assessed in clinical practice. There is an urgent need to focus on developing more potent antitussive treatments and improve the management of this complex and distressing symptom.
    • Current role of sentinel lymph node biopsy in the management of cutaneous melanoma: A UK consensus statement

      Peach, H; Board, R; Cook, M; Corrie, P; Ellis, S; Geh, J; King, P; Laitung, G; Larkin, J; Marsden, J; et al. (2020)
      Sentinel node biopsy (SNB) has been at the forefront of the surgical staging of melanoma patients for the past 15 years. The high accuracy of this prognostic staging procedure is now recognised in all international guidelines for melanoma. However during this period there have been a number of important changes in the management of melanoma, many occurring within the past five years. The outcomes of five recent randomised Phase 3 trials have established the role of adjuvant targeted therapy and immunotherapy in resected Stage 3 and Stage 4 disease and have potentially changed the role of SNB. Two landmark international prospective studies have examined the benefit of performing a completion lymph node dissection (CLND) following the detection of microscopicallyinvolved sentinel nodes. Finally, the marked increase in the incidence of melanoma and the role of SNB in potentially guiding therapy has resulted in a significant increase in the pathological workload of the dermatopathology services. To address these issues a multi-disciplinary consensus meeting involving many melanoma experts from the UK was convened in May 2018. Three main areas were considered: oncology, surgery and pathology. This report is a summary of the conclusions reached, which were agreed by the clinicians attending the meeting and then externally peer reviewed. The recommendations summarised in this Consensus Statement.
    • First-line trifluridine/tipiracil plus bevacizumab for unresectable metastatic colorectal cancer: SOLSTICE study design

      Andre, T; Saunders, Mark P; Kanehisa, A; Gandossi, E; Fougeray, R; Amellal, NC; Falcone, A; Sorbonne Universite & Saint-Antoine Hospital, Paris, France (2020)
      Trifluridine/tipiracil (TT) is an orally administered combination of the thymidine-based nucleoside analogue trifluridine and the thymidine phosphorylase inhibitor tipiracil hydrochloride, which increases the bioavailability of cytotoxic trifluridine. Encouraging antitumor activity of first-line TT + bevacizumab (TT-B) has been observed in a Phase II study in patients with unresectable metastatic colorectal cancer ineligible for combination oxaliplatin- or irinotecan-based therapy. Here, we describe the design of SOLSTICE (NCT03869892), an open-label, Phase III trial in unresectable metastatic colorectal cancer patients who are not candidates for, or do not require, intensive therapy. The 854 patients were randomized 1:1 to receive first-line TT-B versus capecitabine + bevacizumab. The primary objective is to demonstrate superior progression-free survival with TT-B over capecitabine + bevacizumab. The first patient was enrolled in March 2019.
    • EAU-ESMO consensus statements on the management of advanced and variant bladder cancer-an international collaborative multistakeholder effort under the auspices of the EAU-ESMO guidelines committees

      Witjes, JA; Babjuk, M; Bellmunt, J; Bruins, HM; De Reijke, TM; De Santis, M; Gillessen, Silke; James, N; Maclennan, S; Palou, J; et al. (2020)
      BACKGROUND: Although guidelines exist for advanced and variant bladder cancer management, evidence is limited/conflicting in some areas and the optimal approach remains controversial. OBJECTIVE: To bring together a large multidisciplinary group of experts to develop consensus statements on controversial topics in bladder cancer management. DESIGN: A steering committee compiled proposed statements regarding advanced and variant bladder cancer management which were assessed by 113 experts in a Delphi survey. Statements not reaching consensus were reviewed; those prioritised were revised by a panel of 45 experts prior to voting during a consensus conference. SETTING: Online Delphi survey and consensus conference. PARTICIPANTS: The European Association of Urology (EAU), the European Society for Medical Oncology (ESMO), experts in bladder cancer management. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Statements were ranked by experts according to their level of agreement: 1-3 (disagree), 4-6 (equivocal), and 7-9 (agree). A priori (level 1) consensus was defined as ?70% agreement and ?15% disagreement, or vice versa. In the Delphi survey, a second analysis was restricted to stakeholder group(s) considered to have adequate expertise relating to each statement (to achieve level 2 consensus). RESULTS AND LIMITATIONS: Overall, 116 statements were included in the Delphi survey. Of these statements, 33 (28%) achieved level 1 consensus and 49 (42%) achieved level 1 or 2 consensus. At the consensus conference, 22 of 27 (81%) statements achieved consensus. These consensus statements provide further guidance across a broad range of topics, including the management of variant histologies, the role/limitations of prognostic biomarkers in clinical decision making, bladder preservation strategies, modern radiotherapy techniques, the management of oligometastatic disease, and the evolving role of checkpoint inhibitor therapy in metastatic disease. CONCLUSIONS: These consensus statements provide further guidance on controversial topics in advanced and variant bladder cancer management until a time when further evidence is available to guide our approach. PATIENT SUMMARY: This report summarises findings from an international, multistakeholder project organised by the EAU and ESMO. In this project, a steering committee identified areas of bladder cancer management where there is currently no good-quality evidence to guide treatment decisions. From this, they developed a series of proposed statements, 71 of which achieved consensus by a large group of experts in the field of bladder cancer. It is anticipated that these statements will provide further guidance to health care professionals and could help improve patient outcomes until a time when good-quality evidence is available.
    • Fulvestrant plus capivasertib versus placebo after relapse or progression on an aromatase inhibitor in metastatic, oestrogen receptor-positive breast cancer (FAKTION): a multicentre, randomised, controlled, phase 2 trial

      Jones, RH; Casbard, A; Carucci, M; Cox, C; Butler, R; Alchami, F; Madden, TA; Bale, C; Bezecny, P; Joffe, J; et al. (2020)
      BACKGROUND: Capivasertib (AZD5363) is a potent selective oral inhibitor of all three isoforms of the serine/threonine kinase AKT. The FAKTION trial investigated whether the addition of capivasertib to fulvestrant improved progression-free survival in patients with aromatase inhibitor-resistant advanced breast cancer. METHODS: In this randomised, double-blind, placebo-controlled, phase 2 trial, postmenopausal women aged at least 18 years with an Eastern Cooperative Oncology Group performance status of 0-2 and oestrogen receptor-positive, HER2-negative, metastatic or locally advanced inoperable breast cancer who had relapsed or progressed on an aromatase inhibitor were recruited from 19 hospitals in the UK. Enrolled participants were randomly assigned (1:1) to receive intramuscular fulvestrant 500 mg (day 1) every 28 days (plus a loading dose on day 15 of cycle 1) with either capivasertib 400 mg or matching placebo, orally twice daily on an intermittent weekly schedule of 4 days on and 3 days off (starting on cycle 1 day 15) until disease progression, unacceptable toxicity, loss to follow-up, or withdrawal of consent. Treatment allocation was done using an interactive web-response system using a minimisation method (with a 20% random element) and the following minimisation factors: measurable or non-measurable disease, primary or secondary aromatase inhibitor resistance, PIK3CA status, and PTEN status. The primary endpoint was progression-free survival with a one-sided alpha of 0·20. Analyses were done by intention to treat. Recruitment is complete, and the trial is in follow-up. This trial is registered with ClinicalTrials.gov, number NCT01992952. FINDINGS: Between March 16, 2015, and March 6, 2018, 183 patients were screened for eligibility, of whom 140 (76%) were eligible and were randomly assigned to receive fulvestrant plus capivasertib (n=69) or fulvestrant plus placebo (n=71). Median follow-up for progression-free survival was 4·9 months (IQR 1·6-11·6). At the time of primary analysis for progression-free survival (Jan 30, 2019), 112 progression-free survival events had occurred, 49 (71%) in 69 patients in the capivasertib group compared with 63 (89%) of 71 in the placebo group. Median progression-free survival was 10·3 months (95% CI 5·0-13·2) in the capivasertib group versus 4·8 months (3·1-7·7) in the placebo group, giving an unadjusted hazard ratio (HR) of 0·58 (95% CI 0·39-0·84) in favour of the capivasertib group (two-sided p=0·0044; one-sided log rank test p=0·0018). The most common grade 3-4 adverse events were hypertension (22 [32%] of 69 patients in the capivasertib group vs 17 [24%] of 71 in the placebo group), diarrhoea (ten [14%] vs three [4%]), rash (14 [20%] vs 0), infection (four [6%] vs two [3%]), and fatigue (one [1%] vs three [4%]). Serious adverse reactions occurred only in the capivasertib group, and were acute kidney injury (two), diarrhoea (three), rash (two), hyperglycaemia (one), loss of consciousness (one), sepsis (one), and vomiting (one). One death, due to atypical pulmonary infection, was assessed as possibly related to capivasertib treatment. One further death in the capivasertib group had an unknown cause; all remaining deaths in both groups (19 in the capivasertib group and 31 in the placebo group) were disease related. INTERPRETATION: Progression-free survival was significantly longer in participants who received capivasertib than in those who received placebo. The combination of capivasertib and fulvestrant warrants further investigation in phase 3 trials. FUNDING: AstraZeneca and Cancer Research UK.
    • Molecular MRD status and outcome after transplantation in NPM1 mutated AML: results from the UK NCRI AML17 study

      Dillon, R; Hills, RK; Freeman, SD; Potter, N; Jovanovic, J; Ivey, A; Kanda, AS; Runglall, M; Foot, N; Valganon, M; et al. (2020)
      Relapse remains the most common cause of treatment failure for patients with acute myeloid leukaemia (AML) who undergo allogeneic stem cell transplantation (alloSCT) and carries a grave prognosis. Multiple studies have identified the presence of measurable residual disease (MRD) assessed by flow cytometry (FCM) prior to alloSCT as a strong predictor of relapse, but it is not clear how these findings apply to patients who test positive in molecular MRD assays which have far greater sensitivity. We analysed pre-transplant blood and bone marrow samples by reverse-transcription polymerase chain reaction (RT-qPCR) in 107 patients with NPM1 mutant AML enrolled in the UK National Cancer Research Institute (NCRI) AML17 study. After a median follow-up of 4.9 years, patients with negative, low (<200 copies / 105 ABL in the PB and <1000 copies in the BM) and high levels of MRD had an estimated 2y overall survival (OS) of 83%, 63% and 13% respectively (p<0.0001). Focussing on patients with low level MRD prior to alloSCT, those with FLT3 ITD had significantly poorer outcome (hazard ratio, HR, 6.14, p=0.01). Combining these variables was highly prognostic, dividing patients into two groups with 2y OS of 17% and 82% (HR 13.2, p<0.0001). T-depletion was associated with significantly reduced survival both in the entire cohort (2y OS 56% vs 96%, HR 3.24, p=0.0005) and in MRD positive patients (2y OS 34% vs 100%, HR 3.78, p=0.003) but there was no significant effect of either conditioning regimen or donor source on outcome. Registered at ISRCTN (http://www.isrctn.com/ISRCTN55675535).
    • Reply to Comment on 'The effectiveness of home versus community-based weight control programmes initiated soon after breast cancer diagnosis: a randomised controlled trial'

      Harvie, M; Pegington, Mary; Bundred, Nigel J; Campbell, A; Belcher, J; Howell, Sacha J; Howell, Anthony; Prevent Breast Cancer Research Unit, The Nightingale Centre, Manchester University NHS Foundation Trust, Manchester, UK. (2020)
    • Temozolomide-capecitabine chemotherapy for neuroendocrine neoplasms: the dilemma of treatment duration

      Lamarca, Angela; Barriuso, Jorge; McNamara, Mairéad G; Hubner, Richard A; Manoharan, Prakash; Mansoor, Was; Valle, Juan W; Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester (2020)
    • Association between immune-related adverse events and recurrence-free survival among patients with stage III melanoma randomized to receive pembrolizumab or placebo: a secondary analysis of a randomized clinical trial

      Eggermont, AMM; Kicinski, M; Blank, CU; Mandala, M; Long, GV; Atkinson, V; Dalle, S; Haydon, A; Khattak, A; Carlino, MS; et al. (2020)
      IMPORTANCE: Whether immune-related adverse events (irAEs) indicate drug activity in patients treated with immune checkpoint inhibitors remains unknown. OBJECTIVE: To investigate the association between irAEs and recurrence-free survival (RFS) in the double-blind EORTC 1325/KEYNOTE-054 clinical trial comparing pembrolizumab therapy and placebo for the treatment of patients with high-risk stage III melanoma. DESIGN, SETTING, AND PARTICIPANTS: A total of 1019 adults with stage III melanoma were randomly assigned on a 1:1 ratio to receive treatment with pembrolizumab therapy or placebo. Eligible patients were adults 18 years and older with complete resection of cutaneous melanoma metastatic to lymph nodes, classified with stage IIIA (at least 1 micrometastasis measuring >1 mm in greatest diameter), IIIB, or IIIC (without in-transit metastasis) cancer. Patients were randomized from August 26, 2015, to November 14, 2016. The clinical cutoff for the data set was October 2, 2017. Analyses were then performed on the database, which was locked on November 28, 2017. INTERVENTIONS: Participants were scheduled to receive 200 mg of pembrolizumab or placebo every 3 weeks for a total of 18 doses for approximately?1 year or until disease recurrence, unacceptable toxic effects, major protocol violation, or withdrawal of consent. MAIN OUTCOMES AND MEASURES: The association between irAEs and RFS was estimated using a Cox model adjusted for sex, age, and AJCC-7 stage, with a time-varying covariate that had a value of 0 before irAE onset and 1 after irAE onset. RESULTS: Of 1011 patients who began treatment with pembrolizumab therapy or placebo, 622 (61.5%) were men and 389 (38.5%) were women; 386 patients (38.2%) were aged 50 to 64 years, 377 (37.3%) were younger than 50 years, and 248 (24.5%) were 65 years and older. Consistent with the reported main analysis in the intent-to-treat population, RFS was longer in the pembrolizumab arm compared with the placebo arm (hazard ratio [HR], 0.56; 98.4% CI, 0.43-0.74) among patients who started treatment. The incidence of irAEs was 190 (37.4%) in the pembrolizumab arm (n?=?509) and 45 (9.0%) in the placebo arm (n?=?502); in each treatment group, the incidence was similar for men and women. The occurrence of an irAE was associated with a longer RFS in the pembrolizumab arm (HR, 0.61; 95% CI, 0.39-0.95; P?=?.03) in both men and women. However, in the placebo arm, this association was not significant. Compared with the placebo arm, the reduction in the hazard of recurrence or death in the pembrolizumab arm was greater after the onset of an irAE than without or before an irAE (HR, 0.37; 95% CI, 0.24-0.57 vs HR, 0.61; 95% CI, 0.49-0.77, respectively; P?=?.03). CONCLUSIONS AND RELEVANCE: In this study, the occurrence of an irAE was associated with a longer RFS in the pembrolizumab arm.
    • Ten year outcomes of moderately hypofractionated salvage post prostatectomy radiotherapy and external validation of a contemporary multivariable nomogram for biochemical failure

      Chin, Stephen; Fatimilehin, Abiola; Walshaw, Richard; Argarwal, Arjun; Mistry, Hitesh; Elliott, Tony; Logue, John P; Wylie, James P; Choudhury, Ananya; Department of Clinical Oncology, The Christie NHS Foundation Trust, Manchester (2020)
      PURPOSE: Although there is high level evidence supporting moderately hypofractionated radiotherapy for definitive prostate treatment, there is less evidence for its use in the post prostatectomy setting. We externally validated a contemporary nomogram predicting biochemical failure (BF) after salvage radiotherapy (SRT) and report long term disease control outcomes for hypofractionated SRT to the prostate bed. METHODS AND MATERIALS: A retrospective review was performed for 112 patients treated with hypofractionated SRT (52.5Gy/20 fractions using 3D conformal radiotherapy) for pT2-4R0-1N0/XM0 prostate adenocarcinoma, with post-operative PSA greater than 0.1ng/mL or rising. Freedom from biochemical failure (FFBF), distant metastasis (DM), cancer specific mortality (CSM) and overall survival (OS) were analysed from commencement of radiotherapy. Cox regression was performed on FFBF to account for covariates. BF was defined as a PSA ?0.4 ng/mL and rising after SRT. Early SRT was defined as SRT commencing at a pre-SRT PSA of ?0.2 ng/mL. RESULTS: Median follow up was 10.0 years (interquartile range 9.3-10.7 years), median pre-SRT PSA was 0.4 ng/mL and ADT was used in 14% of patients. Five/ten year FFBF, DM, CSM and OS was 68%/51%, 7%/16%, 5%/11%, and 90%/75%. FFBF for early SRT compared to late SRT was 81% vs 66% at five years and 68% vs 49% at ten years. On multivariable analysis, pre-SRT PSA, ISUP grade group, SVI, and ADT use were associated with FFBF. The nomogram c-index was 0.67, and it overestimated FFBF by 10/15% at five/ten years, with confidence intervals overlapping the line of unity. CONCLUSION: Hypofractionated SRT provides long term disease control outcomes comparable to conventionally fractionated radiotherapy. Early SRT provides improved disease control, with two thirds of patients with pre-SRT PSA of ?0.2 ng/mL being free of BF at 10 years. We performed the first external validation of the Tendulkar salvage nomogram which showed a robust model performance.
    • Brentuximab vedotin with chemotherapy for Stage III/IV classical Hodgkin lymphoma: 3-year update of the ECHELON-1 study

      Straus, DJ; Dlugosz-Danecka, M; Alekseev, S; Illes, A; Picardi, M; Lech-Maranda, E; Feldman, T; Smolewski, P; Savage, KJ; Bartlett, NL; et al. (2020)
      The phase 3 ECHELON-1 study demonstrated that brentuximab vedotin (A) with AVD (A+AVD) exhibited superior modified PFS versus ABVD for the frontline treatment of patients with stage III/IV classical Hodgkin lymphoma (cHL) (NCT01712490; 2011-005450-60). Maturing data from positron emission tomography (PET)-adapted trials highlight potential limitations of PET-adapted approaches, including toxicities with dose intensification and higher-than-expected relapse rates in PET2(-) patients. We present here an update of the ECHELON-1 study, including an exploratory analysis of 3-year PFS per investigator. 1334 patients with stage III or IV cHL were randomized 1:1 to receive six cycles of A+AVD (n = 664) or ABVD (n = 670). Interim PET scan after cycle 2 (PET2) was required. At a median follow-up of 37 months, 3-year PFS rates were 83.1% with A+AVD and 76.0% with ABVD; 3-year PFS rates in PET2(-) patients aged <60 years were 87.2% versus 81.0%, respectively. A beneficial trend in PET2(+) patients aged <60 years on A+AVD was also observed, with a 3-year PFS rate of 69.2% versus 54.7% with ABVD. The benefit of A+AVD in the intent-to-treat population appeared independent of disease stage and prognostic risk factors. Upon continued follow-up, 78% of patients with peripheral neuropathy (PN) on A+AVD had either complete resolution or improvement compared with 83% on ABVD. These data highlight that A+AVD provides a durable efficacy benefit compared with ABVD for frontline stage III/IV cHL which is consistent across key subgroups regardless of patient status at PET2, without need for treatment intensification or exposure to bleomycin.