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Surgery for rectal cancer: the impact of perioperative factors
Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.ORCID iD: 0000-0003-4958-6965
2020 (English)Doctoral thesis, comprehensive summary (Other academic)Alternative title
Kirurgi för rektalcancer : inverkan av perioperativa faktorer (Swedish)
Abstract [en]

Rectal cancer is one of the most common and deadly cancer forms worldwide. A large proportion of rectal cancer patients are surgically treated with curative intention, with anterior resection being the most frequently used method today. During surgery, the inferior mesenteric artery is either ligated proximal (high tie) or distal to the left colic artery (low tie). It is not known whether the tie level affects the oncologic nor the functional outcome. Postoperatively, about one in ten patients develop an anastomotic leakage. It is unclear whether treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) affects the risk of leakage, or whether having a leakage influences the functional outcome. 

The general aims of this dissertation were to increase the knowledge of intra- and postoperative treatment for rectal cancer, with the goal of improving the oncologic and functional outcomes, as well as reducing postoperative complications. National registers, predominantly the Swedish Colorectal Cancer Registry, were used in all of the dissertation’s four retrospective cohort studies to identify and retrieve information regarding patients. Various statistical methods have been used in all studies with the aim of eliminating bias, including confounding.

In Study I, high tie slightly increased the total number of harvested lymph nodes in the included 8287 patients, as compared with low tie, while the primary outcome cancer-specific survival, as well as secondary oncologic outcomes, were not affected. This indicates that the oncologic outcome does not have to be considered when the surgeon determines the level of tie.

In Study II, investigating the effect of tie level on the functional outcome, the outcome was any defecatory or urogenital symptoms two years after anterior resection, assessed with a mailed questionnaire. With a response rate of 86%, 805 patients were included. High tie did not, except for increasing the need of defecation at night, influence the risk of major dysfunction. Again, this would facilitate the choice of tie level.

Study III used the same outcome, and in part the same study population, as Study II, but instead with the exposure anastomotic leakage. With a response rate of 82%, 1180 patients were included. We found that anastomotic leakage increased the risk of reduced sexual activity and increased the use of aid products for fecal incontinence after anterior resection, while the risk of urinary incontinence was unexpectedly decreased. Other outcomes were not clearly affected. 

In Study IV, in addition to the register, information was gathered from patient records. In the included 1495 patients who had undergone anterior resection, postoperative NSAID treatment was not found to increase the risk of symptomatic anastomotic leakage. There were no differences between non-selective and COX-2 selective NSAIDs. This study does not support that NSAID treatment increases the risk of anastomotic leakage after such surgery.

Abstract [sv]

Bakgrund

Varje år insjuknar kring 700 000 personer världen över i den åttonde vanligaste cancerformen, ändtarmscancer, varav omkring 2 000 i Sverige. Merparten av dessa patienter genomgår bukkirurgi i botande syfte, där valet av operationsmetod bland annat baseras på tumörens allvarlighetsgrad, patientens hälsostatus samt hur nära ändtarmsöppningen tumören är belägen. Gemensamt för alla operationsmetoder är att kirurgen måste bestämma huruvida det blodkärl som försörjer den drabbade delen av tarmen ska delas antingen högt upp i en så kallad hög ligatur (avknytning) nära den stora kroppspulsådern (aorta), eller något längre ned på kärlträdet i en låg ligatur. Trots idog diskussion i över ett århundrade råder det fortfarande ingen enighet kring vilken ligaturnivå som är den bästa. En teoretisk fördel med hög ligatur är att den skulle kunna möjliggöra avlägsnandet av aortanära lymfkörtlar, eventuellt innehållande spridda cancerceller som annars lämnas orörda, och därigenom förbättra det cancerrelaterade (onkologiska) utfallet. Å andra sidan skulle hög ligatur kunna leda till försämrat funktionellt resultat, eftersom den utförs i närheten av nervfibrer som svarar för viktiga aspekter av tarm-, urinvägs- och sexualfunktion. Det är dock ej i dagsläget klarlagt huruvida något av dessa teoretiska resonemang har betydelse i praktiken.

Den enskilt vanligaste operationsmetoden är en så kallad främre resektion, där tumören avlägsnas och tarmändarna sammanfogas i en tarmskarv (anastomos). Efter operationen drabbas ungefär var tionde patient av att anastomosen havererar. Detta leder i värsta fall till döden, medan de överlevande har ökad risk för bland annat permanent stomi (”påse på magen”) samt troligen även för canceråterfall. Eftersom ett sådant anastomosläckage ofta medför en påtaglig inflammation i bäckenet och inte sällan leder till nya operationer, skulle ett läckage även kunna försämra det funktionella långtidsresultatet. Detta är sparsamt undersökt tidigare, särskilt vad gäller urinvägs- och sexualfunktion.

Under det senaste årtiondet har ett flertal publicerade observationsstudier varnat för att smärtbehandling efter främre resektion med läkemedel av typen NSAID (nonsteroidal anti-inflammatory drug), såsom ibuprofen (Ipren®), kan öka risken för anastomosläckage. Många kirurgiska kliniker runtom i landet har därför upphört med NSAID-behandling efter denna typ av kirurgi, till förmån för ökad morfinanvändning, som i sin tur är känd för biverkningar såsom förstoppning och beroende. Det är dock fortfarande inte bevisat att NSAID verkligen orsakar anastomosläckage och heller inte om risken i sådana fall skiljer sig åt mellan de två olika huvudtyperna av NSAID.

Målsättning

Avhandlingens målsättning är att öka kunskaperna kring intra- och postoperativ behandling av ändtarmscancer, i syfte att minska risken för canceråterfall och komplikationer efter kirurgin, samt att förbättra det funktionella utfallet.

Delarbeten

Det Svenska Kolorektalcancerregistret har använts i avhandlingens alla fyra bakåtblickande observationsstudier för att hitta och samla information kring patienter. Ett flertal olika statistiska metoder ingår i delarbetena för att kontrollera för bland annat störfaktorer och därigenom öka resultatens tillförlitlighet.

I det första delarbetet undersökte vi kopplingen mellan hög ligatur och risken för cancerrelaterad död samt canceråterfall genom att inkludera 8 287 patienter som opererats för rektalcancer i Sverige under åren 2007–2014. I detta arbete hämtades även information från två andra register, varav det ena var Dödsorsaksregistret. Vi kunde inte se någon skillnad i det onkologiska utfallet mellan patienter opererade med hög eller låg ligatur. Detta skulle innebära att kirurgen ej behöver ta hänsyn till detta vid valet av ligaturnivå. 

I det andra delarbetet fick alla patienter som opererats med främre resektion i Sverige mellan april 2011 och september 2012 en enkät hemskickad till sig två år efter operationen. Enkäten användes för att avgöra förekomsten och graden av symtom relaterade till tarm-, urinvägs- och sexualfunktion. Med en svarsfrekvens på 86 procent inkluderades 805 patienter i studien, hos vilka vi analyserade kopplingen mellan hög ligatur och förekomsten av symptom. Vi fann att hög ligatur, frånsett ett ökat behov av tarmtömning nattetid, inte var förenad med påtagliga funktionella bortfall. Detta antyder att det funktionella utfallet inte är en viktig faktor i valet av ligaturnivå.

I det tredje delarbetet inkluderades samma patientgrupp som i det andra delarbetet, med tillägg av patienter som opererats fram till juni 2013. Det funktionella resultatet utvärderades hos dessa patienter på samma sätt som i det andra delarbetet, men nu i relation till förekomsten av anastomosläckage. Med en svarsfrekvens på 82 procent inkluderades 1 180 patienter, varav 7,5 procent utvecklade anastomosläckage. Vi fann att anastomosläckage ökade risken för minskad sexuell aktivitet samt ökad användning av skyddsprodukter mot avföringsinkontinens (ofrivilligt avföringsläckage), medan förekomsten av urininkontinens oväntat var minskad. De andra symtomen var opåverkade.

I det fjärde delarbetet inkluderades 1 495 patienter som opererats med främre resektion vid något av 15 sjukhus mellan 2007 och 2013 i de norra, västra och södra sjukvårdsregionerna i Sverige. Patientjournaler granskades gällande användning av NSAID och förekomsten av anastomosläckage, varpå kopplingen mellan dessa två faktorer analyserades. Vi fann att nästan 14 procent av alla patienter hade drabbats av anastomosläckage, men att risken inte ökade efter behandling med NSAID. Detta var oberoende av vilken sorts NSAID som användes. Studien ger inget stöd för att smärtläkemedel av typen NSAID ökar risken för anastomosläckage.

Place, publisher, year, edition, pages
Umeå: Umeå universitet , 2020. , p. 59
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 2050
Keywords [en]
Rectal cancer, abdominal surgery, anastomotic leakage, anastomotic dehiscence, postoperative complications, vascular tie, ligation level, oncologic outcome, surgical oncology, survival, recurrence, functional outcome, urogenital, anorectal, incontinence, NSAID, COX
National Category
Surgery
Research subject
Surgery
Identifiers
URN: urn:nbn:se:umu:diva-167164ISBN: 978-91-7855-121-7 (print)OAI: oai:DiVA.org:umu-167164DiVA, id: diva2:1385214
Public defence
2020-02-07, Hörsal D by 1A, 9tr, Norrlands universitetssjukhus, Umeå, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2020-01-17 Created: 2020-01-13 Last updated: 2020-01-15Bibliographically approved
List of papers
1. Oncological Impact of High Vascular Tie After Surgery for Rectal Cancer: A Nationwide Cohort Study
Open this publication in new window or tab >>Oncological Impact of High Vascular Tie After Surgery for Rectal Cancer: A Nationwide Cohort Study
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2019 (English)In: Annals of Surgery, ISSN 0003-4932, E-ISSN 1528-1140Article in journal (Refereed) Epub ahead of print
Abstract [en]

Objective: The purpose of this study was to investigate the impact of tie level on oncological outcomes in rectal cancer surgery.

Summary background data: Theoretically, a high tie of the inferior mesenteric artery could facilitate removal of apical node metastases and improve tumor staging accuracy. However, no appropriately sized randomized controlled trial exists and results from observational studies are not consistent.

Methods: All stage I–III rectal cancer patients who underwent abdominal surgery with curative intention in 2007 to 2014 were identified and followed, using the Swedish Colorectal Cancer Registry. Primary outcome was cancer-specific survival, whereas overall and relative survival, locoregional and distant recurrence, and lymph node harvest were secondary outcomes, with high tie as exposure. We used propensity score matching to emulate a randomized controlled trial, and then performed Cox regression analyses to estimate hazard ratios (HRs) with confidence intervals (CIs).

Results: Some 8287 patients remained for analysis, of which 37% had high tie surgery. After propensity score matching, the 5-year cancer-specific survival rate was overall 86% and we found no association between the level of tie and cancer-specific (HR 0.92, 95% CI 0.79–1.07) or overall (HR 0.98, 95% CI 0.89–1.08) survival, nor to locoregional (HR 0.85, 95% CI 0.59–1.23) or distant (HR 1.01, 95% CI 0.88–1.15) recurrence, nor to relative survival (HR 1.05, 95% CI 0.85–1.28). Stratification and sensitivity analyses were similarly insignificant, after adjustment for confounding. Total lymph node harvest was, however, increased after high tie surgery (P < 0.01), but no differences were seen regarding positive nodes (P = 0.72).

Conclusion: In this nationwide cohort study, the level of tie did not influence any patient-oriented oncological outcome, neither overall nor in node-positive patients. This would allow the patient's anatomical configuration and the surgeon's preferences to determine the level of tie.

Keywords
level of tie, ligation level, mortality, rectal cancer, recurrence, survival
National Category
Surgery
Research subject
Surgery
Identifiers
urn:nbn:se:umu:diva-166887 (URN)10.1097/SLA.0000000000003663 (DOI)
Available from: 2020-01-07 Created: 2020-01-07 Last updated: 2020-01-14
2. Level of vascular tie and its effect on functional outcome 2 years after anterior resection for rectal cancer
Open this publication in new window or tab >>Level of vascular tie and its effect on functional outcome 2 years after anterior resection for rectal cancer
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2017 (English)In: Colorectal Disease, ISSN 1462-8910, E-ISSN 1463-1318, Vol. 19, no 11, p. 987-995Article in journal (Refereed) Published
Abstract [en]

Aim Previous research indicates that high tie of the inferior mesenteric artery during anterior resection for rectal cancer might be associated with an increased risk of postoperative functional disturbances. The goal of this population-based retrospective cohort study was to further investigate that association.

Method Patients who underwent anterior resection for rectal cancer from April 2011 to September 2012 were identified through the Swedish Colorectal Cancer Registry. Bowel and urogenital function were assessed by a postal questionnaire 2 years after surgery. Information on the level of mesenteric tie and clinical variables was retrieved from the registry. The outcome was defined as any defaecatory, urinary or sexual dysfunction as reported by the patient. The association between high tie and the outcome was evaluated with multivariable logistic and linear regression with adjustment for confounders, such as sex, body mass index, comorbidity and preoperative radiation.

Results With a response rate of 86%, 805 patients were included in the study. Of these, 46% were operated with high tie. After adjustment for confounders, high tie did not affect the risk of faecal incontinence (OR 0.85; 95% CI 0.59-1.22), urinary incontinence (OR 0.94; 95% CI 0.63-1.41) or various aspects of sexual dysfunction (erectile dysfunction, anejaculation, dyspareunia and coital vaginal dryness). However, an association between high tie and defaecation at night was detected (OR 1.44; 95% CI 1.02-2.03).

Conclusion This study does not support that the level of vascular tie influences the risk of major defaecatory, urinary or sexual disturbances 2 years after anterior resection for rectal cancer.

Place, publisher, year, edition, pages
John Wiley & Sons, 2017
Keywords
Autonomic function, ligation level, faecal incontinence, urinary incontinence, sexual function
National Category
Gastroenterology and Hepatology
Identifiers
urn:nbn:se:umu:diva-141980 (URN)10.1111/codi.13745 (DOI)000414180900010 ()28544473 (PubMedID)
Available from: 2017-12-06 Created: 2017-12-06 Last updated: 2020-01-14Bibliographically approved
3. The Impact of Anastomotic Leakage on Long-Term Function after Anterior Resection for Rectal Cancer
Open this publication in new window or tab >>The Impact of Anastomotic Leakage on Long-Term Function after Anterior Resection for Rectal Cancer
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Background It is still not clear whether anastomotic leakage after anterior resection for rectal cancer affects long-term functional outcome.

Objective To evaluate how anastomotic leakage following anterior resection for rectal cancer influences defecatory, urinary and sexual function.

Design In this retrospective population-based cohort study, patients were identified through the Swedish Colorectal Cancer Registry, which was also used for information on the exposure variable anastomotic leakage, and covariates.

Settings A nationwide register was used for including patients.

Patients All patients undergoing anterior resection for rectal cancer in Sweden from April 2011– June 2013 were included.

Main Outcome Measures Outcome was any defecatory, sexual or urinary dysfunction, assessed two years after surgery by a postal questionnaire. The association between anastomotic leakage and function was assessed in multivariable logistic and linear regression models, with adjustment for confounding.

Results Response rate was 82%, resulting in 1180 included patients. Anastomotic leakage occurred in 7.5%. A permanent stoma was more common among leak patients (44% vs. 9%; p<0.001). Leakage patients had an increased risk of aid use for fecal incontinence (OR 2.27; 95% CI 1.20-4.30) and reduced sexual activity (90% vs. 82%; p=0.003), while the risk of urinary incontinence was decreased (OR 0.53; 95% CI 0.31-0.90). A sensitivity analysis assuming that a permanent stoma was created due to anorectal dysfunction strengthened the negative impact of leakage on defecatory dysfunction.

Limitations Limitations include the used questionnaire not having been previously validated, underreporting of anastomotic leakage in the register, and small patient numbers in the analysis of sexual symptoms.

Conclusions Anastomotic leakage was found to statistically significantly increase the risk of aid use due to fecal incontinence and reduced sexual activity, though the impact on defecatory dysfunction might be underestimated, as permanent stomas are sometimes fashioned due to anorectal dysfunction. Further research is warranted, especially regarding urogenital function.

Keywords
Anastomotic dehiscence, postoperative complications, incontinence, sexual function, dysfunction, anastomotic leakage, anorectalfunction
National Category
Surgery
Research subject
Surgery
Identifiers
urn:nbn:se:umu:diva-166884 (URN)
Note

Peer-review-granskat och accepterat för publikation i tidsskriften Diseases of the Colon & Rectum.

Available from: 2020-01-07 Created: 2020-01-07 Last updated: 2020-01-13
4. Nonsteroidal anti-inflammatory drugs and the risk of anastomotic leakage after anterior resection for rectal cancer
Open this publication in new window or tab >>Nonsteroidal anti-inflammatory drugs and the risk of anastomotic leakage after anterior resection for rectal cancer
Show others...
2017 (English)In: European Journal of Surgical Oncology, ISSN 0748-7983, E-ISSN 1532-2157, Vol. 43, no 10, p. 1908-1914Article in journal (Refereed) Published
Abstract [en]

Background: Nonsteroidal anti-inflammatory drugs (NSAIDs) have been widely used in colorectal surgery due to their opioid-sparing effect. However, several studies have indicated an increased risk of anastomotic leakage following NSAID treatment, although conflicting results exist. The primary goal of this study was to further examine whether postoperative NSAIDs are independently associated with anastomotic leakage after anterior resection for rectal cancer. Methods: Patients who underwent anterior resection for rectal cancer during 2007-2013 in 15 different hospitals in three healthcare regions in Sweden were included in the study. Registry data and information from patient records were retrieved. The association between NSAID treatment (for at least two days in the first postoperative week) and symptomatic anastomotic leakage (within 90 days) was evaluated with multiple logistic regression, with adjustment for pertinent confounding factors. Results: Some 1495 patients were included in the study. Of these, 27% received postoperative NSAIDs for at least two days in the first postoperative week. Symptomatic anastomotic leakage occurred in 11% and 14% in the NSAID and non-NSAID group, respectively. With adjustment for confounders, the odds ratio for leakage among patients who received NSAIDs compared with those who did not was 0.88 (95% CI 0.65-1.20). No differences were seen between non-selective and COX-2-selective NSAIDs. Conclusion: Postoperative NSAID treatment does not seem to increase the risk of symptomatic anastomotic leakage after anterior resection for rectal cancer. NSAID use appears to be safe, but a well-powered randomized clinical trial is warranted.

Place, publisher, year, edition, pages
Elsevier, 2017
Keywords
NSAID, COX-2 selective, Non-selective, Anastomotic dehiscence, Postoperative complications
National Category
Cancer and Oncology Surgery
Identifiers
urn:nbn:se:umu:diva-141825 (URN)10.1016/j.ejso.2017.06.010 (DOI)000413615600014 ()28687432 (PubMedID)
Available from: 2017-11-27 Created: 2017-11-27 Last updated: 2020-01-13Bibliographically approved

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