Status: Open
Specialty: Prostate/ gastro-oesophageal
Date Opened: 23/10/2015
Planned Close Date: 31/10/2023
Sponsor: Cancer Research UK/ Royal Marsden
Principal Investigator: Dr Lau
Study Title: Add Aspirin
Background: Cancer is a global problem. There is significant pre-clinical and epidemiological evidence demonstrating that aspirin has anti-cancer effects. Recently, individual patient data meta-analyses, from trials designed to assess cardiovascular benefits of aspirin, have shown reductions in cancer incidence and mortality associated with regular aspirin use. Additionally, the CAPP2 trial has demonstrated that daily aspirin prevents cancers associated with the Lynch syndrome.
In the meta-analyses, short-term effects on cancer mortality and a decrease in risk of metastases suggest a role for aspirin in the treatment as well as prevention of cancer. This is supported by several large observational datasets. Concerns over toxicity, particularly serious haemorrhage, have limited the use of aspirin in the primary prevention of cancer. In the adjuvant setting the benefit:risk ratio will be different, with higher morbidity and mortality from recurrent cancer potentially outweighing risks associated with regular aspirin use.
Aim: To assess whether regular aspirin use after standard therapy prevents recurrence and prolongs survival in patients with early stage common solid tumours. International recruitment will allow assessment of the intervention in different communities.
Methods: The question will be addressed in four tumour sites (colorectal, breast, gastrooesophageal, prostate) using parallel trials with a common infrastructure. Each trial will be a multicentre, phase III, double-blind, placebo-controlled randomised trial. Participants will be randomised to 100mg aspirin, 300mg aspirin or a matching placebo, to be taken daily for 5 years.
Primary outcomes will depend on tumour site and trials will be separately powered, requiring 2000-3000 patients with each tumour type to demonstrate effects of aspirin on disease recurrence and survival. Secondary outcomes include overall survival, adherence, gastrointestinal complications and cardiovascular events.
COMMON INCLUSION CRITERIA
1. Written informed consent
2. WHO performance status 0, 1 or 2
3. Previous or current participants of other primary treatment trials if agreed in advance between trials
4. No clinical or radiological evidence of residual or distant disease
BREAST COHORT INCLUSION CRITERIA
1. Men or women with histologically confirmed invasive breast cancer
2. Undergone complete primary invasive tumour excision with clear margins
3. Surgical staging of the axilla must have been undertaken by sentinel node biopsy, axillary sampling or dissection
4. In those patients with a positive sentinel node biopsy:
a. If 1, 2 or 3 nodes are positive, subsequent management of the axilla (with surgery, radiotherapy or no further
intervention) should be completed prior to registration
b. If 4 or more nodes are involved, patients must have undergone completion axillary node dissection
5. Radiotherapy (RT)
a. Patients who have undergone breastconserving
surgery should receive adjuvant RT
b. Patients who have undergone mastectomy should receive RT if they have more than 3 axillary lymph nodes involved
c. Patients who have undergone mastectomy and have T3 tumours and/or 1, 2 or 3 involved lymph nodes may (or not)
receive radiation per institutional practice
6. Final histology must fall within at least one of these 3 groups:
a. Node positive
b. Node negative with highrisk
features 2
or more of:
i. ER negative
ii. HER2 positive
iii. Grade 3
iv. Lymphovascular invasion present
v. Age <35
vi. Oncotype Dx score of >25
c. In patients who have received neoadjuvant
chemotherapy, patients are eligible if they have both a hormone receptor
negative/HER2 negative tumour, a HER2 positive tumour or a hormone receptor positive grade 3 tumour and did not achieve a pathological complete response with neoadjuvant systemic therapy
7. Patients who received standard neoadjuvant
and/or adjuvant chemotherapy or RT are eligible.
8. Known HER2 and ER status
9. Participants may receive endocrine therapy and trastuzumab. All ER positive patients should be planned to undergo
at least 5 yrs of adjuvant endocrine therapy
COLORECTAL COHORT INCLUSION CRITERIA
1. Histologically confirmed stage II or III adenocarcinoma of the colon or rectum and patients who have undergone
resection of liver metastases with clear margins and no residual metastatic disease
2. Patients with synchronous tumours if one of the tumours is at least stage II or III
3. Serum CEA ideally ≤1.5 x upper limit of normal
4. Have undergone curative (R0) resection with clear margins
GASTROOESOPHAGEAL
COHORT INCLUSION CRITERIA
1. Patients with histologically confirmed adenocarcinoma, adenosquamous carcinoma or squamous cell cancer of the
oesophagus, gastrooesophageal
junction or stomach
2. Have undergone curative (R0) resection with clear margins or primary chemoRT given with curative intent
PROSTATE COHORT INCLUSION CRITERIA
1. Men with histologically confirmed node negative nonmetastatic
adenocarcinoma of the prostate
2. Have undergone curative treatment, either:
a. Radical prostatectomy
b. Radical RT
c. Salvage RT (following rise in PSA after prostatectomy)
3. Intermediate or high risk according to D’Amico classification
Treatment pathway specific inclusion criteria:
(a) Prostatectomy patients
4. Open, laparoscopic or robotic radical prostatectomy
5. Men treated with immediate adjuvant RT
6. Men receiving adjuvant hormone therapy planned for a maximum duration of 3 yrs
7. Men randomised to any of the 3 arms of RADICALS HD are eligible
(b) Radical RT patients
9. Men receiving neoadjuvant
and/or adjuvant hormone therapy planned for a
maximum duration of 3yrs
(c) Salvage RT patients following PSA rise after previous radical prostatectomy
13. Men treated with salvage RT following a rise in PSA are eligible
14. Men receiving neoand/
or adjuvant hormone therapy planned for a maximum of
3yrs
15. Men randomised to any of the 3 arms of RADICALS HD are eligible
Participants must not meet any of the common or their tumourspecific
exclusion criteria.
COMMON EXCLUSION CRITERIA
1. Current or previous regular use of aspirin (at any dose) or current use of another NSAID for any indication.
2. A past history of adverse reaction or hypersensitivity to NSAIDs, celecoxib, aspirin or other salicylates or
sulphonamides, including asthma, that is exacerbated by use of NSAIDs.
3. Current use of anticoagulants.
4. Current or longterm
use of oral corticosteroids. The treating physician should make the clinical decision whether a
patient has been exposed to longterm
therapy.
5. Active or previous peptic ulceration or gastrointestinal bleeding within the last year, except where the cause of
bleeding has been surgically removed.
7. Active or previous history of inflammatory bowel disease.
8. History of moderate or severe renal impairment, with eGFR<45ml/min/1.73m2.
9. Previous invasive or noninvasive
malignancy except:
DCIS
where treatment consisted of resection alone.
Prostate
cancer initially treated with prostatectomy and now being treated with salvage radiotherapy following a rise in
PSA.
Cervical
carcinoma in situ where treatment consisted of resection alone.
Basal
cell carcinoma where treatment consisted of resection alone or radiotherapy.
Superficial
bladder carcinoma where treatment consisted of resection alone.
Other
cancers where the patient has been diseasefree
for ≥15 years.
10. Any other physical condition which is associated with increased risk of aspirinrelated
morbidity or, in the opinion of
the Investigator, makes the patient unsuitable for the trial, including but not limited to severe asthma, haemophilia and other bleeding diatheses, macular degeneration and patients with a highrisk
of mortality from another cause within
the trial treatment period.
11. Known glucose6phosphate
dehydrogenase deficiency.
12. Known lactose intolerance
13. LFTs greater than 1.5x the upper limit of normal unless agreed with TMG.
14. Anticipated difficulties in complying with trial treatment or followup
schedules.
15. <16 years old.
16. Participants in other treatment trials where this has not been agreed in advance by both trial teams.
17. Pregnant or breast feeding, or intending to become pregnant or breast feed during the trial treatment period.
BREAST COHORT EXCLUSION CRITERIA
1. Metastatic or bilateral breast cancer.
COLORECTAL COHORT EXCLUSION CRITERIA
1. Proven (or clinically suspected) metastatic disease (patients who have undergone resection of liver metastases with
clear margins and no residual metastatic disease are eligible).
GASTROOESOPHAGEAL
COHORT EXCLUSION CRITERIA
1. Proven (or clinically suspected) metastatic disease.
PROSTATE COHORT PARTICIPANT CRITERIA
1. Biopsy proven or radiologically suspected nodal involvement, or distant metastases from prostate cancer.
2. Adjuvant hormone therapy planned for >3 years.
3. Bilateral orchidectomy.
Research Nurse: Emma Davies (Tel/Ext. No) emma.davies16@nhs.net
Administrator: Arun Prakash
Link to EDGE