The Role of Aspirin Following Treatment for Early … › media › 1373 › 2018_augis-oral...The Role of Aspirin Following Treatment for Early Stage Gastro-Oesophageal Cancer: Adherence

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 1279CRC-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 4164BC mortality: RR=0.36 (0.24 – 0.65)

Overall Survival: RR=0.54 (0.41 - 0.70)

Fraser 2014 4627All-cause mortality: HR=0.53 (0.45 – 0.63)

BC mortality: HR=0.42 (0.31 – 0.55)

Gastro-

oesophageal

Liu 2009 17165 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 1696OG-specific survival: HR 0.45 in oesophageal

HR 0.87 in gastric cancer

Prostate

Zaorsky 2012 2051Reduced 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 siteEstimated risk* in

control group

Estimated risk*

on aspirin

Serious bleeding**

gastrointestinal or other

extracranial site

0.07%

per year

0.1%

per year

Intracranial bleed0.03%

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 proceduren 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 surgeryn 68 Neo-adjuvant chemotherapy 53 Neo-adjuvant chemoradiotherapy 5 Adjuvant chemotherapy 35

TOTAL 81

n %

Total registered 106 Registration data available 81

GenderMale 66 81%Female 15 19%

Age at registrationn 81Median (IQR) 64 (57 - 70)Range 23 - 78

HistologyAdenocarcinoma 67 83%Squamous 14 17%

Tumour stageT0 4 5%T1 15 19%T2 8 10%T3 43 53%T4 10 12%

Nodal stageN0 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 radicaltreatment for common solid tumours

• Toxicity is low

• Bleeding events are rare

• Recruitment to Add-Aspirin has exceeded 5500participants in the UK and India

• Soon to open in Ireland

Recruitment (August 2018)

Cumulative registrations vs targets

0

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

0

500

1000

1500

2000

2500

Oct-

15

De

c-1

5

Feb

-16

Apr-

16

Jun-1

6

Aug-1

6

Oct-

16

De

c-1

6

Feb

-17

Apr-

17

Jun-1

7

Aug-1

7

Oct-

17

De

c-1

7

Feb

-18

Apr-

18

Jun-1

8

Aug-1

8

Colorectal cohort

Cumulative registrations

0

100

200

300

400

500

600

700

Oct-

15

De

c-1

5

Feb

-16

Apr-

16

Jun-1

6

Aug-1

6

Oct-

16

De

c-1

6

Feb

-17

Apr-

17

Jun-1

7

Aug-1

7

Oct-

17

De

c-1

7

Feb

-18

Apr-

18

Jun-1

8

Aug-1

8Gastro-oesophageal cohort

Cumulative registrations

0

200

400

600

800

1000

1200

1400

Oct-

15

De

c-1

5

Feb

-16

Apr-

16

Jun-1

6

Aug-1

6

Oct-

16

De

c-1

6

Feb

-17

Apr-

17

Jun-1

7

Aug-1

7

Oct-

17

De

c-1

7

Feb

-18

Apr-

18

Jun-1

8

Aug-1

8

Prostate cohort

Cumulative registrations

Current Targets (from Oct15)

Add-Aspirin Trial Group

MRC CTUProfessor Max ParmarProf Ruth LangleyDr Fay CaffertyDr Nalinie Joharatnam,Lynda Harper, Gemma Wood, Alex

Robbins, Tessa Dibble

IndiaProfessor CS Pramesh Dr Sudeep Gupta (Breast cancer)Dr Durga Gadgil

Breast CancerDr Alistair RingProfessor David Cameron

Colorectal CancerProfessor Richard WilsonProfessor Bob SteeleProfessor Tim IvesonDr Dan SwinsonMiss Farhat Din

Prostate CancerProfessor Howard KynastonMr Paul CathcartDr Duncan Gilbert

Gastro-oesophageal CancerProfessor Janusz JankowskiDr Richard HubnerProfessor Anne Thomas Mr Tim UnderwoodProfessor John Bridgewater

AspirinProfessor Peter RothwellProfessor Sir John Burn Professor Carlo PatronoDr Louise BowmanDr Geoffrey Venning

CardiologistDr David Adlam

Participant RepresentativesLindy Berkman, Mairead Mackenzie, Arnold Goldman, Sue Campbell, Yvonne Carse, Vandana Gupta

Translational Group ChairProfessor David Cameron

Funders: Cancer Research UKNIHR HTA

Disclosures/ Funding

• The trial is being jointly funded by

– Cancer Research UK (grant number C471 /A15015)

– The National Institute for Health Research Health TechnologyAssessment 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 necessarilythose of the NHS, the NIHR or the Department of Health.