The Role of Aspirin Following Treatment for Early Stage Gastro- Oesophageal Cancer: Adherence and Tolerability Data from the Add-Aspirin Trial AUGIS 21 st Annual Scientific Conference Thursday 20th September 2018 Professor Tim Underwood
Rationale for the trial • Possible therapeutic role for several of the most common cancers • Low cost, generic drug, available worldwide • Accessible in lower resource settings (unlike many new agents or complex regimens) • Generally safe with known side effects • Potential for huge global impact • Evidence of a therapeutic effect in Gastro-oesophageal cohort, where outcomes are poor Aim: to assess whether regular aspirin use following primary treatment for an early stage common cancer can prevent recurrence and prolong survival
Aspirin & Primary Prevention of Cancer Cancer/Study No of Studies No of Cases RR (95% CI) Colorectal Cancer Case-control 15 21,414 0.63 (0.56-0.70) Cohort 15 16,105 0.82 (0.75-0.89) Overall 30 37,519 0.73 (0.67-0.79) Gastric Cancer Case-control 7 2411 0.60 (0.44-0.82) Cohort 6 2108 0.77 (0.58-1.04) Overall 13 4519 0.67 (0.54-0.83) Breast Cancer Case-control 10 28.835 0.83 (0.76-0.91) Cohort 22 27,091 0.93 (0.87-1.00) Overall 32 52.926 0.90 (0.85-0.95) Prostate Cancer Case-control 9 5795 0.87 (0.74-1.02) Cohort 15 31,657 0.91 (0.85-0.97) Overall 24 37,452 0.90 (0.85- 0.96) Bosetti et al. Annals of Oncology 2012
Randomised vascular trials • A major part of the evidence base relating to aspirin and cancer has emerged from RCT’s designed to evaluate the vascular effect of aspirin. (Rothwell, Lancet 2010, 2011, 2012) • 51 randomised trials with ~77,000 participants • Decreased incidence cancer HR 0.81 (0.7-0.93) Rx > 5yrs and reduced cancer deaths by ~ 15% particularly adenocarcinomas of gastrointestinal tract • Reduction in cancer mortality seen by 3 years suggesting potential use in the treatment of cancer, as well as for primary prevention
Randomised vascular trials Comparison of the effect of aspirin on cancer risk from case-control and randomised trials. (Algra, Lancet 2012 )
Effect of aspirin on metastasis Cancer with no metastasis at Cancer with metastasis at presentation in which metastasis presentation developed on follow-up Rothwell, Lancet 2012
Adjuvant setting: non-randomised data for the use of aspirin Tumour Study/Year No of cases Result (in favour of aspirin) CRC-specific mortality: HR 0.71 (0.53-0.95) Chan 2009 1279 All-cause mortality: HR 0.79 (0.65-0.97) CRC-specific mortality: HR 0.53 (0.50-0.57) Colorectal Bains 2015 25644 All-cause mortality: HR 0.71 (0.68-0.75) CRC-specific mortality: HR 0.58 (0.45-0.75) McCowan 2013 2990 All-cause mortality: HR 0.67 (0.57-0.79) BC mortality: RR=0.36 (0.24 – 0.65) Holmes 2010 4164 Overall Survival: RR=0.54 (0.41 - 0.70) Breast All-cause mortality: HR=0.53 (0.45 – 0.63) Fraser 2014 4627 BC mortality: HR=0.42 (0.31 – 0.55) 5 year Overall Survival Liu 2009 1716 Aspirin 51.2%, placebo 41%, no tablet 42.3% Gastro- Staalduinen 2016 560 OS adjusted RR=0.42 (0.30-0.57) oesophageal OG-specific survival: HR 0.45 in oesophageal Frouws 2017 1696 HR 0.87 in gastric cancer Reduced interval to biochemical failure Zaorsky 2012 2051 OR=2.05 (1.33 – 3.17) Aspirin non-use Prostate PC mortality: HR=0.43 (0.21 – 0.87) Choe 2012 5955 PC mortality: HR=0.60 (0.37 – 0.97) Jacobs 2014 8427
Serious haemorrhage Aspirin increases bleeding risk, however this increase is small Estimated risk* in Estimated risk* Bleeding site control group on aspirin Serious bleeding** 0.07% 0.1% gastrointestinal or other per year per year extracranial site 0.03% 0.04% Intracranial bleed per year per year Antithrombotic Trialists Collaboration (ATTC) meta-analysis ~ 95,000 participants, (mean age 56 years, 46% men) **Serious bleeding = hospital admission or blood transfusion
Trial design of Add-Aspirin
Gastro-oesophageal Cohort Participant Treatment Pathway Online Standard Timing of Randomised registration therapy entry by phone for run-in Surgery + ≥6 weeks of adjuvant CT adjuvant CT* and (+/- neo- ≤8 weeks from adjuvant end of CT therapy) FOLLOW- RUN-IN UP RANDOMISED Surgery 100mg 6-14 weeks after TREATMENT 5 years + (+/- neo- aspirin long-term (BLIND) surgery adjuvant f/up daily for 8 daily for 5 years therapy) through weeks registries After completion of CRT and ≤14 weeks after CRT Primary (or ≤16 weeks after CRT CRT where a patient has an endoscopy) Patients can be approached and consented prior to the registration window * with platelet count >100 x 10 9 /L on day 1 of each preceding cycle CT= Chemotherapy, RT= Radiotherapy, CRT= Chemoradiotherapy
Data from Run-in Period Gastro-oesophageal cohort baseline characteristics n % Total registered 106 Registration data available 81 n % Primary therapy Gender Surgery 68 84% Male 66 81% Chemoradiotherapy 13 16% Female 15 19% PARTICIPANTS UNDERGOING SURGERY ONLY Age at registration n 81 Surgical procedure Median (IQR) 64 (57 - 70) n 68 Range 23 - 78 Transhiatal oesophagectomy 3 4% Transthoracic oesophagectomy 12 18% Oesophagogastrectomy 21 31% Histology Total gastrectomy 7 10% Adenocarcinoma 67 83% Sub-total gastrectomy 8 12% Squamous 14 17% Other 16 24% Tumour stage Treatment in addition to surgery T0 4 5% n 68 T1 15 19% Neo-adjuvant chemotherapy 53 T2 8 10% Neo-adjuvant chemoradiotherapy 5 T3 43 53% Adjuvant chemotherapy 35 T4 10 12% TOTAL 81 Nodal stage N0 33 41% N1 21 26% N2 20 25% N3 6 7%
Data from Run-in Period (Between Oct 2015-2017, 3494 registered; n=2253 with end of run-in data) – 85% proceeded from run-in period to randomisation - very similar across all cohorts and close to what was expected (90%) • Reasons for not proceeding often multi-factorial – main reasons minor toxicity and participant choice • Most common grade 1/2 toxicities were low-grade dyspepsia and bruising • 13/2253 (0.6%) participants had grade 3 toxicities; 1 grade 4 (lower GI bleed in prostate patient). No grade ≥ 3 upper GI bleeds • Only 1 grade ≥ 3 toxicity in OG cohort = oesophageal pain • Adherence generally very good across all cohorts – 2148/2253 (95%) taking 6-7 tablets per week
Conclusion • Aspirin acceptable and well-tolerated after radical treatment for common solid tumours • Toxicity is low • Bleeding events are rare • Recruitment to Add-Aspirin has exceeded 5500 participants in the UK and India • Soon to open in Ireland
100 200 300 400 500 600 700 1000 1500 2000 2500 3000 500 0 0 Oct-15 Oct… Dec-15 Dec… Feb-16 Cumulative registrations Feb… Cumulative registrations Apr-16 Apr… Jun-16 Gastro-oesophageal cohort Jun… Aug-16 Aug… Oct-16 Oct… Breast cohort Recruitment (August 2018) Dec-16 Dec… Feb-17 Feb… Apr-17 Apr… Jun-17 Jun… Aug-17 Aug… Cumulative registrations vs targets Oct-17 Oct… Dec-17 Dec… Feb… Feb-18 Apr… Apr-18 Jun… Jun-18 Aug… Aug-18 1000 1200 1400 1000 1500 2000 2500 200 400 600 800 500 0 0 Oct-15 Oct-15 Dec-15 Dec-15 Current Targets (from Oct15) Cumulative registrations Feb-16 Feb-16 Cumulative registrations Apr-16 Apr-16 Jun-16 Jun-16 Aug-16 Aug-16 Colorectal cohort Prostate cohort Oct-16 Oct-16 Dec-16 Dec-16 Feb-17 Feb-17 Apr-17 Apr-17 Jun-17 Jun-17 Aug-17 Aug-17 Oct-17 Oct-17 Dec-17 Dec-17 Feb-18 Feb-18 Apr-18 Apr-18 Jun-18 Jun-18 Aug-18 Aug-18
Add-Aspirin Trial Group MRC CTU Prostate Cancer Participant Representatives Lindy Berkman, Mairead Mackenzie, Professor Max Parmar Professor Howard Kynaston Prof Ruth Langley Mr Paul Cathcart Arnold Goldman, Sue Campbell, Dr Fay Cafferty Dr Duncan Gilbert Yvonne Carse, Vandana Gupta Dr Nalinie Joharatnam, Translational Group Chair Lynda Harper, Gemma Wood, Alex Gastro-oesophageal Cancer Professor David Cameron Robbins, Tessa Dibble Professor Janusz Jankowski Dr Richard Hubner Funders: India Cancer Research UK Professor Anne Thomas NIHR HTA Professor CS Pramesh Mr Tim Underwood Dr Sudeep Gupta (Breast cancer) Professor John Bridgewater Dr Durga Gadgil Aspirin Breast Cancer Professor Peter Rothwell Dr Alistair Ring Professor Sir John Burn Professor David Cameron Professor Carlo Patrono Dr Louise Bowman Colorectal Cancer Dr Geoffrey Venning Professor Richard Wilson Professor Bob Steele Cardiologist Professor Tim Iveson Dr David Adlam Dr Dan Swinson Miss Farhat Din
Disclosures/ Funding • The trial is being jointly funded by – Cancer Research UK (grant number C471 /A15015) – The National Institute for Health Research Health Technology Assessment Programme (project number 12/01/38) – The MRC Clinical Trials Unit at UCL. • In India, the Sir Dorabji Tata Trust provides funding. • Bayer Pharmaceuticals AG is providing aspirin and placebos The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health.
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