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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.

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 postoperatively. These proteins were all normalised one year 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 patients with peritoneal infection might suffer increased cancer recurrence, mortality and cardiovascular morbidity.

BACKGROUND: Early death after cancer surgery is higher in low-income and middle-income countries (LMICs) compared with in high-income countries, yet the impact of facility characteristics on early postoperative outcomes is unknown. The aim of this study was to examine the association between hospital infrastructure, resource availability, and processes on early outcomes after cancer surgery worldwide.

METHODS: A multimethods analysis was performed as part of the GlobalSurg 3 study-a multicentre, international, prospective cohort study of patients who had surgery for breast, colorectal, or gastric cancer. The primary outcomes were 30-day mortality and 30-day major complication rates. Potentially beneficial hospital facilities were identified by variable selection to select those associated with 30-day mortality. Adjusted outcomes were determined using generalised estimating equations to account for patient characteristics and country-income group, with population stratification by hospital.

FINDINGS: Between April 1, 2018, and April 23, 2019, facility-level data were collected for 9685 patients across 238 hospitals in 66 countries (91 hospitals in 20 high-income countries; 57 hospitals in 19 upper-middle-income countries; and 90 hospitals in 27 low-income to lower-middle-income countries). The availability of five hospital facilities was inversely associated with mortality: ultrasound, CT scanner, critical care unit, opioid analgesia, and oncologist. After adjustment for case-mix and country income group, hospitals with three or fewer of these facilities (62 hospitals, 1294 patients) had higher mortality compared with those with four or five (adjusted odds ratio [OR] 3·85 [95% CI 2·58-5·75]; p<0·0001), with excess mortality predominantly explained by a limited capacity to rescue following the development of major complications (63·0% vs 82·7%; OR 0·35 [0·23-0·53]; p<0·0001). Across LMICs, improvements in hospital facilities would prevent one to three deaths for every 100 patients undergoing surgery for cancer.

INTERPRETATION: Hospitals with higher levels of infrastructure and resources have better outcomes after cancer surgery, independent of country income. Without urgent strengthening of hospital infrastructure and resources, the reductions in cancer-associated mortality associated with improved access will not be realised.

FUNDING: National Institute for Health and Care Research.

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.

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.

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.