Aspirin and Cancer Recent Developments

Transcription

1 Recent Developments ICPV Brighton Conference 7 th September 2012 Alistair Ring Brighton and Sussex Medical School

2 Bowel cancer death risks slashed by taking an aspirin a day. The Mirror 25 th April Aspirin may be the breakthrough in war on lung cancer. Daily Mail May Why a daily aspirin could have saved Bee Gee Robin: Breakthrough for families living with 'death sentence' bowel cancer gene. Daily Mail 2 nd June Aspirin a day slashed the risk of breast cancer. The Sun 24 th March 2010.

3 Aspirin: mechanisms of action Langley et al, BJC 2011; 105,

4 First Anti-Cancer Effects Group Treatment Tumour No. of lung metastases* mean±s.e 1 Control MCA2 245±13 2 ASA, 6 days MCA2 143±12 < Control T241 24±3 4 ASA, 13 days T241 17±3 <0.2 5 Control T241 24±5 6 ASA, 13 days T241 9±2 <0.01 p ASA = Aspirin *Metastases of groups 1-4 induced by intravenous injection of tumour cells; metastases in groups 5 and 6 occur spontaneously Gasic et al. Lancet Oct 28;2(7783):932-3

5 Recent Developments Primary prevention (cardiovascular studies) Primary prevention (in high risk groups) Secondary prevention (aspirin following a diagnosis of cancer)

6 Primary prevention (cardiovascular studies) Pooled analysis of effect of allocation to aspirin on incidence of cancer during 6 randomised trials of daily low dose aspirin versus placebo in primary prevention of vascular events Rothwell et al, Lancet 2012.

7 Primary prevention (cardiovascular studies) Effect of daily aspirin on risk of cancer metastasis The effect of aspirin on risk of metastases due to any incident cancer diagnosed during five trials of aspirin versus control. (BDAT, UKTIA, TPT, POPADAD, AAA) Rothwell et al. Lancet 2012

8 Primary prevention (cardiovascular studies) 987 new solid cancers Aspirin all cancers with distant metastases HR 0.64 (95% CI ) p=0.001 (more marked for adenocarcinoma) metastases at all sites excl. bone Independent of dose metastases at diagnosis HR 0.69 p=0.02 metastases if no metastases at diagnosis HR 0.45 p= Rothwell et al. Lancet Apr 28;379(9826):

9 Primary prevention (cardiovascular studies) Rothwell et al, Lancet 2011; 377: 31 41

10 Primary prevention (cardiovascular studies) Bosetti et al. Annals of Oncology 2012

11 Primary prevention (cardiovascular studies) Pooled analysis of effect of allocation to aspirin on incidence of cancer during 6 randomised trials of daily low dose aspirin versus placebo in primary prevention of vascular events Rothwell et al, Lancet 2012.

12 Burn et al, Lancet 2011 CAPP-2 -Time to 1st Lynch syndrome cancer in participants aspirin vs placebo restricted to participants who had taken the intervention for 2 years

13 Secondary prevention No randomised trials Colorectal cancer mortality HR 0.71 ( ) (Chan JAMA 2009) Colorectal cancer mortality RR 0.65 ( , p = 0.001) (Bastiaannet BJC 2012) Prostate cancer mortality HR 0.43 (0.21 to 0.87, p=0.02) (Choe et al, 2012) Breast cancer mortality HR 0.36 ( , p<0.001) (Holmes JCO 2010)

14 Secondary prevention Prostate cancer-specific mortality, post radical radiotherapy Choe et al, 2012

15 Secondary prevention Nurses Health Study Prospective observational study 4164 women stage I-III breast cancer: Relative risk of breast cancer death according to aspirin intake Model None Past Current 1 day/week Current 2-5 days/week Current 6-7 days/week P linear trend Person-years 5,707 17,450 4,921 4,902 11,416 Simple model RR <0.001 (95% CI) ( ) (0.7 to 1.55) ( ) ( ) Multivariate model RR (95% CI) ( ) 1.07 (0.7 to 1.63) 0.29 ( ) 0.36 ( ) <0.001 Risk of recurrence: RR: 0.35 (2-5 days/week) and 0.44 (6-7 days per week), test for trend, P= Risk of death from any cause: RR: 0.53 and 0.54, test for trend P= Holmes et al. J Clin Oncol 2010; 28:

16 Side-effects and toxicity Metaanalysis of 24 randomised controlled trials (almost participants). Gastrointestinal haemorrhage occurred in 2.47% of patients taking aspirin compared with 1.42% taking placebo (odds ratio 1.68; 95% confidence interval 1.51 to 1.88). The number needed to harm was 106 (82 to 140) based on an average of 28 months' therapy. At doses below 163 mg/day gastrointestinal haemorrhage occurred in 2.30% of patients taking aspirin compared with 1.45% taking placebo (1.59; 1.40 to 1.81). Derry S and Loke YK. BMJ 2000;321:1183 7

17 Add-Aspirin Add Aspirin Trial: A phase III double-blind placebocontrolled randomized trial assessing the addition of aspirin after standard primary therapy in early stage common solid tumours.

18 Add-Aspirin FOUR PARALLEL TRIALS Eligible participants will have undergone primary treatment with curative intent for an early stage common solid tumour COLORECTAL STUDY Stage II or stage III adenocarcinoma of the colon or rectum BREAST STUDY Node positive or high-risk node negative invasive breast cancer UPPER GI STUDY Adenocarcinoma or squamous cell cancer of the oesophagus, OG junction or stomach PROSTATE STUDY Non-metastatic prostatic adenocarcinoma, intermediate to high risk (D Amico) RANDOMIZE (1:1:1, double-blind) PLACEBO daily for 5 years 100mg ASPIRIN daily for 5 years 300mg ASPIRIN daily for 5 years FOLLOW-UP 5 years, including active f/up largely aligned with standard care, and long term passive f/up through NCIN Outcome measures include cancer recurrence, cancer mortality, cardiovascular morbidity & mortality and toxicity.

19 Add-Aspirin Trial Primary outcome overall or disease-free survival, with target 4-5% improvement with aspirin. 10,000 patients required across 4 tumour sites Secondary outcomes:toxicity, compliance, cardiovascular morbidity/mortality Translational components: Compliance assessment Investigate potential biomarkers of treatment response

20 Rationale for Add-Aspirin Trial Low cost generic drug available worldwide. Accessible in lower resource settings (unlike many new agents or complex regimens). Low toxicity, known safety profile. Possible therapeutic role for several of the most common cancers. Potential for huge global impact.

21 Summary Aspirin has potential anti-cancer effects when examined in pre-clinical (laboratory) studies. Patients receiving aspirin for cardio/cerebrovascular disease are: Less likely to be diagnosed with cancer, If diagnosed less likely to have metastases Less likely to die from cancer The risk of developing cancer in those with a high risk, may be reduced by aspirin (Lynch syndrome). In those who have been diagnosed with early cancer, trials are planned to examine if aspirin reduces the risks of cancer recurring.

22