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1. Concept: A randomised multicentre trial of first line chemotherapy comparing three weekly cabazitaxel versus weekly paclitaxel in HER2 negative metastatic breast cancer

Author

Amit Bahl, William Wilson, Jessica Ball, Emily Renninson, Sidharth Dubey, Alicia Bravo, Emily Foulstone, Saiqa Spensley, Rebecca Bowen, Janine Mansi, Simon Waters, Pippa Riddle, Duncan Wheatley, Peter Stephens, Pavel Bezecny, Srinivasan Madhusudan, Mark Verrill, Jeremy Braybrooke, Charles Comins, Vivek Mohan, Abigail Gee, Hannah Kirk, Alison Markham, Heidi Evans, Eve Watson, Mark Callaway, Sylvia Pearson, Allan Hackshaw, and Mark Churn

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Background: Paclitaxel is commonly used as first-line chemotherapy for HER2-negative metastatic breast cancer (MBC) patients. However, with response rates of 21.5–53.7% and significant risk of peripheral neuropathy, there is need for better chemotherapy. Patients and methods: This open-label phase II/III trial randomised HER2-negative MBC patients 1:1 to either 6 cycles of three-weekly cabazitaxel (25 mg/m2), or, weekly paclitaxel (80 mg/m2) over 18 weeks.The primary endpoint was progression free survival (PFS). Secondary endpoints included objective response rate (ORR), time to response (TTR), overall survival (OS), safety and tolerability and quality of life (QoL). Results: 158 patients were recruited. Comparing cabazitaxel to paclitaxel, median PFS was 6.7 vs 5.8 months (HR 0.87; 80%CI 0.70–1.08, P = 0.4). There was no difference in median OS (20.6 vs 18.2 months, HR 1.00; 95%CI 0.69–1.45, P = 0.99), ORR (41.8% vs 36.7%) or TTR (HR 1.09; 95%CI 0.68–1.75, P = 0.7).Grade ≥3 adverse events occurred in 41.8% on cabazitaxel and 46.8% on paclitaxel; the most common being neutropenia (16.5%) and febrile neutropenia (12.7%) cabazitaxel and neutropenia (8.9%) and lung infection (7.6%) paclitaxel. Peripheral neuropathy of any grade occurred in 54.5% paclitaxel vs 16.5% cabazitaxel.Mean EQ-5D-5L single index utility score (+0.05; 95%CI 0.004–0.09, P = 0.03) and visual analogue scale score (+7.7; 95%CI 3.1–12.3, P = 0.001) were higher in cabazitaxel vs paclitaxel. Conclusions: Three-weekly cabazitaxel in HER2-negative MBC does not significantly improve PFS compared to weekly paclitaxel, although it has a lower risk of peripheral neuropathy with better patient reported QoL outcomes. It is well tolerated and requires fewer hospital visits.

Published
2022
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3. Quality of life after breast-conserving therapy and adjuvant radiotherapy for non-low-risk ductal carcinoma in situ (BIG 3-07/TROG 07.01): 2-year results of a randomised, controlled, phase 3 trial

Author

Madeleine T King, Emma K Link, Tim J Whelan, Ivo A Olivotto, Ian Kunkler, Antonia Helen Westenberg, Guenther Gruber, Penny Schofield, Boon H Chua, Claire Phillips, Guy Bryant, Helen Westenberg, Om Pra-Kesh Purohit, Verity Ahern, Peter Graham, Mohamed Akra, Orla McArdle, Peter O'Brien, Jane Ludbrook, Jennifer Harvey, John H Maduro, Isabelle Gabelle-Flandin, Carine Kirkove, Carolyn Bedi, Joseph Martin, Tony Vu, Theirry Muanza, Anthony Neal, Adel Courdi, Juliette Thariat, Eileen Rakovitch, Laurien Daniels, Marjan van Hezewijk, Wlasyslawa Cwajna, Adelheid Roelstraete, Angela van Baardwijk, Nicola Russel, Anne Koch, Jennifer Croke, Imogen Locke, Peter Jeal, Quenten Walker, Kandeepeepan Thuraisingham, Anupam Chauduri, David Joseph, Mandy Taylor, Sabine Vanderkam, Tony Woo, Johann Tang, Michael Yassa, Elaine Wai, Susan Hewitt, Shazia Mahmood, Jennifer Gilmore, Bolante Ofi, Amit Bahl, Olga Vujovic, Edward Yu, Duc Le, Iwa Kong, Alan Nichol, Nina Bijker, Geoff Delaney, Malcolm Feigen, Adeline Lim, Michael Chao, Margaret Latham, Hafiz Algurafi, Christoph Tausch, Eric Khoo, Sam Leung, Karen Taylor, Sasha Senthi, Andrea Stevens, Abhro Chaudhuri, Susan Cleator, Adrian Murray Brunt, Scott Babington, David Christie, Daniel Zwahlen, Ulrich Schratzenstaller, Laurence Masson, Nicola Storey, Eshwar Kumar, Liz Sherwin, Reinhilde Weytjens, Sharma Ravi, Patricia Lawton, Ruth Angell, Glenys Round, Angela Allen, Ziad Thotathil, Margaret Anthes, Christiane Reuter, Laura Pettit, Yvonne Zissiadis, Christine Elder, Antoinette Verbeek-de Kanter, Andree Lirette, Ludwig Plasswilm, David Spooner, Fiona Hoar, Islam Mohamed, Kristina Lossl, Vivienne Loo, Antonella Richetti, Tamasin Evans, Aisling Hennessy, Medhat El-Mallah, Marketa Skala, Raef Awad, Isabelle Germain, Carine Mitine, Hilde Van Parijs, Mark Churn, Nawaz Walji, Michael Francis, Karin Stellamans, Gunther Gruber, Giovanni Ivaldi, Abdulla Alhasso, Lizbeth Kenny, Ken Tiver, Matthew Griffin, Gillian Lamoury, Marco Trovo, Hafiz Algufarfi, Minjae Lah, Scott Carruthers, George Papadatos, Gabriel Paardekooper, Mojca Persic, Bernadette Lavery, Radiotherapy, and CCA - Cancer Treatment and Quality of Life

Subjects
Oncology, medicine.medical_specialty, medicine.medical_treatment, Breast surgery, Brachytherapy, Breast Neoplasms, Mastectomy, Segmental, law.invention, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, Randomized controlled trial, law, Internal medicine, medicine, Clinical endpoint, Humans, Breast, 030212 general & internal medicine, Neoplasm Staging, Intention-to-treat analysis, business.industry, Middle Aged, medicine.disease, Radiation therapy, Carcinoma, Intraductal, Noninfiltrating, Treatment Outcome, 030220 oncology & carcinogenesis, Quality of Life, Female, Radiotherapy, Adjuvant, Neoplasm Recurrence, Local, business, Mastectomy
Abstract

Summary Background BIG 3-07/TROG 07.01 is an international, multicentre, randomised, controlled, phase 3 trial evaluating tumour bed boost and hypofractionation in patients with non-low-risk ductal carcinoma in situ following breast-conserving surgery and whole breast radiotherapy. Here, we report the effects of diagnosis and treatment on health-related quality of life (HRQOL) at 2 years. Methods The BIG 3-07/TROG 07.01 trial is ongoing at 118 hospitals in 11 countries. Women aged 18 years or older with completely excised non-low-risk ductal carcinoma in situ were randomly assigned, by use of a minimisation algorithm, to tumour bed boost or no tumour bed boost, following conventional whole breast radiotherapy or hypofractionated whole breast radiotherapy using one of three randomisation categories. Category A was a 4-arm randomisation of tumour bed boost versus no boost following conventional whole breast radiotherapy (50 Gy in 25 fractions over 5 weeks) versus hypofractionated whole breast radiotherapy (42·5 Gy in 16 fractions over 3·5 weeks). Category B was a 2-arm randomisation between tumour bed boost versus no boost following conventional whole breast radiotherapy, and category C was a 2-arm randomisation between tumour bed boost versus no boost following hypofractionated whole breast radiotherapy. Stratification factors were age at diagnosis, planned endocrine therapy, and treating centre. The primary endpoint, time to local recurrence, will be reported when participants have completed 5 years of follow-up. The HRQOL statistical analysis plan prespecified eight aspects of HRQOL, assessed by four questionnaires at baseline, end of treatment, and at 6, 12, and 24 months after radiotherapy: fatigue and physical functioning (EORTC QLQ-C30); cosmetic status, breast-specific symptoms, arm and shoulder functional status (Breast Cancer Treatment Outcome Scale); body image and sexuality (Body Image Scale); and perceived risk of invasive breast cancer (Cancer Worry Scale and a study-specific question). For each of these measures, tumour bed boost was compared with no boost, and conventional whole breast radiotherapy compared with hypofractionated whole breast radiotherapy, by use of generalised estimating equation models. Analyses were by intention to treat, with Hochberg adjustment for multiple testing. This trial is registered with ClinicalTrials.gov , NCT00470236 . Findings Between June 1, 2007, and Aug 14, 2013, 1208 women were enrolled and randomly assigned to receive no tumour bed boost (n=605) or tumour bed boost (n=603). 396 of 1208 women were assigned to category A: conventional whole breast radiotherapy with tumour bed boost (n=100) or no boost (n=98), or to hypofractionated whole breast radiotherapy with tumour bed boost (n=98) or no boost (n=100). 447 were assigned to category B: conventional whole breast radiotherapy with tumour bed boost (n=223) or no boost (n=224). 365 were assigned to category C: hypofractionated whole breast radiotherapy with tumour bed boost (n=182) or no boost (n=183). All patients were followed up at 2 years for the HRQOL analysis. 1098 (91%) of 1208 patients received their allocated treatment, and most completed their scheduled HRQOL assessments (1147 [95%] of 1208 at baseline; 988 [87%] of 1141 at 2 years). Cosmetic status was worse with tumour bed boost than with no boost across all timepoints (difference 0·10 [95% CI 0·05–0·15], global p=0·00014, Hochberg-adjusted p=0·0016); at the end of treatment, the estimated difference between tumour bed boost and no boost was 0·13 (95% CI 0·06–0·20; p=0·00021), persisting at 24 months (0·13 [0·06–0·20]; p=0·00021). Arm and shoulder function was also adversely affected by tumour bed boost across all timepoints (0·08 [95% CI 0·03–0·13], global p=0·0033, Hochberg adjusted p=0·045); the difference between tumour bed boost and no boost at the end of treatment was 0·08 (0·01 to 0·15, p=0·021), and did not persist at 24 months (0·04 [–0·03 to 0·11], p=0·29). None of the other six prespecified aspects of HRQOL differed significantly after adjustment for multiple testing. Conventional whole breast radiotherapy was associated with worse body image than hypofractionated whole breast radiotherapy at the end of treatment (difference –1·10 [95% CI –1·79 to –0·42], p=0·0016). No significant differences were reported in the other PROs between conventional whole breast radiotherapy compared with hypofractionated whole breast radiotherapy. Interpretation Tumour bed boost was associated with persistent adverse effects on cosmetic status and arm and shoulder functional status, which might inform shared decision making while local recurrence analysis is pending. Funding National Health and Medical Research Council, Susan G Komen for the Cure, Breast Cancer Now, OncoSuisse, Dutch Cancer Society.

Published
2020
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4. HER2-enriched subtype and novel molecular subgroups drive aromatase inhibitor resistance and an increased risk of relapse in early ER+/HER2+ breast cancer

Author

Milana A. Bergamino, Elena López-Knowles, Gabriele Morani, Holly Tovey, Lucy Kilburn, Eugene F. Schuster, Anastasia Alataki, Margaret Hills, Hui Xiao, Chris Holcombe, Anthony Skene, John F. Robertson, Ian E. Smith, Judith M. Bliss, Mitch Dowsett, Maggie C.U. Cheang, Abigail Evans, Adrian Ball, Akhil Johri, Ali Nejim, Alison Jones, Allan Corder, Amanda Thorne, Ambika Anand, Amitabha Chakrabarti, Anne Robinson, Anupam Modi, Ashraf Patel, Ashutosh Kothari, Brendan McFall, Caroline Mortimer, Caroline Lee, Charlie Chan, Charlotte Abson, Christopher Holcombe, Christopher Hinton, Ciaran Hollywood, Claire Murphy, Clare Crowley, Claudia Harding-Mackean, Clive Griffith, Conrad Lewanski, Daniel Rea, David Hwang, Derek Crawford, Dinesh Thekkinkattil, Douglas Ferguson, Douglas Adamson, Duncan Wheatley, Duraisamy Ravichandran, Ed Babu, Elaine Hyett, Fawzia Ashkanani, Fiona Hoar, Frances Kenny, Gary Dyke, Geoffrey Sparrow, null Gilbert, Giles Cunnick, Hafiz Algurafi, Helen Sweetland, Highes-Davies Prof, Hisham Hamed, Ian Smith, Ian Laidlaw, Ilyas Khattak, Jacqueline Newby, Jacqueline Rees-Lee, Jalal Kokan, Jane Barrett, Jay Dolatrai Naik, Jayant Vaidya, Jennifer Forrest, Jitendra Parmar, Jocelyn Adams, John Fox, Jonathan Roberts, Jonathan Dawson, Julie Doughty, Jull Donnelly, Kathleen Dunn, Kian Chin, Kieran Horgan, Kislaya Thakur, Ludger Barthelmes, Lynda Wyld, Madhumita Bhattacharyya, Maher Hadaki, Makam Kishore, Marcus Ornstein, Maria Bramley, Maria Bews-Hair, Marina Parton, Mark Sibbering, Mark Kissin, Mark Churn, Martin Hogg, Mary Quigley, Matthew Hatton, Matthew Winter, Matthew Adelekan, Michael Shere, Michael Carr, Michael Williams, Mohammed Absar, Muhammad Sharif, Muireann Kelleher, Nawaz Walji, Nicholas Williams, Nicholas Gallegos, Nigel Bundred, Olivia Hatcher, Perric Crellin, Peter Crane, Peter Donnelly, Peter Kneeshaw, Philip Walker, Prakash Sinha, Pudhupalayam Bhaskar, Racheal Soulsby, Radha Todd, Raghavan Vidya, Rakesh Mehra, Ramachandran Prasad, Ramsay Cutress, Ravi Sharma, Rebecca Roylance, Rebecca Goranova, Reem Ramzi Salman, Riccardo Bonom, Richard Johnson, Richard Sutton, Rick Linforth, Rob Coleman, Robert Grieve, Robert Leonard, Robert Reichert, Robert Kennedy, Roshan Agarwal, Rozenn Allerton, Russell Burcombe, Ruth Davis, Sankaran Narayanan, Sankaran Chandrasekharan, Sarah Vesty, Seema Seetharam, Serena Ledwidge, Shabana Iqbal, Shamaela Wahee, Shobha Silva, Simon Pain, Simon Holt, Simon Thomson, Simon Smith, Simon Ellenbogen, Siobhan Laws, Stephen Chan, Stephen Johnston, Steve Holt, Steven Thrush, Stuart McIntosh, Sumohan Chatterjee, Susan Cleator, Tamoor Usman, Tayo Johnson, Tibor Kovacs, Tracey Irvine, Urmila Barthkur, Vanessa Pope, Victoria Alexandra Brown, Vummiti Muralikrishna, Walid Samra, William Maxwell, and Zoe Winters

Subjects
Clinical Trials as Topic, Ki-67 Antigen, Receptors, Estrogen, Aromatase Inhibitors, Receptor, ErbB-2, Biomarkers, Tumor, Humans, Breast Neoplasms, Female, General Medicine, Neoplasm Recurrence, Local, Receptors, Progesterone, General Biochemistry, Genetics and Molecular Biology
Abstract

Background: oestrogen receptor positive/ human epidermal growth factor receptor positive (ER+/HER2+) breast cancers (BCs) are less responsive to endocrine therapy than ER+/HER2- tumours. Mechanisms underpinning the differential behaviour of ER+HER2+ tumours are poorly characterised. Our aim was to identify biomarkers of response to 2 weeks’ presurgical AI treatment in ER+/HER2+ BCs. Methods: all available ER+/HER2+ BC baseline tumours (n=342) in the POETIC trial were gene expression profiled using BC360™ (NanoString) covering intrinsic subtypes and 46 key biological signatures. Early response to AI was assessed by changes in Ki67 expression and residual Ki67 at 2 weeks (Ki67 2wk). Time-To-Recurrence (TTR) was estimated using Kaplan-Meier methods and Cox models adjusted for standard clinicopathological variables. New molecular subgroups (MS) were identified using consensus clustering. Findings: HER2-enriched (HER2-E) subtype BCs (44.7% of the total) showed poorer Ki67 response and higher Ki67 2wk (p2wk. Five new MS that were associated with differential response to AI were identified. HER2-E had significantly poorer TTR compared to Luminal BCs (HR 2.55, 95% CI 1.14–5.69; p=0.0222). The new MS were independent predictors of TTR, adding significant value beyond intrinsic subtypes. Interpretation: our results show HER2-E as a standardised biomarker associated with poor response to AI and worse outcome in ER+/HER2+. HRD, TP53 mutational score and immune-tumour tolerance are predictive biomarkers for poor response to AI. Lastly, novel MS identify additional non-HER2-E tumours not responding to AI with an increased risk of relapse. Funding: Cancer Research UK (CRUK/07/015).

Published
2022

5. Hypofractionated breast radiotherapy for 1 week versus 3 weeks (FAST-Forward): 5-year efficacy and late normal tissue effects results from a multicentre, non-inferiority, randomised, phase 3 trial

Author

Adrian Murray Brunt, Joanne S Haviland, Duncan A Wheatley, Mark A Sydenham, Abdulla Alhasso, David J Bloomfield, Charlie Chan, Mark Churn, Susan Cleator, Charlotte E Coles, Andrew Goodman, Adrian Harnett, Penelope Hopwood, Anna M Kirby, Cliona C Kirwan, Carolyn Morris, Zohal Nabi, Elinor Sawyer, Navita Somaiah, Liba Stones, Isabel Syndikus, Judith M Bliss, John R Yarnold, Anne Armstrong, Judith Bliss, David Bloomfield, Jo Bowen, Murray Brunt, Hannah Chantler, Charlotte Coles, Ellen Donovan, Andy Goodman, Susan Griffin, Jo Haviland, Penny Hopwood, Anna Kirby, Julie Kirk, Cliona Kirwan, Marjory MacLennan, Mark Sculphur, Judith Sinclair, Mark Sydenham, Jean Tremlett, Karen Venables, Duncan Wheatley, John Yarnold, and Apollo - University of Cambridge Repository

Subjects
medicine.medical_treatment, Kaplan-Meier Estimate, 030204 cardiovascular system & hematology, law.invention, 0302 clinical medicine, Randomized controlled trial, law, Radiotherapy, Adjuvant/adverse effects, Clinical endpoint, 030212 general & internal medicine, Neoplasm Metastasis, Mastectomy, Neoplasm Recurrence, Local/epidemiology, Aged, 80 and over, Manchester Cancer Research Centre, United Kingdom/epidemiology, Hazard ratio, General Medicine, Middle Aged, Treatment Outcome, Female, Radiation Dose Hypofractionation, Adult, Breast Neoplasms/mortality, Breast Neoplasms, Risk Assessment, Article, 03 medical and health sciences, Breast cancer, medicine, Humans, Risk Assessment/methods, Radiation Injuries, Aged, Neoplasm Staging, business.industry, ResearchInstitutes_Networks_Beacons/mcrc, medicine.disease, R1, United Kingdom, Mastectomy/methods, Radiation therapy, Clinical trial, Regimen, Radiation Injuries/epidemiology, Radiotherapy, Adjuvant, Neoplasm Grading, Neoplasm Recurrence, Local, business, Nuclear medicine, RA, Follow-Up Studies
Abstract

BACKGROUND: We aimed to identify a five-fraction schedule of adjuvant radiotherapy (radiation therapy) delivered in 1 week that is non-inferior in terms of local cancer control and is as safe as an international standard 15-fraction regimen after primary surgery for early breast cancer. Here, we present 5-year results of the FAST-Forward trial.METHODS: FAST-Forward is a multicentre, phase 3, randomised, non-inferiority trial done at 97 hospitals (47 radiotherapy centres and 50 referring hospitals) in the UK. Patients aged at least 18 years with invasive carcinoma of the breast (pT1-3, pN0-1, M0) after breast conservation surgery or mastectomy were eligible. We randomly allocated patients to either 40 Gy in 15 fractions (over 3 weeks), 27 Gy in five fractions (over 1 week), or 26 Gy in five fractions (over 1 week) to the whole breast or chest wall. Allocation was not masked because of the nature of the intervention. The primary endpoint was ipsilateral breast tumour relapse; assuming a 2% 5-year incidence for 40 Gy, non-inferiority was predefined as ≤1·6% excess for five-fraction schedules (critical hazard ratio [HR] of 1·81). Normal tissue effects were assessed by clinicians, patients, and from photographs. This trial is registered at isrctn.com, ISRCTN19906132.FINDINGS: Between Nov 24, 2011, and June 19, 2014, we recruited and obtained consent from 4096 patients from 97 UK centres, of whom 1361 were assigned to the 40 Gy schedule, 1367 to the 27 Gy schedule, and 1368 to the 26 Gy schedule. At a median follow-up of 71·5 months (IQR 71·3 to 71·7), the primary endpoint event occurred in 79 patients (31 in the 40 Gy group, 27 in the 27 Gy group, and 21 in the 26 Gy group); HRs versus 40 Gy in 15 fractions were 0·86 (95% CI 0·51 to 1·44) for 27 Gy in five fractions and 0·67 (0·38 to 1·16) for 26 Gy in five fractions. 5-year incidence of ipsilateral breast tumour relapse after 40 Gy was 2·1% (1·4 to 3·1); estimated absolute differences versus 40 Gy in 15 fractions were -0·3% (-1·0 to 0·9) for 27 Gy in five fractions (probability of incorrectly accepting an inferior five-fraction schedule: p=0·0022 vs 40 Gy in 15 fractions) and -0·7% (-1·3 to 0·3) for 26 Gy in five fractions (p=0·00019 vs 40 Gy in 15 fractions). At 5 years, any moderate or marked clinician-assessed normal tissue effects in the breast or chest wall was reported for 98 of 986 (9·9%) 40 Gy patients, 155 (15·4%) of 1005 27 Gy patients, and 121 of 1020 (11·9%) 26 Gy patients. Across all clinician assessments from 1-5 years, odds ratios versus 40 Gy in 15 fractions were 1·55 (95% CI 1·32 to 1·83, pINTERPRETATION: 26 Gy in five fractions over 1 week is non-inferior to the standard of 40 Gy in 15 fractions over 3 weeks for local tumour control, and is as safe in terms of normal tissue effects up to 5 years for patients prescribed adjuvant local radiotherapy after primary surgery for early-stage breast cancer.FUNDING: National Institute for Health Research Health Technology Assessment Programme.

Published
2020
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6. FAST-Forward Phase III Randomised Controlled Trial of 1-Week Hypofractionated Breast Radiotherapy: 5-Year Results for Efficacy and Late Normal Tissue Effects

Author

A. Murray Brunt, Joanne S. Haviland, Duncan A. Wheatley, Mark A Sydenham, Abdulla Alhasso, David J Bloomfield, Charlie Chan, Mark Churn, Susan Cleator, Charlotte E Coles, Andrew Goodman, Adrian Harnett, Penelope Hopwood, Anna M. Kirby, Cliona C. Kirwan, Carolyn Morris, Zohal Nabi, Eleanor Sawyer, Navita Somaiah, Liba Stones, Isabel Syndikus, Judith M. Bliss, John R. Yarnold, and FAST-Forward Trial Management Group

Subjects
medicine.medical_specialty, business.industry, medicine.medical_treatment, Incidence (epidemiology), Hazard ratio, Odds ratio, medicine.disease, law.invention, Regimen, Breast cancer, Randomized controlled trial, law, Internal medicine, medicine, Clinical endpoint, business, Mastectomy
Abstract

Background: FAST-Forward aims to identify a 5-fraction (Fr) schedule of adjuvant radiotherapy (radiation therapy) delivered in 1 week which is non-inferior for local cancer control and as safe as an international standard 15Fr regimen after primary surgery for early breast cancer. Five-year results are presented. Methods: FAST-Forward (ISRCTN19906132) randomised (1:1:1) patients with invasive carcinoma of the breast (pT1-3 pN0-1 M0) after breast conservation surgery or mastectomy to 40Gy in 15Fr (3 weeks), 27Gy or 26Gy in 5Fr (1 week) to whole breast/chest wall. Primary endpoint was ipsilateral breast tumour relapse (IBTR); assuming 2% 5-year incidence for 40Gy, non-inferiority was pre-defined as < 1.6% excess for 5Fr schedules (critical hazard ratio HR=1.81). Normal tissue effects (NTE) were assessed by clinicians, patients and photographs. Findings: 4096 consenting patients (1361 40Gy, 1367 27Gy, 1368 26Gy) were recruited November 2011-June 2014 from 97 UK centres. At 71 months median follow-up, 79 IBTR events were reported (40Gy: 31, 27Gy: 27, 26Gy: 21); HRs (95%CI) versus 40Gy/15Fr were 27Gy/5Fr: 0.86 (0.51,1.44), 26Gy/5Fr: 0.67 (0.38,1.16). Five-year incidence of IBTR after 40Gy was 2.1% (1.4,3.1); estimated absolute differences versus 40Gy/15Fr were -0.3% (-1.0,0.9) for 27Gy/5Fr (p=0.0022 for non-inferiority) and -0.7% (-1.3,0.3) for 26Gy/5Fr (p=0.00019). 5-year prevalence of any clinician-assessed moderate/marked breast NTE after 40Gy: 98/986 (9.9%), 27Gy: 155/1005 (15.4%), 26Gy: 121/1020 (11.9%). Across all clinician assessments from 1-5 years, odds ratios versus 40Gy/15Fr were 1.55 (1.32,1.83, p

Published
2020
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7. OC-0610: FAST-Forward phase 3 RCT of 1-week hypofractionated breast radiotherapy: 5-year results

Author

Joanne S Haviland, C. Coles, Adrian Harnett, Abdulla Alhasso, Isabel Syndikus, Mark Churn, C. Morris, A.M. Brunt, C C Kirwan, Andrew Goodman, Duncan Wheatley, Anna M. Kirby, E. Sawyer, Navita Somaiah, C. Chan, John Yarnold, Penelope Hopwood, M. Wilcox, D. Bloomfield, Z. Nabi, Judith M Bliss, M. Sydenham, L. Stones, M. Emson, and S. Cleator

Subjects
medicine.medical_specialty, Oncology, Randomized controlled trial, business.industry, law, Phase (matter), medicine, Radiology, Nuclear Medicine and imaging, Breast radiotherapy, Hematology, Radiology, business, law.invention
Published
2020
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8. 6 versus 12 months of adjuvant trastuzumab for HER2-positive early breast cancer (PERSEPHONE) : 4-year disease-free survival results of a randomised phase 3 non-inferiority trial

Author

Jane Brown, Roshan Agarwal, Catherine Harper-Wynne, A. Humphreys, Eliot Sims, Peter Hall, Mukesh Mukesh, Sundus Yahya, Nawaz Walji, Mojca Persic, Donna L. Howe, Simon Waters, Wendy Taylor, Anita Chhabra, Karen Tipples, Helen Innes, Mark Churn, Peter Ostler, Pamela Woodings, Helen Roe, Lisa H Barraclough, Shrushma Loi, Maggie Wilcox, Susan Lupton, Adrian Harnett, Rebecca Bowen, Peter Simmonds, Natasha Mithal, H. M. Earl, Apurna Jegannathen, Kathryn Wright, A.S. Dhadda, Rozenn Allerton, Jean Abraham, Karen McAdam, Ioannis Gounaris, Mohini Varughese, Mark Harries, Helen Neville-Webbe, Catherine Bale, Narottam Thanvi, Carolyn Bedi, Carlos Caldas, Fharat A. Raja, Helena M. Earl, David Miles, Trevor McGolick, Andrew D. Goodman, Kerry Raynes, Anthony Neal, Richard Simcock, Hartmut Kristeleit, Carol MacGregor, Christopher McCabe, Caroline Archer, Laura Pettit, Chris Bradley, Anne-Laure Vallier, Urmila Barthakur, Perric Crellin, S O'Reilly, Betania Mahler Araujo, Andrew Eichholz, Louise Hiller, Anne Rigg, Janine Mansi, Jacqueline Newby, Janet A. Dunn, Sarah Smith, Chris Plummer, Jennifer Marshall, Aian Moss, Zafar Malik, Larry Hayward, Mohammad Butt, Andrew M Wardley, Anup Vinayan, Shiroma De Silva-Minor, Mei-Lin Ah-See, Sue Down, Helen B Higgins, Catherine Reed, Kim Benstead, Rakesh Mehra, Luke Hughes-Davies, David Cameron, Daniel Nelmes, O.S. Din, Charlotte Moss, Daniel Epurescu, Anne C Armstrong, Nicola Storey, David J. Eaton, Hafiz Algurafi, Mariam Jafri, Daniel Rea, Nihal Shah, Elena Provenzano, Susan Cleator, Muireann Kelleher, Claire Hulme, Daniela Lee, D. Bloomfield, Margaret Daly, Joanne Cliff, Chee Goh, Sanjay Raj, Maher Hadaki, Jayant S. Vaidya, Robert Grieve, and PERSEPHONE Steering Committee and Trial Investigators

Subjects
Oncology, medicine.medical_specialty, medicine.medical_treatment, Breast Neoplasms, 030204 cardiovascular system & hematology, Article, Disease-Free Survival, RC0254, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, Adjuvants, Immunologic, Trastuzumab, Internal medicine, medicine, Adjuvant therapy, Humans, 030212 general & internal medicine, Young adult, Prospective cohort study, Adjuvants, Pharmaceutic, Early breast cancer, Chemotherapy, business.industry, General Medicine, medicine.disease, business, Adjuvant, medicine.drug
Abstract

Background: Adjuvant trastuzumab significantly improves outcomes for patients with HER2-positive early breast cancer. The standard treatment duration is 12 months but shorter treatment could provide similar efficacy while reducing toxicities and cost. We aimed to investigate whether 6-month adjuvant trastuzumab treatment is non-inferior to the standard 12-month treatment regarding disease-free survival.Methods: This study is an open-label, randomised phase 3 non-inferiority trial. Patients were recruited from 152 centres in the UK. We randomly assigned patients with HER2-positive early breast cancer, aged 18 years or older, and with a clear indication for chemotherapy, by a computerised minimisation process (1:1), to receive either 6-month or 12-month trastuzumab delivered every 3 weeks intravenously (loading dose of 8 mg/kg followed by maintenance doses of 6 mg/kg) or subcutaneously (600 mg), given in combination with chemotherapy (concurrently or sequentially). The primary endpoint was disease-free survival, analysed by intention to treat, with a non-inferiority margin of 3% for 4-year disease-free survival. Safety was analysed in all patients who received trastuzumab. This trial is registered with EudraCT (number 2006–007018–39), ISRCTN (number 52968807), and ClinicalTrials.gov (number NCT00712140).Findings: Between Oct 4, 2007, and July 31, 2015, 2045 patients were assigned to 12-month trastuzumab treatment and 2044 to 6-month treatment (one patient was excluded because they were double randomised). Median follow-up was 5·4 years (IQR 3·6–6·7) for both treatment groups, during which a disease-free survival event occurred in 265 (13%) of 2043 patients in the 6-month group and 247 (12%) of 2045 patients in the 12-month group. 4-year disease-free survival was 89·4% (95% CI 87·9–90·7) in the 6-month group and 89·8% (88·3–91·1) in the 12-month group (hazard ratio 1·07 [90% CI 0·93–1·24], non-inferiority p=0·011), showing non-inferiority of the 6-month treatment. 6-month trastuzumab treatment resulted in fewer patients reporting severe adverse events (373 [19%] of 1939 patients vs 459 [24%] of 1894 patients, p=0·0002) or stopping early because of cardiotoxicity (61 [3%] of 1939 patients vs 146 [8%] of 1894 patients, pInterpretation: We have shown that 6-month trastuzumab treatment is non-inferior to 12-month treatment in patients with HER2-positive early breast cancer, with less cardiotoxicity and fewer severe adverse events. These results support consideration of reduced duration trastuzumab for women at similar risk of recurrence as to those included in the trial.Funding: UK National Institute for Health Research, Health Technology Assessment Programme.

Published
2019
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9. Randomized multicenter trial of 3 weekly cabazitaxel versus weekly paclitaxel chemotherapy in the first-line treatment of HER2 negative metastatic breast cancer (MBC)

Author

Sidharth Dubey, William R. Wilson, Pippa Riddle, Peter Stephens, Alison Markham, Saiqa Spensley, Jessica Ball, Mark Churn, Pavel Bezecny, Mark Verrill, Rebecca Bowen, Sylvia Pearson, Duncan Wheatley, Alicia Bravo, Amit Bahl, Jeremy P Braybrooke, Srinivasan Madhusudan, S Waters, Emily J. Foulstone, and Janine Mansi

Subjects
Oncology, Cancer Research, medicine.medical_specialty, Chemotherapy, business.industry, medicine.medical_treatment, HER2 negative, Weekly paclitaxel, medicine.disease, Metastatic breast cancer, chemistry.chemical_compound, Peripheral neuropathy, Paclitaxel, chemistry, Cabazitaxel, Internal medicine, Multicenter trial, medicine, business, medicine.drug
Abstract

1008 Background: Paclitaxel is commonly used as first line chemotherapy for HER2 negative MBC. However, with response rates of 21.5-53.7% and a significant risk of peripheral neuropathy there is a need for more effective and better tolerated chemotherapy (CCT). Methods: This open label randomised (1:1) phase 2 trial compared 6 cycles of cabazitaxel (25 mg/m2) every 3 weeks, with weekly paclitaxel (80mg/m2) over 18 weeks as first line CCT. HER2 negative and performance status ≤1 patients were eligible. Patients on cabazitaxel received GCSF prophylaxis. Primary endpoint was Progression Free Survival (PFS) with 127 events required to detect a hazard ratio (HR) of 0.65 with 85% power. Secondary endpoints included objective response rate (ORR; RECIST 1.1), time to response (TTR), overall survival (OS), safety and tolerability and quality of life (QoL). Results: 158 patients were recruited from 14 UK hospitals (79 in each arm). Median age (range) was 56(34-81) in the cabazitaxel arm and 61(34-79) in the paclitaxel arm. 61% of patients were performance status 0. Median time on treatment was 15 weeks for both arms, but more patients on paclitaxel had a treatment delay (61% vs 39%) or dose reduction (37% vs 24%). Comparing cabazitaxel to paclitaxel after 146 PFS events, median PFS was 6.7 vs 5.8 months (HR 0.84; 95%CI 0.60–1.18, P = 0.3). There was no difference in OS, median 19.3 vs 20.0 months (HR 0.94; 95%CI 0.63-1.40, P = 0.7), ORR (42% vs 37%) or TTR (HR 1.09; 95%CI 0.68–1.74, P = 0.7). Grade ≥3 adverse events occurred in 42% of patients on cabazitaxel and 48% on paclitaxel. Diarrhoea, febrile neutropenia and nausea were the most common grade ≥3 events in the cabazitaxel arm with rates of 11%, 11% and 10% respectively compared to 1%, 1% and 0% in the paclitaxel arm. In the paclitaxel arm the top grade ≥3 events were lung infection and peripheral neuropathy, 6% and 5% respectively compared to 2.5% and 0% in the cabazitaxel arm. Peripheral neuropathy of any grade was reported by 55% of patients treated with paclitaxel vs 17% on cabazitaxel. Alopecia occurred in 41% of patients on paclitaxel compared to 27% on cabazitaxel. Adverse events leading to discontinuation were more frequent with paclitaxel (22%) than cabazitaxel (14%). Over the course of treatment, mean EQ5D single index utility score (+0.05; 95%CI 0.004-0.09, P = 0.03) and visual analogue scale score (+7.7; 95%CI 3.1-12.3, P = 0.001) were higher in the cabazitaxel arm compared to paclitaxel suggestive of better QoL on Cabazitaxel. Conclusions: 3 weekly cabazitaxel as first line chemotherapy in HER2 negative MBC does not significantly improve PFS compared to weekly paclitaxel, though it has a lower risk of peripheral neuropathy with better patient reported overall health outcomes. Cabazitaxel is safe and well tolerated for MBC and requires fewer hospital visits, an important consideration in the COVID pandemic and beyond. Clinical trial information: NCT03048942 .

Published
2021
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10. Safety and tolerability of subcutaneous trastuzumab for the adjuvant treatment of human epidermal growth factor receptor 2-positive early breast cancer: SafeHer phase III study's primary analysis of 2573 patients

Author

Jose Chacon, Katja Ziegler-Löhr, Kamran Rashid, Stanley Madretsma, Hortense Laharie Mineur, Soo Hyeon Lee, Bohuslav Melichar, Jasna Pesic, Julia Hall, Jörg Schilling, Paola Morales Espinosa, Wendy Taylor, Francesco Cognetti, Doris Augustin, Ines Sandri, Laura Murillo Jaso, Alejandro Juarez Ramiro, Nora Artagaveytia, Rocio Reategui, Nataliia Voitko, Teresa Gamucci, Lisa H Barraclough, Jérôme Alexandre, Mohammed Butt, Frank Priou, A.J. van de Wouw, Cristina Marinela Oprean, Isabel Alonso, Suzana Vasovic, Fernando Roque, Marc Thill, Viktoria Dvornichenko, K. Bouzid, Idris Yucel, Andrea Stefek, Jose Manuel Lopez Vega, Daniil Stroyakovskiy, R. Chiara Forcignanò, Mohammed Harb, Andrzej Mruk, Jana Prausová, Lydia Dreosti, Prabir Chakraborti, Armando Santoro, Lee Wei Ching, Anna Tuczek, Jane Beith, Larisa Ciule, Hakan Bozcuk, Antonino Musolino, Hartmut Kristeleit, Clare Crowley, T.C. Kok, Dhurata Koroveshi, Natasha Mithal, Laura Garcia Sanchis, Stephan Henschen, Carmen Cañabate Arias, A. Contu, Antoaneta Tomova, Alper Sevinc, Helga Droogendijk, Gustavo Fernando Ismael, Konstantinos Papazisis, Laurent Gasnault, Sandra Bakker, Judit Kocsis, Bernd Christensen, Stephen Kelly, Rosana Jarcau, Christian Jackisch, George Fountzilas, Cyril Foa, Annebeth W. Haringhuizen, Silvia Neciosup, Juan Matos Santos, Finlander Rosales Osegueda, Robinson Rodriguez, Marcus Schmidt, Bart de Valk, Kathryn Wright, A.S. Dhadda, Elizabeth Sherwin, Sabino De Placido, Luigi Cavanna, Joelle Egreteau, Shazza Rehman, Giacomo Allegrini, Doerte Luedders, Poovandren Govender, Hugues Barletta, Iztok Takač, Yuraima Garcia, Michael Green, Geneviève Jolimoy, Marcela Urrego, Chanyoot Bandidwattanawong, Vito Lorusso, Annette van der Velden, Rene Muñoz, Djumhana Atmakusuma, Christos Papandreou, Craig Macmillan, Hassan Errihani, Iris Schrader, Isabelle Desmoulins, Jean-Marc Ferrero, Mohamed Idris, B. Ataseven, Andre Farrokh, Isabelle Moullet, Iain R. Macpherson, N. Al-Sakaff, Stephen Chia, Blanca Hernando Fernandez De Aranguiz, Lorena Lion, Alexandros Ardavanis, Ani Zlatareva-Petrova, Ernesto Pablo Korbenfeld, Hugo Castro, Mirta Garcia, Heike Passmann-Kegel, Lionel Uwer, Gary Richardson, Marion Paul, Georgia Demetriou, Andreas Köhler, V. Kovcin, Eliot Sims, Gerasimos Aravantinos, Adriana Dominguez, Daniel Rauch, Greta Beyer, Laurence J. C. van Warmerdam, Roberto Bordonaro, Raymond Ng, David Coeffic, Rostislav Vyzula, Bernard Leduc, Jozef Mardiak, Andrea Pigi, Ingo Runnebaum, Jose Angel Garcia Saenz, Areewan Somwangprasert, Cristina Llorca Ferrandiz, Coskun Hasan Senol, Martin Griesshammer, Friedrich Overkamp, Suzanne Nguyen, Maria Turdean, Udaiveer Panwar, Zsuzsanna Nagy, Francesco Giotta, Andreas Schneeweiss, Teresa Ramon y Cajal Asensio, Jae Hong Seo, Joohyuk Sohn, Jean-Philippe Jacquin, Daniela Grecea, Jasmina Nedovic, Arrate Plazaola Alcibar, Tadeusz Pienkowski, Jetske M. Meerum Terwogt, Elmar Stickeler, Hazem I. Assi, Vadim Shirinkin, Grzegorz Slomian, Etela Mišurová, Roberto Hegg, K. Friedrichs, Corinne Dagada, Jean-François Berdah, Fulden Yumuk, Alexandru Eniu, Amit Chakrabarti, Mathias Fehr, Christoph Salat, Dan Lungulescu, Heinrik Martin Strebel, Antonio Llombart Cussac, Rémy Largillier, Stefan Curescu, Albert von der Assen, Emmanuel Guardiola, Andras Csejtei, Tamas Hickish, Krzysztof Krzemieniecki, Yaroslav Shparyk, Ramon Perez Carrion, Michela Donadio, Purificacion Martinez del Prado, Sandra Franco, J.J. Braun, Michael Friedlander, Suhail Anwar, Thierry Petit, Sarah Smith, Rafael Gutierrez Pilarte, Laia Garrigos Cubells, Frans L. G. Erdkamp, Jedzada Maneechavakajorn, Mastura Yusof, Jocelyn Adams, Diana Cascallar, Luis Antonio Fernandez Morales, Max S. Mano, Simon Waters, Carlos Beato, Philippe Martin, Martin Hogg, Isabelle Sillet Bach, Monica Casalnuovo, Klara Mezei, Alexey Manikhas, Margarida Damasceno, Sergey Emelyanov, Gabriella Mariani, Kecman Gordana, Gianfilippo Bertelli, Ignacio Pelaez Fernandez, Damir Vrbanec, Maria Wagnerova, Johannes Petrus Jordaan, Marina Cazzaniga, Mustafa Deryal, Ruth Davis, Abdurrahman Isikdogan, Sanjay Raj, José Juan Illarramendi Mañas, Vinod Ganju, Maria Dolores Torregrosa Maicas, Glenda Ramos, Nugroho Prayogo, H. Orfeuvre, Filipovic S, Joke Tio, Andrew Redfern, M. Shing, Eduardo Yanez, Khalil Zaman, Jin-Seok Ahn, Dino Amadori, Bahriye Aktas, Miriam O'Connor, Uta Ringsdorf, Christophe Desauw, J. Gligorov, Jorge Corona, Michele De Laurentiis, Arthur Wischnik, Paolo Pedrazzoli, Katalin Boér, Caroline Archer, Anne Kendall, Ori Freedman, Maya Tsakova, Dana Lucia Stanculeanu, Kevin Patterson, Cathy Kelly, Nellie Lay Chin Cheah, X. Artignan, Anil A. Joy, Steffi Busch, Monica Nave, Bryan Hennessy, Lorenzo Livi, X. Pivot, R.J.B. Blaisse, Adolfo Murias Rosales, Juan Carlos Alcedo, Dalila Marcano, Emmanuel Beguier, Andreas Müller, László Csaba Mangel, Christina Schlatter, Fernando Gaion, Tjoung-Won Park-Simon, Sebastian Wojcinski, Ute Bückner, Florinel Badulescu, Cynthia Mayte Villarreal Garza, Rozenn Allerton, Mikhail Lichinitser, Damir Gugić, Manuela Rabaglio, Jens Kisro, Iris Scheffen, Vincent Phua, Marc A. Bollet, Giampaolo Biti, M. Verrill, Adrien Melis, Andrew M Wardley, Ali Arican, Hamdy A. Azim, Lelia-Eveline Bauer, Tsai-Wang Chang, Nik Hauser, René Lazaro González Mendoza, Dominique Jaubert, Samreen Ahmed, Mazhar Shah, János Szántó, Kunibert Latos, Xavier Pivot, Helen Gogas, Elona Juozaityte, Luca Moscetti, Helene Simon, Giacomo Carterni, Dan-Corneliu Jinga, Olivia Pagani, Elena Rota Caremoli, Esther Arbona, Cornelia Liedtke, Stylianos Kakolyris, Abdulla Alhasso, Omalkhair Abulkhair, Jose Ponce Lorenzo, Julian Singer, Tony Branson, Claudia Hänle, Ingvild Mjaaland, Chiun-Sheng Huang, Heri Fadjari, Jonathan Joffe, Laetitia Stefani, Dieter Lampe, Franck Burki, S. Lauer, Sabine Schmatloch, Gracieux Fernando, Dina Sakaeva, Christina Balser, Michael Martin, Nora Bittner, Andrea Heider, Antonio Frassoldati, Serafin Morales Murillo, Hakan Akbulut, Saad Tahir, Tilmann Lantzsch, Christine Brezden-Masley, Vanessa Helena, Tran Van Thuan, F.E. de Jongh, Roger K.C. Ngan, Elke Faust, Hugues Bourgeois, Flora Li Tze Chong, Nehal Masood, Keun Seok Lee, J. Bishop, Mathias Warm, Dimitris Mavroudis, Petrosian Veersamy, Judith Fraser, Andres Garcia-Palomo Perez, Heiko Graf, Vanesa Quiroga Garcia, Jyh-Cherng Yu, Maria Jose Villanueva Silva, Elke Simon, Diana Aleman, Kazim Uygun, Cosima Brucker, Michael Weigel, Volkmar Müller, Djohan Kurnianda, Duncan Wheatley, Amr Abdel Aziz, Benno Lex, Laura G. Estévez, Darren Teoh, María Isabel León, Noemia Afonso, Frances Yuille, Amelia Tienghi, Gernot Seipelt, Jose Alberto Nogueira, Dumitru Filip, Zafar Malik, Fatima Cardoso, Giorgio Cruciani, Winnie Yeo, Luis Vera, Santiago Gonzalez Santiago, Richard North, M.W. Dercksen, Zsolt Horváth, Noelia Martinez Jañez, Marta Mion, Marcela Ferrari, Natalia Valdiviezo, Oana Zveltlana Cojocarasu, Alessandra Morelle, Medy Tsalic, Sonia Pernas Simon, Christoph Maintz, Daniele Farci, Alvaro Edson Lessa, Jeremy Monge, Joseph Gligorov, Anthony Neal, Norberto Batista Lopez, Piotr Tomczak, Yesim Eralp, Kasan Seetalarom, Thitiya (Sirisinha) Dejthevaporn, Jamal Zekri, Steven John Proctor, Saira Nasim, Muireann Kelleher, Eftal Yucel, Quirine Clementine van Rossum-Schornagel, Linda Coate, Paolo Marchetti, Theresa Howe, Carlos Alberto Hernandez, Roberto Torres, Konstanta Timcheva, Evaristo Maiello, Anita Prechtl, Jamil Asselah, Branislav Bystricky, Kate Scatchard, Zeba Aziz, Jaroslava Leskova, Sherko Kuemmel, Paolo Bidoli, Richard Ashford, Piotr Sawrycki, Claude Bressac, Alberto Bottini, Pilar Lopez Alvarez, Nadine Dohollou, Alejandro Andres Acevedo Gaete, M. De Laurentiis, T.J. Smilde, Andrew Proctor, Catherine Prady, Michele Aieta, Jan Henry Svensson, Reda Garidi, Erik Wist, Antonia Perello Martorell, Mohammed Jaloudi, Graeme Lumsden, Eva-Maria Grischke, Ali Youssef, Annemieke van der Padt, Kadri Altundag, Christina Bechtner, Mireille Mousseau, Heba El Zawahry, Maartje Los, Alvydas Česas, Alfredo Falcone, Salima Hamizi, Franchette W P J van den Berkmortel, Cesar Estuardo Hernandez-Monroy, K.H. Jung, Swati Kulkarni, R.K. Agrawal, Hwei Chung Wang, Hany Eldeeb, Fredrika Killander, Jose Luis Alonso Romero, Antonio Pazzola, Daan ten Bokkel Huinink, Mario Campone, Beena C.R. Devi, Florence Dalenc, Pedro Jimenez Gallego, Mawin Vongsaisuwon, Timur Ceric, Chantal Bernard Marty, R. A. Popescu, J. van den Bosch, Luis Matamala, Sylvia Ruth, Maria Litwiniuk, Maria Lomas Garrido, Mark Churn, Christian Kersten, Francesco Del Piano, Eddie Herman Tanggo, Antonio Fernandez Aramburo, Kyung Hae Jung, Christos Papadimitriou, Hamdy Abdel Azeem, Patricia Bastick, Tobias Hesse, Maree Colosimo, Lucia Gonzalez Cortijo, Mark Verrill, Gligorov, J, Ataseven, B, Verrill, M, De Laurentiis, M, Jung, K. H, Azim, H. A, Al-sakaff, N, Lauer, S, Shing, M, Pivot, X., de Laurentiis, M, Jung, K, Azim, H, Al-Sakaff, N, Pivot, X, Koroveshi, D, Bouzid, K, Casalnuovo, M, Cascallar, D, Korbenfeld, E, Bastick, P, Beith, J, Colosimo, M, Friedlander, M, Ganju, V, Green, M, Patterson, K, Redfern, A, Richardson, G, Ceric, T, Gordana, K, Beato, C, Ferrari, M, Hegg, R, Helena, V, Ismael, G, Lessa, A, Mano, M, Morelle, A, Nogueira, J, Timcheva, K, Tomova, A, Tsakova, M, Zlatareva-Petrova, A, Asselah, J, Assi, H, Brezden-Masley, C, Chia, S, Freedman, O, Harb, M, Joy, A, Kulkarni, S, Prady, C, Gaete, A, Matamala, L, Torres, R, Yanez, E, Franco, S, Urrego, M, Gugic, D, Vrbanec, D, Melichar, B, Prausova, J, Vyzula, R, Pilarte, R, Leon, M, Munoz, R, Ramos, G, Azeem, H, Aziz, A, El Zawahry, H, Osegueda, F, Alexandre, J, Artignan, X, Barletta, H, Beguier, E, Berdah, J, Marty, C, Bollet, M, Bourgeois, H, Bressac, C, Burki, F, Campone, M, Coeffic, D, Cojocarasu, O, Dagada, C, Dalenc, F, Del Piano, F, Desauw, C, Desmoulins, I, Dohollou, N, Egreteau, J, Ferrero, J, Foa, C, Garidi, R, Gasnault, L, Guardiola, E, Hamizi, S, Jarcau, R, Jacquin, J, Jaubert, D, Jolimoy, G, Mineur, H, Largillier, R, Leduc, B, Martin, P, Melis, A, Monge, J, Moullet, I, Mousseau, M, Nguyen, S, Orfeuvre, H, Petit, T, Priou, F, Bach, I, Simon, H, Stefani, L, Uwer, L, Youssef, A, Aktas, B, von der Assen, A, Augustin, D, Balser, C, Bauer, L, Bechtner, C, Beyer, G, Brucker, C, Buckner, U, Busch, S, Christensen, B, Deryal, M, Farrokh, A, Faust, E, Friedrichs, K, Graf, H, Griesshammer, M, Grischke, E, Hanle, C, Heider, A, Henschen, S, Hesse, T, Jackisch, C, Kisro, J, Kohler, A, Kuemmel, S, Lampe, D, Lantzsch, T, Latos, K, Lex, B, Liedtke, C, Luedders, D, Maintz, C, Muller, V, Overkamp, F, Park-Simon, T, Paul, M, Prechtl, A, Ringsdorf, U, Runnebaum, I, Ruth, S, Salat, C, Scheffen, I, Schilling, J, Schmatloch, S, Schmidt, M, Schneeweiss, A, Schrader, I, Seipelt, G, Simon, E, Stefek, A, Stickeler, E, Thill, M, Tio, J, Tuczek, A, Warm, M, Weigel, M, Wischnik, A, Wojcinski, S, Ziegler-Lohr, K, Aravantinos, G, Ardavanis, A, Fountzilas, G, Gogas, H, Kakolyris, S, Mavroudis, D, Papadimitriou, C, Papandreou, C, Papazisis, K, Castro, H, Hernandez-Monroy, C, Ngan, R, Yeo, W, Bittner, N, Boer, K, Csejtei, A, Horvath, Z, Kocsis, J, Mangel, L, Mezei, K, Nagy, Z, Szanto, J, Atmakusuma, D, Fadjari, H, Kurnianda, D, Prayogo, N, Tanggo, E, Coate, L, Hennessy, B, Kelly, C, Martin, M, Nasim, S, O'Connor, M, Aieta, M, Allegrini, G, Amadori, D, Bidoli, P, Biti, G, Bordonaro, R, Bottini, A, Carterni, G, Cavanna, L, Cazzaniga, M, Cognetti, F, Contu, A, Cruciani, G, Donadio, M, Falcone, A, Farci, D, Forcignano, R, Frassoldati, A, Gaion, F, Gamucci, T, Giotta, F, Livi, L, Lorusso, V, Maiello, E, Marchetti, P, Mariani, G, Mion, M, Moscetti, L, Musolino, A, Pazzola, A, Pedrazzoli, P, Pigi, A, de Placido, S, Caremoli, E, Santoro, A, Tienghi, A, Ahn, J, Lee, K, Lee, S, Seo, J, Sohn, J, Cesas, A, Juozaityte, E, Cheah, N, Chong, F, Devi, B, Phua, V, Teoh, D, Ching, L, Yusof, M, Corona, J, Dominguez, A, Mendoza, R, Hernandez, C, Ramiro, A, Santos, J, Espinosa, P, Villarreal Garza, C, Errihani, H, Bakker, S, van den Berkmortel, F, Blaisse, R, Huinink, D, van den Bosch, J, Braun, J, Dercksen, M, Droogendijk, H, Erdkamp, F, Haringhuizen, A, de Jongh, F, Kok, T, Los, M, Madretsma, S, Terwogt, J, van der Padt, A, van Rossum-Schornagel, Q, Smilde, T, de Valk, B, van der Velden, A, van Warmerdam, L, van de Wouw, A, North, R, Kersten, C, Mjaaland, I, Wist, E, Aziz, Z, Masood, N, Rashid, K, Shah, M, Alcedo, J, Aleman, D, Neciosup, S, Reategui, R, Valdiviezo, N, Vera, L, Fernando, G, Roque, F, Strebel, H, Krzemieniecki, K, Litwiniuk, M, Mruk, A, Pienkowski, T, Sawrycki, P, Slomian, G, Tomczak, P, Afonso, N, Cardoso, F, Damasceno, M, Nave, M, Badulescu, F, Ciule, L, Curescu, S, Eniu, A, Filip, D, Grecea, D, Jinga, D, Lungulescu, D, Oprean, C, Stanculeanu, D, Turdean, M, Dvornichenko, V, Emelyanov, S, Lichinitser, M, Manikhas, A, Sakaeva, D, Shirinkin, V, Stroyakovskiy, D, Abulkhair, O, Zekri, J, Filipovic, S, Kovcin, V, Nedovic, J, Pesic, J, Vasovic, S, Ng, R, Bystricky, B, Leskova, J, Mardiak, J, Misurova, E, Wagnerova, M, Takac, I, Demetriou, G, Dreosti, L, Govender, P, Jordaan, J, Veersamy, P, Romero, J, Lopez, N, Arias, C, Chacon, J, Aramburo, A, Morales, L, Garcia, M, Estevez, L, Garcia-Palomo Perez, A, Garcia Saenz, J, Garcia Sanchis, L, Cubells, L, Cortijo, L, Santiago, S, De Aranguiz, B, Manas, J, Gallego, P, Cussac, A, Ferrandiz, C, Garrido, M, Alvarez, P, Vega, J, Del Prado, P, Janez, N, Murillo, S, Rosales, A, Jaso, L, Fernandez, I, Martorell, A, Carrion, R, Simon, S, Alcibar, A, Lorenzo, J, Garcia, V, Asensio, T, Maicas, M, Villanueva Silva, M, Killander, F, Svensson, J, Fehr, M, Hauser, N, Muller, A, Pagani, O, Passmann-Kegel, H, Popescu, R, Rabaglio, M, Rauch, D, Schlatter, C, Zaman, K, Chang, T, Huang, C, Wang, H, Yu, J, Bandidwattanawong, C, Maneechavakajorn, J, Seetalarom, K, Dejthevaporn, T, Somwangprasert, A, Vongsaisuwon, M, Akbulut, H, Altundag, K, Arican, A, Bozcuk, H, Eralp, Y, Idris, M, Isikdogan, A, Senol, C, Sevinc, A, Uygun, K, Yucel, E, Yucel, I, Yumuk, F, Shparyk, Y, Voitko, N, Jaloudi, M, Adams, J, Agrawal, R, Ahmed, S, Alhasso, A, Allerton, R, Anwar, S, Archer, C, Ashford, R, Barraclough, L, Bertelli, G, Bishop, J, Branson, T, Butt, M, Chakrabarti, A, Chakraborti, P, Churn, M, Crowley, C, Davis, R, Dhadda, A, Eldeeb, H, Fraser, J, Hall, J, Hickish, T, Hogg, M, Howe, T, Joffe, J, Kelleher, M, Kelly, S, Kendall, A, Kristeleit, H, Lumsden, G, Macmillan, C, Macpherson, I, Malik, Z, Mithal, N, Neal, A, Panwar, U, Proctor, A, Proctor, S, Raj, S, Rehman, S, Sandri, I, Scatchard, K, Sherwin, E, Sims, E, Singer, J, Smith, S, Tahir, S, Taylor, W, Tsalic, M, Wardley, A, Waters, S, Wheatley, D, Wright, K, Yuille, F, Alonso, I, Artagaveytia, N, Rodriguez, R, Arbona, E, Garcia, Y, Lion, L, Marcano, D, and Van Thuan, T

Subjects
0301 basic medicine, Oncology, Cancer Research, Receptor, ErbB-2, medicine.medical_treatment, Medizin, Antineoplastic Agent, 0302 clinical medicine, Breast cancer, Trastuzumab, Adjuvant, Aged, 80 and over, education.field_of_study, Middle Aged, HER2/neu, Tolerability, Chemotherapy, Adjuvant, 030220 oncology & carcinogenesis, Herceptin, Subcutaneous, subcutaneous, Female, Survival Analysi, Breast Neoplasm, medicine.drug, Human, Adult, medicine.medical_specialty, Injections, Subcutaneous, Population, Socio-culturale, Antineoplastic Agents, Breast Neoplasms, Injections, Subcutaneou, 03 medical and health sciences, Young Adult, Internal medicine, medicine, Adjuvant therapy, Humans, Subcutaneou, education, Adverse effect, Aged, Chemotherapy, Adjuvant, breast cancer, HER2/neu, herceptin, trastuzumab, business.industry, medicine.disease, Survival Analysis, Surgery, Discontinuation, 030104 developmental biology, business
Abstract

Aim To assess the safety and tolerability of adjuvant subcutaneous trastuzumab (Herceptin ® SC, H SC), delivered from an H SC Vial via hand-held syringe (Cohort A) or single-use injection device (Cohort B), with or without chemotherapy, for human epidermal growth factor receptor 2 (HER2)-positive stage I to IIIC early breast cancer (EBC) in the phase III SafeHer study (NCT01566721). Methods Patients received 600 mg fixed-dose H SC every 3 weeks for 18 cycles. The chemotherapy partner was at the investigators' discretion (H SC monotherapy was limited to ≤10% of the population). Data from the first H SC dose until 28 days (plus a 5-day window) after the last dose are presented. Results are descriptive. Results In the overall population, 2282/2573 patients (88.7%) experienced adverse events (AEs). Of the above, 128 (5.0%) patients experienced AEs leading to study drug discontinuation; 596 (23.2%) experienced grade ≥ 3 AEs and 326 (12.7%) experienced serious AEs. Grade ≥ 3 cardiac disorders were reported in 24 patients (0.9%), including congestive heart failure in eight (0.3%). As expected, the AE rates varied according to the timing of chemotherapy in both cohorts, with higher rates in concurrent versus sequential chemotherapy subgroups. In the concurrent chemotherapy subgroup, AEs were more common during the actual period of concurrent chemotherapy compared with the period when patients did not receive concurrent chemotherapy. Conclusion SafeHer confirms the safety and tolerability of the H SC 600 mg fixed dose for 1 year (every 3 weeks for 18 cycles) as adjuvant therapy with concurrent or sequential chemotherapy for HER2-positive EBC. These primary analysis results are consistent with the known safety profile for intravenous H and H SC.

Published
2017

11. OC-0595: FAST-Forward phase 3 RCT of 1-week hypofractionated breast radiotherapy:3-year normal tissue effects

Author

A.M. Brunt, Rada Zotova, Duncan Wheatley, Anna M. Kirby, Joanne S Haviland, C. Chan, M. Wilcox, Cliona C. Kirwan, Adrian Harnett, Abdulla Alhasso, E. Sawyer, John Yarnold, Navita Somaiah, Andrew Goodman, C. Morris, Penelope Hopwood, Judith M Bliss, S. Cleator, M. Sydenham, Clare Griffin, Mark Churn, D. Bloomfield, C. Coles, M. Emson, and Isabel Syndikus

Subjects
0301 basic medicine, medicine.medical_specialty, business.industry, Phase (waves), Normal tissue, Breast radiotherapy, Hematology, law.invention, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Oncology, Randomized controlled trial, law, 030220 oncology & carcinogenesis, Medicine, Radiology, Nuclear Medicine and imaging, Radiology, business
Published
2018
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12. Synchronous Chemo-radiation Can Reduce Local Recurrence in Early Stage Breast Cancer: Results of the SECRAB Trial (ISRCTN: 84214355) Presented on Behalf of the SECRAB Steering Committee

Author

David Spooner, Sarah Bowden, A.M. Brunt, Peter Canney, I. N. Fernando, Robert Grieve, Cassandra Brookes, R.K. Agrawal, D.W. Rea, and Mark Churn

Subjects
Oncology, Cancer Research, medicine.medical_specialty, Breast cancer, business.industry, Internal medicine, Steering committee, medicine, Stage (cooking), business, medicine.disease, Chemo radiation
Published
2011
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13. Acute skin toxicity associated with a 1-week schedule of whole breast radiotherapy compared with a standard 3-week regimen delivered in the UK FAST-Forward Trial

Author

M. Sydenham, Amit Bahl, Navita Somaiah, Stephen Kelly, Duncan Wheatley, James P Morden, Andrew Goodman, John Yarnold, Clare Griffin, Adrian Harnett, Charlotte E. Coles, Rada Zotova, Mark Churn, A Murray Brunt, and Judith M Bliss

Subjects
medicine.medical_specialty, Pathology, medicine.medical_treatment, Phases of clinical research, Breast Neoplasms, Whole breast radiotherapy, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, Internal medicine, Clinical endpoint, Medicine, Humans, Radiology, Nuclear Medicine and imaging, Breast, Radiation Injuries, Skin, Radiotherapy, business.industry, Phase III randomised trial, Radiotherapy Dosage, Hematology, medicine.disease, R1, Radiation therapy, Regimen, Skin toxicity, Oncology, Radiology Nuclear Medicine and imaging, 030220 oncology & carcinogenesis, Toxicity, Hypofractionation, Female, Radiodermatitis, business
Abstract

Background and purposeFAST-Forward is a phase 3 clinical trial testing a 1-week course of whole breast radiotherapy against the UK standard 3-week regimen after primary surgery for early breast cancer. Two acute skin toxicity substudies were undertaken to test the safety of the test schedules with respect to early skin reactions.Material and methodsPatients were randomly allocated to 40 Gy/15 fractions (F)/3-weeks, 27 Gy/5F/1-week or 26 Gy/5F/1-week. Acute breast skin reactions were graded using RTOG (first substudy) and CTCAE criteria v4.03 (second substudy) weekly during treatment and for 4 weeks after treatment ended. Primary endpoint was the proportion of patients within each treatment group with grade ⩾3 toxicity (RTOG and CTCAE, respectively) at any time from the start of radiotherapy to 4 weeks after completion.Results190 and 162 patients were recruited. In the first substudy, evaluable patients with grade 3 RTOG toxicity were: 40 Gy/15F 6/44 (13.6%); 27 Gy/5F 5/51 (9.8%); 26 Gy/5F 3/52 (5.8%). In the second substudy, evaluable patients with grade 3 CTCAE toxicity were: 40 Gy/15F 0/43; 27 Gy/5F 1/41 (2.4%); 26 Gy/5F 0/53.ConclusionsAcute breast skin reactions with two 1-week schedules of whole breast radiotherapy under test in FAST-Forward were mild.

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