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Modulating the inflammatory response after colorectal cancer surgery: friend or foe?
Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.ORCID iD: 0000-0002-7206-6493
2024 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Colorectal cancer was the second most deadly and third most common cancer globally in 2020. In Sweden, more than 5,000 new colonic cancer cases and more than 2,000 rectalcancer cases were reported in 2021, making colorectal cancer the third most common in Sweden (excluding skin malignancies).

Anastomotic leakage after colorectal cancer surgery is a feared complication that confers substantial morbidity, including a higher risk of permanent stoma and cardiovascular morbidity, but can also impart an increased risk of recurrence and mortality; the reason why leakage might cause this is not established. Perioperative inflammation including upregulation of cyclooxygenase-enzymes, which is further increased by anastomotic leakage, can possibly modulate both anastomotic healing as well as impact minimal residual disease. Non-steroidal anti-inflammatory drugs (NSAIDs) act by inhibiting COX-enzymes and can be part of a postoperative multimodal analgesia protocol. However, their postoperative use has been debated, with fears of NSAIDs possibly increasing anastomotic leakage rates.

Study I was a retrospective cohort study on 1,341 patients who had undergone anterior resection for rectal cancer. Exposure was at least two days with NSAIDs during the first postoperative week, and the primary outcome was recurrence-free survival. A Cox regression model could not demonstrate a significant association with a hazard ratio (HR) of 1.02 (95% confidence interval (CI): 0.79–1.33) and neither did a propensity score-matched analysis. An instrumental variable analysis displayed a tentative improvement in recurrence-free survival in the NSAID-exposed (HR 0.61; 95% CI 0.38–0.99), but the core assumptions to perform such an analysis were not fully satisfied.

Study II was a protocol-based retrospective cohort study with a total of 6,945 patients resected for colorectal cancer with a primary anastomosis formed. NSAID-exposure was determined by each individual hospital’s postoperative analgesia protocol, while patient data and outcomes were retrieved from the Swedish colorectal cancer registry. Some 3,996 (58%) patients were treated at a hospital with NSAIDs included in their postoperative analgesia protocol. No significant association with recurrence-free survival was seen (HR 0.97, 95% CI0.87–1.09). However, a reduction in cancer recurrence was demonstrated (HR 0.83, 95% CI0.72‒0.95), with an increased risk reduction for locoregional (HR 0.68, 95% CI 0.48–0.97) in comparison to distant recurrence (HR 0.85, 95% CI 0.74–0.98). Anastomotic leakage was less frequent as well, mainly because of a reduction in the group with colorectal or ileorectal anastomoses (HR 0.47, 95% CI 0.33–0.68).

In Study III, the aim was to explore proteomic and biological pathway alterations in patients with peritoneal infection. This was a 1:1 matched cohort study on patients resected for colorectal cancer with a primary anastomosis formed, including 32 cases who suffered a postoperative peritoneal infection matched with 32 controls with a complication-free postoperative stay. Serum samples were retrieved from their first postoperative visit and at one year postoperatively. Out of a total of 270 proteins tested, 77 were differentially expressed at the first postoperative visit at a median sampling time of 41 days after surgery. Many of the top hub proteins are known actors in colorectal cancer progression, including survival and invasiveness, potentially enhancing minimal residual disease. Over-represented pathways were related to cardiomyopathy, cell-adhesion, extracellular matrix, phosphatidylinositol-3-kinase/Akt (PI3K-Akt) and transforming growth factor beta (TGF-Beta) signalling.

In Study IV, the aim was to evaluate the frequency of a known polymorphism of the COX-2 gene promotor -765G>C in a Swedish cohort of colorectal cancer patients, and whether a previously reported association between this gene variant with an increase in anastomotic leakage could be reproduced. This was a 1:1 matched case-control study on a total of 94 patients who were resected for colorectal cancer with a subsequent primary anastomosis, with cases suffering a peritoneal infection. Preoperative blood and serum samples were genotyped and analysed using pre-defined protein panels. Of the 94 patients in total, one in each group were homozygous for the minor allele C/C, and ten cases and 14 controls were heterozygous with G/C and the rest were homozygous for the major allele. Thus, there were fewer individuals with the minor allele in the case group, with a non-significant odds ratio of 0.71(p=0.413), ultimately not replicating the finding of the previous study. The protein quantitative trait loci analysis rendered no associations of interest.

In conclusion, no statistically significant effects on recurrence-free survival from postoperative NSAIDs in patients resected for colorectal cancer could be demonstrated in study I, whereas significant associations between NSAID use and reduction in frequency of anastomotic leaks as well as cancer recurrence could be shown in study II. In study III, numerous proteins were differentially expressed in patients suffering a postoperative peritoneal infection, even after more than a month’s duration, potentially stimulating minimal residual disease. The over-representation analysis found pathways related to cardiomyopathy, which could help explain the increase in cardiovascular morbidity in patients suffering anastomotic leakage. Study IV could not reproduce the potentially marked increase in anastomotic leak frequency in carriers of the COX-2 gene promotor -765G>C polymorphism in a Swedish sample. Whether to include NSAIDs or not in postoperative multimodal analgesia is a question still not answered, and it may depend on the genotype, the patient’s preoperative inflammatory state, tumour location, the specific NSAID used, and whether a leak has already occurred. NSAIDs might have effects on both morbidity including cardiovascular and anastomotic leakage as well as minimal residual disease including recurrence and mortality. This thesis suggests potential protective effects regarding both anastomotic leakage as well as cancer recurrence, but it seems to depend on at least some of the aforementioned factors. The proteomic landscape regarding postoperative peritoneal infection has been investigated, and where it has also been demonstrated that the duration of said alterations can be greater than was earlier suspected. Finally, even if a replication attempt was not successful considering the relation between a COX-2 gene promotor polymorphism and anastomotic leakage, it could be worthwhile to attempt further replication studies.

Place, publisher, year, edition, pages
Umeå: Umeå University, 2024. , p. 76
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 2299
Keywords [en]
Anastomotic leakage, colorectal cancer, nsaids, non-steroidal anti-inflammatory drugs, proteomics, genomics, pathways, inflammation, recurrence, survival
National Category
Surgery
Research subject
Surgery
Identifiers
URN: urn:nbn:se:umu:diva-223736ISBN: 978-91-8070-364-2 (print)ISBN: 978-91-8070-365-9 (electronic)OAI: oai:DiVA.org:umu-223736DiVA, id: diva2:1854216
Public defence
2024-05-24, Sal B, Byggnad 1D, Trapphus T, 9 trappor, Norrlands Universitetssjukhus, Umeå, 13:00 (English)
Opponent
Supervisors
Available from: 2024-05-03 Created: 2024-04-24 Last updated: 2024-04-26Bibliographically approved
List of papers
1. Postoperative non-steroidal anti-inflammatory drug use and oncological outcomes of rectal cancer
Open this publication in new window or tab >>Postoperative non-steroidal anti-inflammatory drug use and oncological outcomes of rectal cancer
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2021 (English)In: BJS Open, E-ISSN 2474-9842, Vol. 5, no 1, article id zraa050Article in journal (Refereed) Published
Abstract [en]

Background: Non-steroidal anti-inflammatory drugs (NSAIDs) are known to suppress the inflammatory response after surgery and are often used for pain control. This study aimed to investigate NSAID use after radical surgical resection for rectal cancer and long-term oncological outcomes.

Methods: A cohort of patients who underwent anterior resection for rectal cancer between 2007 and 2013 in 15 hospitals in Sweden was investigated retrospectively. Data were obtained from the Swedish Colorectal Cancer Registry and medical records; follow-up was undertaken until July 2019. Patients who received NSAID treatment for at least 2 days after surgery were compared with controls who did not, and the primary outcome was recurrence-free survival. Cox regression modelling with confounder adjustment, propensity score matching, and an instrumental variables approach were used; missing data were handled by multiple imputation.

Results: The cohort included 1341 patients, 362 (27.0 per cent) of whom received NSAIDs after operation. In analyses using conventional regression and propensity score matching, there was no significant association between postoperative NSAID use and recurrence-free survival (adjusted hazard ratio (HR) 1.02, 0.79 to 1.33). The instrumental variables approach, including individual hospital as the instrumental variable and clinicopathological variables as co-variables, suggested a potential improvement in the NSAID group (HR 0.61, 0.38 to 0.99).

Conclusion: Conventional modelling did not demonstrate an association between postoperative NSAID use and recurrence-free survival in patients with rectal cancer, although an instrumental variables approach suggested a potential benefit.

Place, publisher, year, edition, pages
Oxford University Press, 2021
National Category
Surgery
Identifiers
urn:nbn:se:umu:diva-181655 (URN)10.1093/bjsopen/zraa050 (DOI)000649440900024 ()33609397 (PubMedID)2-s2.0-85102220865 (Scopus ID)
Funder
Knut and Alice Wallenberg Foundation
Available from: 2021-06-11 Created: 2021-06-11 Last updated: 2024-04-24Bibliographically approved
2. Postoperative nonsteroidal anti-inflammatory drugs in relation to recurrence, survival and anastomotic leakage after surgery for colorectal cancer
Open this publication in new window or tab >>Postoperative nonsteroidal anti-inflammatory drugs in relation to recurrence, survival and anastomotic leakage after surgery for colorectal cancer
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2022 (English)In: Colorectal Disease, ISSN 1462-8910, E-ISSN 1463-1318, Vol. 24, no 8, p. 933-942Article in journal (Refereed) Published
Abstract [en]

Aim: The aim of this work was to investigate whether nonsteroidal anti-inflammatory drugs (NSAIDs) could be beneficial or harmful when used perioperatively for colorectal cancer patients, as inflammation may affect occult disease and anastomotic healing. Method: This is a protocol-based retrospective cohort study on colorectal cancer patients operated on between 2007 and 2012 at 21 hospitals in Sweden. NSAID exposure was retrieved from postoperative analgesia protocols, while outcomes and patient data were retrieved from the Swedish Colorectal Cancer Registry. Older or severely comorbid patients, as well as those with disseminated or nonradically operated tumours were excluded. Multivariable regression with adjustment for confounders was performed, estimating hazard ratios (HRs) for long-term outcomes and odds ratios (ORs) for short-term outcomes, including 95% confidence intervals (CIs). Results: Some 6945 patients remained after exclusion, of whom 3996 were treated at hospitals where a NSAID protocol was in place. No association was seen between NSAIDs and recurrence-free survival (HR 0.97, 95% CI 0.87–1.09). However, a reduction in cancer recurrence was detected (HR 0.83, 95% CI 0.72–0.95), which remained significant when stratifying into locoregional (HR 0.68, 95% CI 0.48–0.97) and distant recurrences (HR 0.85, 95% CI 0.74–0.98). Anastomotic leakage was less frequent (HR 0.69%, 95% CI 0.51–0.94) in the NSAID-exposed, mainly due to a risk reduction in colo-rectal and ileo-rectal anastomoses (HR 0.47, 95% CI 0.33–0.68). Conclusion: There was no association between NSAID exposure and recurrence-free survival, but an association with reduced cancer recurrence and the rate of anastomotic leakage was detected, which may depend on tumour site and anastomotic location.

Place, publisher, year, edition, pages
John Wiley & Sons, 2022
Keywords
colon cancer, leak, NSAID, oncological outcomes, postoperative complications, rectal cancer
National Category
Gastroenterology and Hepatology Surgery
Identifiers
urn:nbn:se:umu:diva-192795 (URN)10.1111/codi.16074 (DOI)000756508000001 ()35108455 (PubMedID)2-s2.0-85124836556 (Scopus ID)
Funder
Knut and Alice Wallenberg FoundationSwedish Society of MedicineCancerforskningsfonden i Norrland
Available from: 2022-03-01 Created: 2022-03-01 Last updated: 2024-04-24Bibliographically approved
3. Peritoneal infection after colorectal cancer surgery induces substantial alterations in postoperative protein levels: an exploratory study
Open this publication in new window or tab >>Peritoneal infection after colorectal cancer surgery induces substantial alterations in postoperative protein levels: an exploratory study
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Purpose: Peritoneal infection, due to anastomotic leakage, after resection for colorectal cancer have been shown to associate with increased cancer recurrence and mortality, as well as cardiovascsular morbidity. Alterations in circulating protein levels could help shed light on the underlying mechanisms, prompting this exploratory study of 64 patients operated for colorectal cancer with anastomosis.

Methods: Thirty-two cases who suffered a postoperative peritoneal infection were matched with 32 controls who had a complication-free postoperative stay. Proteins in serum samples at their first postoperative visit and at one year after surgery were analysed using proximity extension assays and enzyme-linked immunosorbent assays. Multivariate projection methods, adjusted for multiple testing, were used to compare levels between groups, and enrichment and network analyses were performed.

Results: Seventy-seven proteins, out of 270 tested, were differentially expressed at a median sampling time of 41 days after surgery. Many of the differentially expressed top hub proteins have known involvement in cancer progression, survival, invasiveness and metastasis. Over-represented pathways were related to cardiomyopathy, cell-adhesion, extracellular matrix, phosphatidylinositol-3-kinase/Akt (PI3K/Akt) and transforming growth factor beta (TGF-β) signaling.

Conclusion: These affected proteins and pathways could provide clues as to why these patients might suffer increased cancer recurrence, mortality and cardiovascular morbidity.

Keywords
Anastomotic leakage, colorectal cancer, proteomics, pathways, inflammation, recurrence, survival
National Category
Surgery
Research subject
Surgery
Identifiers
urn:nbn:se:umu:diva-223591 (URN)
Funder
Knut and Alice Wallenberg FoundationSwedish Society for Medical Research (SSMF)
Available from: 2024-04-21 Created: 2024-04-21 Last updated: 2024-04-24
4. Mutation of the cyclooxygenase 2 gene promoter and anastomotic leakage in colorectal cancer patients: retrospective cohort study
Open this publication in new window or tab >>Mutation of the cyclooxygenase 2 gene promoter and anastomotic leakage in colorectal cancer patients: retrospective cohort study
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2024 (English)In: BJS Open, E-ISSN 2474-9842, Vol. 8, no 1, article id zrae004Article in journal (Refereed) Published
Place, publisher, year, edition, pages
Oxford University Press, 2024
National Category
Surgery Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-221114 (URN)10.1093/bjsopen/zrae004 (DOI)001153893100001 ()38289394 (PubMedID)2-s2.0-85184510640 (Scopus ID)
Funder
Knut and Alice Wallenberg FoundationSwedish Society of MedicineCancerforskningsfonden i Norrland
Available from: 2024-02-27 Created: 2024-02-27 Last updated: 2024-04-24Bibliographically approved

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12345673 of 18
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