Treatment for Early Stage Gastro- Oesophageal Cancer: Adherence and - - PowerPoint PPT Presentation

The Role of Aspirin Following Treatment for Early Stage Gastro- Oesophageal Cancer: Adherence and Tolerability Data from the Add-Aspirin Trial

AUGIS 21st 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

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)

Aspirin & Primary Prevention of Cancer

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 metastasis at presentation Cancer with no metastasis at presentation in which metastasis 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) Colorectal Chan 2009 1279 CRC-specific mortality: HR 0.71 (0.53-0.95) All-cause mortality: HR 0.79 (0.65-0.97) Bains 2015 25644 CRC-specific mortality: HR 0.53 (0.50-0.57) All-cause mortality: HR 0.71 (0.68-0.75) McCowan 2013 2990 CRC-specific mortality: HR 0.58 (0.45-0.75) All-cause mortality: HR 0.67 (0.57-0.79) Breast Holmes 2010 4164 BC mortality: RR=0.36 (0.24 – 0.65) Overall Survival: RR=0.54 (0.41 - 0.70) Fraser 2014 4627 All-cause mortality: HR=0.53 (0.45 – 0.63) BC mortality: HR=0.42 (0.31 – 0.55) Gastro-

• esophageal

Liu 2009 1716 5 year Overall Survival Aspirin 51.2%, placebo 41%, no tablet 42.3% Staalduinen 2016 560 OS adjusted RR=0.42 (0.30-0.57) Frouws 2017 1696 OG-specific survival: HR 0.45 in oesophageal HR 0.87 in gastric cancer Prostate Zaorsky 2012 2051 Reduced interval to biochemical failure Aspirin non-use OR=2.05 (1.33 – 3.17) Choe 2012 5955 PC mortality: HR=0.43 (0.21 – 0.87) Jacobs 2014 8427 PC mortality: HR=0.60 (0.37 – 0.97)

Serious haemorrhage

Aspirin increases bleeding risk, however this increase is small

Antithrombotic Trialists Collaboration (ATTC) meta-analysis ~95,000 participants, (mean age 56 years, 46% men) **Serious bleeding = hospital admission or blood transfusion

Bleeding site Estimated risk* in control group Estimated risk*

• n aspirin

Serious bleeding** gastrointestinal or other extracranial site 0.07% per year 0.1% per year Intracranial bleed 0.03% per year 0.04% per year

Trial design of Add-Aspirin

Primary CRT

After completion of CRT and ≤14 weeks after CRT (or ≤16 weeks after CRT where a patient has an endoscopy)

Surgery + adjuvant CT (+/- neo- adjuvant therapy) ≥6 weeks of adjuvant CT* and ≤8 weeks from end of CT Surgery (+/- neo- adjuvant therapy) 6-14 weeks after surgery

RUN-IN 100mg aspirin daily for 8 weeks RANDOMISED TREATMENT (BLIND) daily for 5 years

FOLLOW- UP 5 years + long-term f/up through registries

Online registration for run-in Randomised by phone

Gastro-oesophageal Cohort Participant Treatment Pathway

Patients can be approached and consented prior to the registration window

* with platelet count >100 x 109/L on day 1 of each preceding cycle

Standard therapy Timing of entry

CT= Chemotherapy, RT= Radiotherapy, CRT= Chemoradiotherapy

Data from Run-in Period

Gastro-oesophageal cohort baseline characteristics

n % Primary therapy Surgery 68 84% Chemoradiotherapy 13 16% PARTICIPANTS UNDERGOING SURGERY ONLY Surgical procedure n 68 Transhiatal oesophagectomy 3 4% Transthoracic oesophagectomy 12 18% Oesophagogastrectomy 21 31% Total gastrectomy 7 10% Sub-total gastrectomy 8 12% Other 16 24% Treatment in addition to surgery n 68 Neo-adjuvant chemotherapy 53 Neo-adjuvant chemoradiotherapy 5 Adjuvant chemotherapy 35 TOTAL 81 n % Total registered 106 Registration data available 81 Gender Male 66 81% Female 15 19% Age at registration n 81 Median (IQR) 64 (57 - 70) Range 23 - 78 Histology Adenocarcinoma 67 83% Squamous 14 17% Tumour stage T0 4 5% T1 15 19% T2 8 10% T3 43 53% T4 10 12% 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

Recruitment (August 2018)

Cumulative registrations vs targets

500 1000 1500 2000 2500 3000 Oct… Dec… Feb… Apr… Jun… Aug… Oct… Dec… Feb… Apr… Jun… Aug… Oct… Dec… Feb… Apr… Jun… Aug…

Breast cohort

Cumulative registrations

500 1000 1500 2000 2500 Oct-15 Dec-15 Feb-16 Apr-16 Jun-16 Aug-16 Oct-16 Dec-16 Feb-17 Apr-17 Jun-17 Aug-17 Oct-17 Dec-17 Feb-18 Apr-18 Jun-18 Aug-18

Colorectal cohort

Cumulative registrations

100 200 300 400 500 600 700 Oct-15 Dec-15 Feb-16 Apr-16 Jun-16 Aug-16 Oct-16 Dec-16 Feb-17 Apr-17 Jun-17 Aug-17 Oct-17 Dec-17 Feb-18 Apr-18 Jun-18 Aug-18

Gastro-oesophageal cohort

Cumulative registrations

200 400 600 800 1000 1200 1400 Oct-15 Dec-15 Feb-16 Apr-16 Jun-16 Aug-16 Oct-16 Dec-16 Feb-17 Apr-17 Jun-17 Aug-17 Oct-17 Dec-17 Feb-18 Apr-18 Jun-18 Aug-18

Prostate cohort

Cumulative registrations Current Targets (from Oct15)

Add-Aspirin Trial Group

MRC CTU Professor Max Parmar Prof Ruth Langley Dr Fay Cafferty Dr Nalinie Joharatnam, Lynda Harper, Gemma Wood, Alex Robbins, Tessa Dibble India Professor CS Pramesh Dr Sudeep Gupta (Breast cancer) Dr Durga Gadgil Breast Cancer Dr Alistair Ring Professor David Cameron Colorectal Cancer Professor Richard Wilson Professor Bob Steele Professor Tim Iveson Dr Dan Swinson Miss Farhat Din Prostate Cancer Professor Howard Kynaston Mr Paul Cathcart Dr Duncan Gilbert Gastro-oesophageal Cancer Professor Janusz Jankowski Dr Richard Hubner Professor Anne Thomas Mr Tim Underwood Professor John Bridgewater Aspirin Professor Peter Rothwell Professor Sir John Burn Professor Carlo Patrono Dr Louise Bowman Dr Geoffrey Venning Cardiologist Dr David Adlam Participant Representatives Lindy Berkman, Mairead Mackenzie, Arnold Goldman, Sue Campbell, Yvonne Carse, Vandana Gupta Translational Group Chair Professor David Cameron Funders: Cancer Research UK NIHR HTA

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.