Does and aspirin a day keep gi cancer away or if you take a cox 2 what does it do
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Does and Aspirin a day keep GI cancer away or If you take a Cox 2 what does it do?. I’m not sure what these do but take them for several years and let me know how you do. Baseline. ASA is derived from the bark of the willow tree- and is a irreversible inhibitor of cyclo-oxygenase 1&2

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Does and Aspirin a day keep GI cancer away or If you take a Cox 2 what does it do?

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Does and aspirin a day keep gi cancer away or if you take a cox 2 what does it do

Does and Aspirin a day keep GI cancer away orIf you take a Cox 2 what does it do?


I m not sure what these do but take them for several years and let me know how you do

I’m not sure what these do but take them for several years and let me know how you do


Baseline

Baseline

  • ASA is derived from the bark of the willow tree- and is a irreversible inhibitor of cyclo-oxygenase 1&2

  • Most of the other NSAIDS are reversible inhibitors although some have very long binding e.g. indomethacin.


Some more baseline

Some more baseline

  • Cyclo-oxygenases are one of 3 key enzymes in arachidonic acid metabolism

  • Cyclo oxygenase converts ADA into prostaglandins, thromboxanes, prostacyclin and malondialdehyde.

  • Cox 1- Prostaglandin H synthetase 1-Responsible for mucosal integrity

  • Cox 2-Prostaglandin H synthetase 2-an inducible enzyme associated with inflammatory response and possible tumor induction. Also may play a part in neo angiogenesis.


Getting tired of baseline yet

Getting tired of baseline yet?

  • Cox 1 converts ADA to prostaglandin G2, an endo peroxidase which is then reduced to an alcohol. During the early peroxidase reaction free radicals are produced. Free radicals are implicated in mutagenesis.

  • A large number of NSAIDS suppress chemical carcinogenesis in rodents eg Cancer Invest 20(4) 490-98,2002


So if they do suppress carcinogenesis what is the mechanism

So if they do suppress carcinogenesis what is the mechanism?

  • May reduce free radicals which are tumor promoting.

  • May suppress prostaglandin production which may act in other ways to promote tumor development or metastases such as modulating an inflammatory response caused by Cox 2. Prostaglandins are known to be involved in several steps of cell transformation, tumor growth and metastases. In this way might suppress polyp formation or subsequent steps from a polyp to cancer

  • Angiogenesis inhibitors


Suppress prostaglandin production

Suppress Prostaglandin production

  • Some NSAIDS decrease growth of tumor cells in vitro at the G1-S phase-ornithine decarboxylase is one of the enzymes inhibited.


Mechanisms

Mechanisms

  • Several studies show that mRNA expression and Cox 2 protein are increased in colorectal, gastric and esophageal tissue around cancer and in the cancers themselves.(Am J Med 2001;110-665-695)

  • Cox 2 is up regulated between 2 and 50 fold in CRC

  • Cox 1 mRNA and protein has been variably associated with an increase.

  • By inhibiting Cox 1 and or 2 production at source carcinogenesis may be inhibited.


So does it work

So does it work?

  • In one study a group used a selective Cox 2 inhibitor vs Sulindac to suppress chemically induced polyps in mice.

  • The number of polyps/mouse in Cox 2 treated-161; Sulindac-312, control-424.

  • Interestingly Cox 2 was not highly expressed in the intestinal epithelium but in the interstitial cells(Cell 87:803-809, 1996) Inflammatory response and neoangiogenesis?


Ok s more but this time from mice to men some human tissue

Ok s’more- but this time from mice to men Some human tissue

  • 14 CRC and 6 adenomas from surgical resections

  • low to normal messenger RNA in normal mucosa for Cox 2

  • Cox 2 increased in 12/14 CRC

  • Cox 1 was equivalent in normal mucosa and in cancers and adenomas

  • Gastroenterol 1994;107;1183-88


So any relationship between tumors and cox

So any relationship between tumors and Cox

  • 60 cases of CRC - immunohistochemistry for Cox 2

  • Cox2 predominantly seen in tumor cells but seen in some stromal and endothelial cells and in normal mucosa adjacent to the cancer but not distant from the cancer

  • They divided the group between low and high Cox2 -(low Cox2- 79% of tumors)

  • Pts with low Cox 2 better survival- Cox 2 therefore might be involved in the transformation of cells that lead to mets.


Anti angiogenesis another twist

Anti Angiogenesis, another twist

  • Cox 2 inhibitor suppresses gastric cancer in vivo (mouse model) but not the growth of cancer cells in vitro

  • Gastrointestinal cancers produce several substances including growth factors (VGEF) which have an effect on angiogenesis

  • Two tumor cell lines were used in mice one over expressed Cox 2, the other did not

  • Mice were treated with Indomethacin and a Cox 2 inhibitor


Twist and shout

Twist and shout

  • Both decreased tumors in a dose dependent fashion regardless of the expression of Cox 2 in the tumors

  • Both decreased angiogenesis

  • VEGF and BFGF were suppressed (Lab Invest 1999;79-1469-77)

  • However, others have found that angiogenesis in xenografts could be suppressed by Cox 1 suppression but not by Cox 2 in Cox 2 negative expressing tumors.


Summary of mechanism

Summary of mechanism

  • Antiangiogenesis

  • Cox 2 inhibition displayed by tumor but not by normal tissue- Low cox 2 expressing tumors may have a better survival so Cox 2 inhibition may increase survival.

  • Prostaglandin inhibition

  • Suppression of the genesis of tumors by reducing free radical expression.


Typical colon cancer patient

Typical Colon Cancer Patient

  • A high risk colon cancer patient is: A tall nulliparous hard drinking male couch potato,who is short for his weight, who had an early menarche, was never on the birth control pill, may or may not have eaten fibre, but little calcium, may or may not have used antioxidants, never taken ASA or a Cox 2 inhib (perhaps), and probably has a high animal fat intake, and may or may not have used tobacco.


Definitions

Definitions

  • Case Control- draw people from an observed population and compare to those “matched” from the general population

  • Cohort study-Follow a group of people over a number of years and note any disease processes that develop and match with the characteristics of that group against the group that did not develop the disease(s) in question


Case controls

Case Controls

  • A large Australian population based c-c study compared ASA use in 715 incident cases of CRC with 727 controls-

  • if one used ASA RR of CRC 0.53-Kune- Cancer Res 1988 48; 4399-4004


Does and aspirin a day keep gi cancer away or if you take a cox 2 what does it do

CC

  • 12174 cases and 34934 controls in a GP Research database-overall risk of 9 cancers- those that received at least 7scripts for NSAIDS 3-36 mo before cancer

  • RR- Esophagus 0.64; Stomach 0.51, colon 0.76; rectum 0.75, Pancreatic 1.49, Prostate 1.33

  • This was in patients largely over 65 who could get these meds free so they did not think they took much over the counter

  • BMJ 320: 1642-6, 2000


Asa what does it keep away

ASA - what does it keep away

  • North West US-1326 incident cases- a decrease in the risk if one used ASA-0.6

  • Summary--8/10 epidemiologic case control studies show some reduction of either colorectal polyps or cancer in aspirin users


Cohort studies

Cohort Studies

  • 13,987 elderly (median age 73) residents of a Leisure home.

  • Those who used ASA 1/day-RR colon cancer 1.3- rectal cancer 1 (JNCI 1991,1182)

  • Gender difference men RR 1.5, women 1.0


Cohort cont d

Cohort cont’d

  • 662,424 adults surveyed for a variety of lifestyle and med issues from 1982-1988

  • Grps non users; ASA < 1/mo; 1-15/mo; >16/mo.

  • 111CRC deaths from CRC recorded

  • RR of >16/mo 0.6 and for rectal 0.8, 1-15 0.72 and <1 .83-.85

  • (NEJM 1991 325:1593)


Yep cohort again

Yep cohort again

  • 12668 people 25-74- ASA use over 30 days previous to survey

  • 1257new incident cases in 12.4 yrs F-up

  • RR CRC 0.9

  • men<65- 0.4 (Epidemiology 1994;5;138)


Cocohort ann int med 1994 121 1241 6

Cocohort-Ann Int Med 1994;121:1241-6

  • 47900 male respondents mailed questionnaires 1986,1988,1990

  • ASA Users (2+times per week)-other drugs recorded including acetaminophen and other NSAIDS-33806 non users and 14094 users

  • 251 diagnosed as CRC-#of cases per persons yr

  • -Non user-184/185310;

  • user 85/75637


Givannucci ann int med cont d

Givannucci Ann Int Med cont’d

  • RR among users 0.7 95%Ci 0.53-0.92- both colon and rectum and both proximal and distal colon- and an inverse association between ASA use and metastatic cancer

  • Excluding men who had endoscopy for occult or overt bleeding men who took ASA were at a decreased risk for adenoma.

  • Stronger association with current users.


Women and giovannucci nejm1995 333 609 14

Women and Giovannucci- NEJM1995;333:609-14

  • Nurses health study (2+ tabs/wk)

  • Initial study 12 yrs of follow up and a slight but NS lower risk of CRC.

  • Subsequent study looking at women who took ASA for >10yrs RR 0.7

  • *If took ASA for >20yrs RR 0.56

  • True for both colon and rectal cases


Asa sturmer et al ann intern med 128 713 720 1998

ASA-Sturmer et al Ann Intern Med 128:713-720 ,1998

  • RCT-22071 male Physicians 40-84

  • 12 years of Follow up

  • ASA 325 EOD for 5 years and b carotene 4 groups ASA and BC, ASA and placebo, BC and p; and p

  • CRC in 341 pts - RR of ASA 1.03

  • This study was a study to examine the effect of ASA on cardiovascular health and was terminated early due to the beneficial effects found. Patients did not have their GI tracts checked routinely and hence patients may have been looked at more closely in ASA group. Thus may have detected more but now 12 yrs of follow up.


Intervention studies

Intervention studies

  • In colorectal cancer it is generally accepted that sporadic cancers especially left sided ones develop from an adenomatous polyp to a premalignant lesion with successive genetic changes as described by Volgelstein

  • Several observational studies suggested the regression of rectal polyps in FAP syndrome with polyps returning after Sulindac (NSAID) stopped


Polyps can they be prevented

Polyps can they be prevented?

  • Three of the earlier studies also looked at polyps- In the northern US cohort study polyps were 0.4 RR in ASA users ( 212 polyp found)

  • In case control of subjects participating in randomized trial of FOB

  • 147 polyps--176 controls without adenomas FOB+ and 153 case of no adenomas FOB -

  • ASA use for 3 mos RR 0.6

  • BMJ 307:285, 1993


Polyps

polyps

  • Post hoc evaluation of pts enrolled in RCT of B carotene,Vit C and VitE for polyp prevention-793 pts asked re ongoing use of ASA at 6 mos and 1 yr

  • 593- no use; 98 inconsistent; 102 consistent

  • Consistent RR 0.52, intermittent-0.92- so despite no difference in CRC may have been in difference in polyp formation.

  • JNCI 1993;85 912-16


Polyps in fap nejm 2002 346 1054 9

Polyps in FAP-NEJM 2002:346:1054-9

  • FAP patients-41- randomized to two doses of sulindac (cox 1&2 inhibitor) vs placebo

  • 4 year treatment with 76% compliance in sulindac group

  • No diff in the mean number 0.69 or size 0.17 of poyps

  • Sulindac did not slow the growth of polyps

  • Mucosal prostaglandin was lowered.


Fap and cox 2 steinbach nejm 2000 342926 1946 52

Fap and cox 2-Steinbach NEJM 2000;342926):1946-52

  • 77 patients with FAP- after 6 mo those on celecoxib 400 mg BID had a mean reduction of 28% in polyps (p=0.003) and a 30.7% reduction in polyp size.

  • Reductions in group receiving 100 mg of Cox 2 BID NS


Any concern about safety profile of cox 2

Any concern about safety profile of Cox 2?

  • The pooled results of 4 randomized trials have suggested an increased risk of cardiovascular events (Mukherjee et al. Risk of cardiovascular events associated with selective Cox-2 inhibitors. JAMA 2001;286:954-9.

  • Interestingly a 7000 person adjuvant trial using rofecoxib is about to begin.


Does and aspirin a day keep gi cancer away or if you take a cox 2 what does it do

So

  • In randomized studies appoximately1.5% of patients hospitalized for bleeding complications secondary to non specific NSAIDS

  • Do not know if specific Cox 2 inhibitors are better although they might be for a subgroup of CRC which over express Cox2- Can Cox 2 prevent mets- Unknown

  • Can ASA or other NSAIDS prevent polyps and then subsequent cancers- unknown


So so

So- So

  • Are there cardiovascular side effects to cox 2 inhibitors?

  • What about the bleeding risks of NSAIDS

  • What about the dose of these drugs- it may be necessary to be higher than we think based on Cox 2 data


Final conclusions

Final conclusions.

  • Mechanistically it is plausible that NSAIDS and Cox 2 inhibitors might inhibit the formation of cancers in the GI tract and there certainly is a wealth of observational studies to support that- but no proof in any randomized trial except for polyps in FAP

  • If you have a headache take an ASA but don’t take it to prevent CRC

  • Do not know anything about dose of ASA

  • Perhaps if you take it- take it for at least 20-30 years and you will probably live that long.


Does and aspirin a day keep gi cancer away or if you take a cox 2 what does it do

I’m not sure what these do but take them for several years and let me know how you do


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