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Antibiotics use in relation to colorectal cancer risk, survival and postoperative complications
Umeå University, Faculty of Medicine, Department of Diagnostics and Intervention. (Bethany van Guelpen Lab)ORCID iD: 0000-0003-2517-6881
2024 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Background: Growing evidence suggests that antibiotic-induced dysbiosis of gut microbiota potentially contributes to colorectal cancer development and oncological outcomes. However, the role of antibiotics in colorectal cancer incidence, survival and postoperative outcomes at a population level remains incompletely understood.

Aims: The overall aim of the thesis is to investigate prescription antibiotics use in relation to colorectal cancer risk, survival and postoperative complications, particularly surgical site infections including anastomotic leakage.

Methods: The thesis work includes matched case-control and cohort studies, leveraging complete population-based data from Swedish national registers. Paper I is a matched case-control study that consists of 40 545 colorectal cancer cases and 202 720 matched controls, aiming to investigate antibiotics use and risk of incident colorectal cancer. Multivariable conditional logistic regression was used. Paper II is a cohort study, including 47 303 colorectal cancer cases, investigating antibiotics use in relation to cancer-specific survival. Stratified Cox proportional-hazards regression was used. Paper III includes 38 839 colorectal cancer cases who had undergone abdominal tumour-resection surgery and assesses antibiotics use in relation to surgical site infections, including anastomotic leakage, within 30 days after surgery. Logistic regression with multi-level mixed-effects models was used.

Results: In paper I, a dose-response association between antibiotics use and a higher risk of proximal colon cancer was found, whereas a slight inverse association with rectal cancer was observed, mainly in women. A null association was found between methenamine hippurate, assessed as a negative control due to no known effect on gut microbiome, and the risk of colorectal cancer. In paper II, the findings did not support any substantial negative effect of antibiotics on cancer-specific survival, except for very high cumulative exposure (>180 days) in stage I-III diseases. In stage IV colorectal cancer, modest inverse relationships between antibiotics use and survival were noted. In paper III, prescription antibiotics use up to 4.5 years before surgery was associated with a higher risk of surgical site infections, including anastomotic leakage, after colon cancer surgery but not rectal cancer surgery. A null association was observed between methanamine hippurate and the risk of surgical site infections. For cardiovascular and/or neurological complications, also considered as a negative control due to expected negligible or null effects of gut microbiome on these outcomes after surgery, associations were null in both colon and rectal cancer.

Conclusion: These studies provided further support for antibiotics use as a modifiable risk factor for proximal colon cancer and identified antibiotics taken long before surgery as a novel risk factor for surgical site infections, including anastomotic leakage, after colon cancer surgery. In contrast, we did not find any substantial negative impact of antibiotics on cancer-specific survival. Taken together, the findings described in this thesis provide etiological insights and may contribute to strategies to prevent colon cancer and improve postoperative outcomes through prudent use of antibiotics, thereby aiding in the reduction of colorectal cancer incidence and mortality.

Place, publisher, year, edition, pages
Umeå: Umeå University, 2024. , p. 64
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 2282
Keywords [en]
colorectal cancer, antibiotics, gut microbiome, dysbiosis, cancer-specific survival, surgical site infections, anastomotic leakage, register-based epidemiology
National Category
Cancer and Oncology
Research subject
Cancer Epidemiology; Cancer Epidemiology; Oncology; Surgery
Identifiers
URN: urn:nbn:se:umu:diva-221316ISBN: 978-91-8070-270-6 (print)ISBN: 978-91-8070-271-3 (electronic)OAI: oai:DiVA.org:umu-221316DiVA, id: diva2:1839382
Public defence
2024-03-22, Hörsal Betula, 6M Building, Umeå University Hospital, Umeå, 13:00 (English)
Opponent
Supervisors
Available from: 2024-03-01 Created: 2024-02-20 Last updated: 2024-02-21Bibliographically approved
List of papers
1. Antibiotics Use and Subsequent Risk of Colorectal Cancer: A Swedish Nationwide Population-Based Study
Open this publication in new window or tab >>Antibiotics Use and Subsequent Risk of Colorectal Cancer: A Swedish Nationwide Population-Based Study
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2022 (English)In: Journal of the National Cancer Institute, ISSN 0027-8874, E-ISSN 1460-2105, Vol. 114, no 1, p. 38-46Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Antibiotics use may increase colorectal cancer (CRC) risk by altering the gut microbiota, with suggestive evidence reported. Our study aims to investigate antibiotics use in relation to subsequent CRC risk.

METHODS: This is a nationwide, population-based study with a matched case-control design (first primary CRC cases and 5 matched, cancer-free controls). Complete-population data, extracted from Swedish national registers for the period 2005-2016, were used to calculate odds ratios and 95% confidence intervals.

RESULTS: We included 40 545 CRC cases and 202 720 controls. Using the full dataset, we found a positive association between more frequent antibiotics use and CRC, excluding antibiotics prescribed within 2 years of diagnosis attenuated results toward the null. In site-specific analyses, excluding the 2-year washout, the positive association was confined to the proximal colon (adjusted odds ratio for very high use vs no use = 1.17, 95% confidence interval = 1.05 to 1.31). For rectal cancer, an inverse association, which appears to be driven by women, was observed. Quinolones and sulfonamides and/or trimethoprims were positively associated with proximal colon cancer, whereas a more general inverse association, across antibiotics classes, was observed for rectal cancer. We found no association between methenamine hippurate, a urinary tract antiseptic not affecting the gut microbiota, and CRC risk.

CONCLUSIONS: This register-based study covering the entire population of Sweden found a robust association between antibiotics use and higher risk of proximal colon cancer and an inverse association with rectal cancer in women. This study strengthens the evidence from previous investigations and adds important insight into site-specific colorectal carcinogenesis.

Place, publisher, year, edition, pages
Oxford University Press, 2022
National Category
Public Health, Global Health, Social Medicine and Epidemiology
Research subject
Epidemiology
Identifiers
urn:nbn:se:umu:diva-188711 (URN)10.1093/jnci/djab125 (DOI)000748167200010 ()34467395 (PubMedID)2-s2.0-85123649937 (Scopus ID)
Funder
Region Västerbotten, RV 932777
Available from: 2021-10-19 Created: 2021-10-19 Last updated: 2024-02-20Bibliographically approved
2. Prediagnostic prescription antibiotics use and survival in patients with colorectal cancer: a swedish national register-based study
Open this publication in new window or tab >>Prediagnostic prescription antibiotics use and survival in patients with colorectal cancer: a swedish national register-based study
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2023 (English)In: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 32, no 10, p. 1391-1401Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Antibiotics use is associated with higher colorectal cancer risk, but little is known regarding any potential effects on survival.

METHODS: We conducted a nationwide cohort study, using complete-population data from Swedish national registers between 2005 and 2020, to investigate prediagnostic prescription antibiotics use in relation to survival in colorectal cancer patients.

RESULTS: We identified 36,061 stage I-III and 11,242 stage IV colorectal cancer cases diagnosed between 2010 and 2019. For stage I-III, any antibiotics use (binary yes/no variable) was not associated with overall or cancer-specific survival. Compared with no use, moderate antibiotics use (total 11-60 days) was associated with slightly better cancer-specific survival [adjusted HR (aHR) = 0.93; 95% confidence interval (CI), 0.86-0.99)], whereas very high use (>180 days) was associated with worse survival [overall survival (OS) aHR = 1.42; 95% CI, 1.26-1.60, cancer-specific survival aHR = 1.31; 95% CI, 1.10-1.55]. In analyses by different antibiotic types, although not statistically significant, worse survival outcomes were generally observed across several antibiotics, particularly macrolides and/or lincosamides. In stage IV colorectal cancer, inverse relationships between antibiotics use and survival were noted.

CONCLUSIONS: Overall, our findings do not support any substantial detrimental effects of prediagnostic prescription antibiotics use on cancer-specific survival after colorectal cancer diagnosis, with the possible exception of very high use in stage I-III colorectal cancer. Further investigation is warranted to confirm and understand these results.

IMPACT: Although the study findings require confirmation, physicians probably do not need to factor in prediagnostic prescription antibiotics use in prognosticating patients with colorectal cancer.

Place, publisher, year, edition, pages
American Association For Cancer Research (AACR), 2023
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-215390 (URN)10.1158/1055-9965.EPI-23-0340 (DOI)37490284 (PubMedID)2-s2.0-85173563887 (Scopus ID)
Funder
Cancerforskningsfonden i Norrland, LP17–2154Cancerforskningsfonden i Norrland, LP21-2275Region Västerbotten, RV-932777
Available from: 2023-10-27 Created: 2023-10-27 Last updated: 2024-02-20Bibliographically approved
3. Antibiotics use up to 4.5 years before colorectal cancer surgery is associated with an elevated risk of surgical site infections, including anastomotic leakage, particularly in colon cancer: a Swedish nationwide study
Open this publication in new window or tab >>Antibiotics use up to 4.5 years before colorectal cancer surgery is associated with an elevated risk of surgical site infections, including anastomotic leakage, particularly in colon cancer: a Swedish nationwide study
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(English)Manuscript (preprint) (Other academic)
National Category
Cancer and Oncology
Research subject
Cancer Epidemiology; Surgery
Identifiers
urn:nbn:se:umu:diva-221304 (URN)
Available from: 2024-02-20 Created: 2024-02-20 Last updated: 2024-02-21

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