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A defunctioning stoma is used to alleviate the consequences of anastomotic leakage after low anterior resection for rectal cancer. A loop ileostomy is often preferred but may lead to dehydration and kidney injury. Here, we present a case series for an alternative: the left-sided loop colostomy. A convenience sample of four patients underwent robotic low anterior resection for rectal cancer. A complete splenic flexure mobilization and a total mesorectal excision were performed. To defunction the anastomosis, the redundant left colon was brought up to a stoma site in the left iliac fossa and matured as a loop colostomy. Two patients experienced minor stoma leaks and one also had a small prolapse, while all patients had their colostomies reversed on average 7 months after surgery without complications. There were no dehydration episodes and creatinine levels remained within baseline levels at end of follow-up (on average 18 months).

Background: Electrolyte disturbances and dehydration are common after anterior resection for rectal cancer with a defunctioning loop ileostomy. High-quality population-based studies on the impact of a defunctioning loop ileostomy on renal failure are lacking.

Methods: This was a nationwide observational study, based on the Swedish Colorectal Cancer Registry of patients undergoing anterior resection for rectal cancer between 2008 and 2016, with follow-up until 2017. Patients with severe co-morbidity, with age greater than 80 years, and with pre-existing renal failure were excluded. Loop ileostomy at index surgery constituted exposure, while a diagnosis of renal failure was the outcome. Acute and chronic events were analysed separately. Inverse probability weighting with adjustment for confounding derived from a causal diagram was employed. Hazards ratios (HRs) with 95 per cent c.i. are reported.

Results: A total of 5355 patients were eligible for analysis. At 5-year follow-up, all renal failure events (acute and chronic) were 7.2 per cent and 3.3 per cent in the defunctioning stoma and no stoma groups respectively. In the weighted analysis, a HR of 11.59 (95 per cent c.i. 5.68 to 23.65) for renal failure in ostomates was detected at 1 year, with the largest effect from acute renal failure (HR 24.04 (95 per cent c.i. 8.38 to 68.93)). Later follow-up demonstrated a similar pattern, but with smaller effect sizes.

Conclusion: Patients having a loop ileostomy in combination with anterior resection for rectal cancer are more likely to have renal failure, especially early after surgery. Strategies are needed, such as careful fluid management protocols, and further research into alternative stoma types or reduction in stoma formation.

Introduction: Numerous prior studies, even from countries with free access to care, have associated long travel time to care with poor survival in patients with colorectal cancer.

Methods: This is a data-linkage study of all 3718 patients with colorectal cancer, diagnosed between 2007 and 2013 in Northern Sweden, one of the most sparsely populated areas in Europe. Travel time to nearest hospital was calculated based on GPS coordinates and multivariable Cox regression was used to analyse possible associations between travel time and cause-specific survival.

Results: No association between travel time and survival was observed, either in univariable analysis (colon HR 1.00 [95% CI 0.998-1.003]; rectal HR 0.998; [95% CI 0.995-1.002]) or in multivariable Cox regression analysis (colon HR 0.999 [95% CI 0.997-1.002]; rectal HR 0.997 [95% CI 0.992-1.002]).

Conclusions: In contrast to most other studies, no association between travel time and colorectal cancer survival was found; despite that longer travel time was associated with known risk factors for poorer outcome. In the Swedish health care setting, travel time does not appear to represent a barrier to care or to negatively influence outcomes.

Whole-genome sequencing is a promising approach for human autosomal dominant disease studies. However, the vast number of genetic variants observed by this method constitutes a challenge when trying to identify the causal variants. This is often handled by restricting disease studies to the most damaging variants, e.g. those found in coding regions, and overlooking the remaining genetic variation. Such a biased approach explains in part why the genetic causes of many families with dominantly inherited diseases, in spite of being included in whole-genome sequencing studies, are left unsolved today. Here we explore the use of a geographically matched control population to minimize the number of candidate disease-causing variants without excluding variants based on assumptions on genomic position or functional predictions. To exemplify the benefit of the geographically matched control population we apply a typical disease variant filtering strategy in a family with an autosomal dominant form of colorectal cancer. With the use of the geographically matched control population we end up with 26 candidate variants genome wide. This is in contrast to the tens of thousands of candidates left when only making use of available public variant datasets. The effect of the local control population is dual, it (1) reduces the total number of candidate variants shared between affected individuals, and more importantly (2) increases the rate by which the number of candidate variants are reduced as additional affected family members are included in the filtering strategy. We demonstrate that the application of a geographically matched control population effectively limits the number of candidate disease-causing variants and may provide the means by which variants suitable for functional studies are identified genome wide.

Background

Colorectal cancer (CRC) – i.e., cancer in the colon or rectum – is one of the most common cancers both globally and in Sweden. The risk for CRC is mainly related to age, heredity, and life-style risk factors. Previous studies have also demonstrated that individuals with lower socioeconomic status (SES), living alone, or far from care facilities may have a higher risk for CRC or a worse outcome.  In contrast to life-style or sociodemographic-associated risks, an inherited risk for CRC is difficult to modify. However, colonoscopic surveillance programs can be help prevent CRC in families with a known hereditary risk.

The Northern Health Care Region (northern Sweden) is the most sparsely populated region in Sweden, and travel distances to care can be long. The population in Northern Sweden is on average older and has lower SES compared with the rest of the country. The impact of these sociodemographic differences on CRC in northern Sweden is not well known. 

Aim

This thesis analyses CRC in a northern Sweden setting with regards to incidence, survival, and associated sociodemographic risk factors, including prevention for individuals with increased hereditary risk.

Methods

Papers I and II, cohort studies from the Risk North database, link individual data from health care registers to other sociodemographic registers. In Paper I, the incidence, mortality, and survival for all CRC cases in northern Sweden were compared with the rest of Sweden for the period 2007-2013. Uni- and multivariable Cox regression analysis were used to assess the impact of sociodemographic factors and tumour stage on survival by calculating hazard ratios (HR). In Paper II, we analysed any association between travel time to care and CRC survival in northern Sweden during 2007-2013 using the same type of Cox regression analysis. 

Papers III and IV are based on a cohort of individuals with a family history of CRC, prospectively recorded from 1995 to 2012 in the colonoscopic surveillance register at the Cancer Prevention Clinic at Umeå University Hospital. In Paper III, we evaluated the cancer preventive effect of the performed colonoscopic surveillance. Observed cases of CRC were compared to a cohort estimate of cases without surveillance. Compliance with surveillance and colonoscopic quality was also analysed. In Paper IV, we examined the cost-effectiveness of the colonoscopic surveillance program in Paper III. A cost-utility analysis with a societal perspective was used and the stability of the results was tested in a sensitivity analysis.

Results

The age-adjusted incidence in colon cancer was 12.7% lower in northern compared to southern Sweden or 35.9/100 000 vs. 41.1/100 000 person years (p < 0.01). For rectal cancer, the incidence was 10.5% lower in the north (17.6 vs. 19.7 p <0.01). In subgroup analysis, the largest difference in incidence between northern and southern Sweden was found among individuals > 79 years age (colon - 190 vs. 237 ≈ 19.6%, rectal 72.4 vs. 88.0 ≈ 17.7%). For all of Sweden, the incidence in colorectal cancer was higher in males, individuals with lower SES, or individuals living alone. 

In univariable analyses of survival (all-cause and cause-specific) for colon and rectal cancer patients in all of Sweden, patients with high SES or co-habiting had a significantly better outcome compared to patients with low SES or living alone. HR for death ranged from 0.60 to 0.85 in the better-favoured risk group. No differences in colon or rectal cancer survival between northern and southern Sweden were demonstrated in the univariable analysis. 

However, in multivariable survival analysis, all-cause survival for colon cancer patients was better in southern Sweden (HR 0.92; 95% CI 0.86 – 0.97).  For cause-specific survival for colon cancer or in any analysis for rectal cancer, no differences between northern and southern Sweden were demonstrated. In analysis of travel time, no association between travel time and survival was found. 

In the evaluation of the colonoscopic surveillance programme, one case of CRC was observed, compared to 9.5-10.5 expected cases. Standardised Incidence Ratio (SIR) between observed and expected cases of CRC was 0.10 (CI 95% 0.0012–0.53) to 0.11 (CI 95% 0.0014–0.59. The compliance to the surveillance program was 90%. The adenoma detection rate was 14%, and 10% of the examinations were incomplete. In the cost-utility analysis, the net cost for surveillance was 233 038 €, while saving 64.8 Quality Adjusted Life Years (QALYs) compared to non-surveillance. The resulting Incremental Cost-Effectiveness Ratio (ICER) was 3596 €/QALY, ranging from -4620 €/QALY in the best-case scenario to 33 779 € /QALY in the worst-case scenario.

Conclusion

The incidence of CRC was lower in northern Sweden and most evident in the elderly, raising questions on differences in life-style between northern and southern Sweden in the past. There were considerable sociodemographic disparities in CRC survival in Sweden, including a lower all-cause survival for colon cancer patients in the north. In this study, travel time to care in northern Sweden did not affect survival and the lower all-cause survival in northern Sweden cannot be fully explained. The colonoscopic surveillance of families in northern Sweden with inherited risk for CRC had a good cancer preventive effect, including a high cost-effectiveness. The reasons for the good effect may be high compliance, since the quality of the colonoscopies was moderate.

Enkel sammanfattning på svenska

Bakgrund

Cancer i tjock- eller ändtarmen – även kallat kolorektalcancer – är en av de vanligaste formerna av cancer. Risken att insjukna i kolorektalcancer ökar med åldern, men risken påverkas även av ärftlighet och faktorer i vår livsstil, såsom kost och övervikt. Tidigare studier har också visat att individer med lägre utbildning eller inkomst (lägre socioekonomisk status) och de som lever ensamma eller har långt till sitt sjukhus kan ha större risk för att få kolorektalcancer eller en sämre överlevnad. Norra sjukvårdsregionen, som utgörs av regionerna(f.d. landstingen) Norrbotten, Västerbotten, Västernorrland och Jämtland-Härjedalen, är den mest glest befolkade delen av Sverige, med ibland långa avstånd till vårdinrättningar. Befolkningen i norra Sverige är också äldre och har en lägre utbildningsnivå jämfört med resten av landet.

Syfte

Att undersöka kolorektalcancer i norra Sverige – om hur utbildningsnivå, att leva ensam eller långt från sjukhus påverkar antalet nyinsjuknade(risken) eller överlevnaden i sjukdomen. Dessutom att utvärdera om ett program med regelbundna koloskopiundersökningar kan förhindra ärftlig kolorektalcancer.

Metod

Avhandlingen grundar sig på 4 olika studier(1-4). Studie 1 och 2 baseras på material från Risk Norr, som är en databas som länkar hälso-och sjukvårdsdata med andra samhällsregister. I studie 1 analyseras skillnader i risk och överlevnad för kolorektalcancer framförallt mellan norra och södra Sverige, med hänsyn till ojämlikheter i bl. a. utbildningsnivå. Studien omfattar alla nyinsjuknade patienter i landet under åren 2007-2013. Studie 2 undersöker om avståndet till närmsta sjukhus påverkade överlevanden för de patienter som diagnostiserades med kolorektalcancer i norra Sverige under åren 2007-2013. Materialet i studie 3 och 4 kommer från ett register över individer med misstänkt ärftlig kolorektalcancer i norra Sverige från åren 1995-2012. I studie 3 undersöks om ett program med regelbundna kontroller av tarmen med koloskopiundersökningar kunde förhindra uppkomst av cancer. Studie 4 är en hälsoekonomisk analys om de regelbundna koloskopiundersökningar i studie 3 är en kostnadseffektiv metod att förbygga cancer.

Resultat

Antalet nyinsjuknade per år, d.v.s. risk att få kolorektalcancer, var över 10 % lägre i norra jämfört med södra Sverige, trots att utbildningsnivån var högre i södra Sverige. Största skillnaden i risk mellan norra och södra Sverige fanns bland människor över 79 år. I hela Sverige var överlevnaden sämre för ensamboende patienter eller de med låg utbildningsnivå. I en överlevnadsanalys som jämför norra och södra Sverige, fanns inga skillnader i risken att dö i tjock- eller ändtarmscancer för patienter som diagnosticerats med en sådan cancer (sjukdomsspecifik överlevnad). Däremot hade patienter med tjocktarmscancer i norra Sverige en sämre överlevnad om man inkluderar alla dödsorsaker(total överlevnad). För ändtarmscancer fanns inga skillnader i total överlevnad. Avståndet till sjukhus påverkade inte överlevnaden. Utvärderingen av koloskopiprogrammet för individer med misstänkt ärftlig kolorektalcancer visade att endast 1 person av 261 undersökta fick cancer jämfört med ett förväntat antal av ca 10 personer under studietiden. I kostnadseffektivitetsanalysen av programmet var kostnaden för att rädda ett s.k. kvalitetsjusterat levnadsår ca 36 00o kr.

Slutsats

Risken för kolorektalcancer är lägre i norra Sverige, framförallt beroende på skillnader i risk hos äldre. Möjligen beror dessa skillnader på historiska olikheter i livsstilsrelaterade riskfaktorer. Överlevanden för patienter med kolorektalcancer var ojämlik i Sverige - med sämre överlevnad för ensamboende eller de med låg utbildningsnivå - men även för patienter med tjocktarmscancer i norra Sverige. Restid till sjukhus påverkade inte överlevnaden. Alla orsaker till den sämre överlevnaden i norra Sverige kan inte förklaras i den här avhandlingen, men skillnader i övrig sjuklighet kan ha en betydelse. Koloskopiprogrammet för individer med ärftlig risk i norra Sverige förhindrade uppkomst av kolorektalcancer och är kostnadseffektivt jämfört med svenska riktlinjer för kostnadseffektivitet och andra cancerförebyggande åtgärder.

Background: Geographic cancer health disparities have been reported in Sweden. The disparities are not fully understood, but may be attributed to differences in exposure to risk factors as well as differences in health care, socioeconomics and demography. The aim of this study was to describe the new nationwide population based RISK North database and its potential by analysing health disparities in colorectal cancer between Northern and Southern Sweden.

Methods: Cancer-specific data from the National Cancer Quality Registers for colorectal, gastric and oesophageal cancer and brain tumours were linked to several nationwide registers hereby creating a new database – RISK North. To exemplify the potential of RISK North, we analyzed differences in colorectal cancer incidence, mortality and survival in relation to gender, age, cohabitation and education between Northern and Southern Sweden 2007–2013.

Results: In colon cancer, the age-adjusted incidence per 100.000 was lower in Northern than Southern Sweden, 35.9 in the North vs. 41.1 in the South (p < .01); mortality rates were 11.0 vs. 12.2 (p < .01). For rectal cancer, incidence rates were 17.6 vs. 19.7 (p < .01) and mortality rates 5.33 vs. 5.89 (p = .07), respectively. The largest difference in incidence was demonstrated for colon cancer among individuals >79 years old (190. vs. 237, i.e., ∼20%). Survival in colon cancer was higher in Southern Sweden, HR 0.92 (0.87–0.98) adjusted for age, gender, co-habiting, education and m-stage at diagnosis. No difference in survival was seen for rectal cancer.

Conclusions: The new RISK North database enabled analysis of cancer disparities between Northern and Southern Sweden. The incidence of colorectal cancer were lower in the North of Sweden whereas colon cancer survival was higher in the South. These differences can be further analysed utilising the RISK North database.

Objective: Approximately 20-30% of all colorectal cancer (CRC) cases may have a familial contribution. The family history of CRC can be prominent (e.g., hereditary colorectal cancer (HCRC)) or more moderate (e.g., familial colorectal cancer (FCRC)). For family members at risk, colonoscopic surveillance is a well-established method to prevent both HCRC and FCRC, although the evidence for the exact procedures of the surveillance is limited. Surveillance can come at a high price if individuals are frequently examined, as this may result in unnecessary colonoscopies in relation to actual risk for CRC. This study analyses the cost-effectiveness of a surveillance programme implemented in the Northern Sweden Health Care Region.

Methods: The study includes 259 individuals prospectively recorded in the colonoscopic surveillance programme registry at the Cancer Prevention Clinic, Umea University Hospital. We performed a cost-utility analysis with a contrafactual design: we compared observed costs and loss of quality-adjusted life years (QALYs) due to CRC with the surveillance programme to an expected outcome without surveillance. The main measure was the incremental cost-effectiveness ratio (ICER) between surveillance and non-surveillance. Scenario analysis was used to explore uncertainty.

Results: The ICER between surveillance and non-surveillance in the base model was 3596Euro/QALY. The ICER varied from -4620Euro in the best-case scenario to 33,779Euro in the worst-case scenario.

Conclusion: Colonoscopic surveillance is a very cost-effective method to prevent HCRC and FCRC compared to current thresholds for cost-effectiveness and other cancer preventive interventions.

Although colonoscopic surveillance is recommended both for individuals with known hereditary colorectal cancer (HCRC) syndromes and those with a more moderate familial colorectal cancer (FCRC) history, the evidence for the benefits of surveillance is limited and surveillance practices vary. This study evaluates the preventive effect for individuals with a family history of CRC of decentralized colonoscopic surveillance with the guidance of a cancer prevention clinic. We performed a population based prospective study of 261 patients with HCRC or FCRC, recorded in the colonoscopic surveillance registry at the Cancer genetics clinic, University Hospital of Umeå, Sweden. Colonoscopic surveillance was conducted every second (HCRC) or fifth (FCRC) year at local hospitals in Northern Sweden. Main outcome measures were findings of high-risk adenomas (HRA) or CRC, and patient compliance to surveillance. Estimations of the expected numbers of CRC without surveillance were made. During a total of 1256 person years of follow-up, one case of CRC was found. The expected numbers of cancers in the absence of surveillance was between 9.5 and 10.5, resulting in a standardized incidence ratio, observed versus expected cases of CRC, between 0.10 (CI 95 % 0.0012–0.5299) and 0.11 (CI 95 % 0.0014–0.5857). No CRC mortality was reported, but three patients needed surgical intervention. HRA were found in 5.9 % (14/237) of the initial and in 3.4 % (12/356) of the follow-up colonoscopies. Patient compliance to the surveillance program was 90 % as 597 of the planned 662 colonoscopies were performed. The study concludes that colonoscopic surveillance with high patient compliance to the program is effective in preventing CRC when using a decentralized method for colonoscopy surveillance with the guidance of a cancer prevention clinic.