Back to Annual Meeting Posters

Introduction:
Increasing evidence suggests a role for nonsteroidal anti-inflammatory drugs (NSAIDs) including aspirin and statins as adjuvant treatment in colorectal cancer (CRC), with reduced recurrence and improved survival in long-term users. Whether this is due to manipulation of CRC-associated inflammation is unclear. Systemic inflammation, a stage independent predictor of outcome may be down-regulated by NSAIDs [1]. Furthermore, local inflammation measured by tumour immune cell infiltration, an independent predictor of disease-free survival, may be up-regulated by pre-operative NSAID administration[2].
Objective:
In a cohort of patients with cancer associated local and systemic inflammatory responses, the aim was to examine whether aspirin (75mg) and statins prescribed for cardiovascular disease influenced CRC-associated inflammation.
Methods:
A retrospective case note review of a prospectively collected CRC database was performed to ascertain pre-diagnosis prescription of aspirin and statins; the effect of aspirin alone or combined aspirin and statin use on the systemic (C-reactive protein, albumin, neutrophil:lymphocyte ratio and modified Glasgow Prognostic score) and local (assessment of peritumoural inflammatory infiltrate using Klintrup-Mäkinen (K-M) grade; assessment of T-lymphocyte (CD3+), regulatory T-cell (FOXP3+) and cytotoxic T-cell (CD8+) infiltration at the invasive margin, within the stroma and overall) inflammatory responses were examined.
Results:
Data for 434 patients were available [Table 1]. Pathological variables were similar and systemic inflammation did not differ between groups. Data on the local inflammatory profile were available for 164 patients. Although K-M did not differ, aspirin and combined use were associated with increased tumour margin and overall infiltration of CD3+ lymphocytes. This association was stronger in patients with local disease (T1-3,N0); compared to no medication there was a significant increase in invasive margin and overall CD3+ infiltration with aspirin or combined use (margin: 42.1%, 60%, 100%, p=0.007; overall: 51.7%, 83.3%, 100%, p=0.007) and a non-significant trend towards increased FOXP3+ and CD8+ margin, stromal and overall infiltration.
Conclusion:
Although K-M grade did not differ, tumour infiltration of T-lymphocytes was increased by aspirin and statins, particularly in patients with early stage disease. Whether commencing these agents following diagnosis, particularly in patients with an attenuated local inflammatory response, results in similar changes prior to surgery and the subsequent oncological implications remains to be determined. Studies to examine whether anti-inflammatory agents can manipulate colorectal cancer associated inflammation are warranted.
References:
1. McMillan DC. Proc Nutr Soc 2008;67(3):257-62,
2. Lönnroth C, et al. Cancer Immun 2008;8:5
Table 1. Patient, tumour and inflammatory characteristics of patients with primary operable colorectal cancer (n=434) according to pre-diagnosis use of aspirin or aspirin and statin use

	No medication	Aspirin alone	Aspirin and statin	P-Value
Patient Variables
Male/Female	147 (49) / 154 (51)	25 (60) / 17 (40)	45 (49) / 46 (51)	0.725
Colon/Rectal	178 (60) / 119 (40)	23 (55) / 19 (45)	53 (59) / 37 (41)	0.77
Neoadjuvant therapy (No/Yes)	261 (89) / 32 (11)	37 (90) / 4 (10)	82 (92) / 7 (8)	0.403
Ischaemic heart disease (No/Yes)	198 (93) / 14 (7)	17 (68) / 8 (32)	22 (29) / 53 (71)	<0.005
Ever smoked (current and ex/never)	111 (55) / 92 (45)	5 (21) / 19 (79)	27 (37) / 46 (63)	0.003
Systemic Inflammatory Response
CRP > 10mg/L (No/Yes)	199 (66) / 101 (34)	27 (64) / 15 (36)	64 (70) / 27 (30)	0.535
mGPS (0/1/2)	200 (66) / 69 (23) /32 (11)	27 (64) / 10 (24) / 5 (12)	64 (71) / 14 (15) / 13 (14)	0.974
NLR > 5 (No/Yes)	132 (86) / 22 (14)	14 (61) / 9 (39)	54 (89) / 7 (11)	0.975
Local Inflammatory Response
K-M Grade (Weak/Strong)	97 (67) / 48 (33)	8 (47) / 9 (53)	16 (67) / 8 (33)	0.615
CD3+ Margin (Weak/Strong)	67 (59) / 47 (41)	7 (41) / 10 (59)	5 (33) / 10 (67)	0.032
CD3+ Stroma (Weak/Strong)	65 (56) / 52 (44)	9 (50) / 9 (50)	6 (37) / 10 (63)	0.175
CD3+ Overall (Weak/Strong)	57 (49) / 60 (51)	6 (33) / 12 (67)	3 (19) / 13 (81)	0.014
FOXP3+ Overall (Weak/Strong)	55 (48) / 59 (52)	7 (41) / 10 (59)	7 (47) / 8 (53)	0.758
CD8+ Overall (Weak/Strong)	61 (53) / 54 (47)	9 (53) / 8 (47)	7 (47) / 8 (53)	0.682

All values given as number of patients (%).Total patient numbers vary due to incomplete data. CRP - C-reactive protein. mGPS: modified Glasgow Prognostic Score. mGPS is a cumulative score based on CRP and albumin; a score of 1 is given if patients has CRP >10mg/L, 2 if CRP>10mg/L and albumin <35g/L. NLR- Neutrophil:lymphocyte ratio