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Page 2 of 5 Singh-Ranger. Mini-invasive Surg 2018;2:39 I http://dx.doi.org/10.20517/2574-1225.2018.23

Table 1. Observational studies with aspirin and colorectal cancer chemoprevention
Study Design Aspirin use Duration Relative risk
Nurses Health Study [8] Cohort More than 2x per week 10 0.62
Cancer Prevention Study [9] Cohort Various 15 0.58-0.61
Health Professionals Study [10] Cohort More than 2x per week 4 0.54

phase. We now know that unregulated prostaglandin expression appears to have some importance in the
early phase of adenoma formation, and transition to invasive cancer .
[2,3]

COLORECTAL CANCER CHEMOPREVENTION
The cyclooxygenase (COX) enzymes act on arachidonic acid to permit formation of prostaglandins. There
are two isoenzymes; Generally speaking, although this is slightly simplistic, COX-1 is responsible for stable
expression of “useful” prostaglandins in cells , whilst COX-2 expression occurs by stimulation in various
[3,4]
pathological environments, and typically by those factors which are present in malignant disease and chronic
inflammation . Once induced, COX-2 can create a situation of uncontrolled prostaglandin release, which
[5,6]
thereby promotes the genesis and growth of malignant cells in various ways . A cell which is initially only
[7]
mildly dysplastic, can, in the environment of persistent prostaglandin release, transform into more severe
dysplasia and frankly, cancer.

The adenoma-cancer transformation occurs over many years in most patients, although there are exceptions.
The lag period provides a potential pathway for a suitable intervention to reduce cancer risk - typically, we
have thought about polyp removal in this regard, the purpose of colon cancer screening program, now
prevalent in most countries. What if however, we could terminate the transition of the cell on the brink of
turning dysplastic or malignant in some way, with drugs that inhibit prostaglandin synthesis?

Low dose aspirin, already taken worldwide to in the secondary prevention of ischaemic heart disease, blocks
COX and prostaglandin formation, so would seem to be a prime candidate. Indeed, studies as far back as 20
years ago suggested some usefulness in this regard [8-10] [Table 1]. The results of formal randomised controlled
trials (RCTs) in the 1990s and early 2000s were disappointing however, and did not substantiate results from
previous observational studies [11,12] .

Towards the end of the last decade however, the longer term results of the aforementioned RCTs and other
more recent trials suggested a significant reduction in colorectal cancer incidence after 10 years of use [13,14]
[Table 2].

Patients probably need to take aspirin or related drugs regularly for about 3 years before realising an anti-
cancer benefit, and even if they then stop using the medication, there still may exist some long term protective
effect lasting up to 10 years or more, which indicates we might be able to suggest patients take aspirin for a
defined period, and then be less strict about compliance and adherence after that time, particularly if there
is an issue with adverse effects.

Furthermore, another positive insight from trials is that maintaining patients on a low dose for example,
75-81 mg, is sufficient to allow risk reduction in those with a polyp history [15,16] - this was actually previously
also suggested by observational work .
[17]
An anticancer action for aspirin at low dose seems paradoxical however - extraordinarily high doses of
aspirin (over 1 g/day) are required to terminate COX-2 expression in nucleated cells . Recent studies
[18]
suggest the low dose strategy works due to inactivation of platelet COX-1 - a strong induction signal for
COX-2 upregulation in damaged cells . Recent work also indicates there may be other isolated mechanisms
[19]