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Contains fulltext : 215772.pdf (Publisher’s version ) (Open Access) BACKGROUND: The time interval between CRT and surgery in rectal cancer patients is still the subject of debate. The aim of this study was to first evaluate the nationwide use of restaging magnetic resonance imaging (MRI) and its impact on timing of surgery, and, second, to evaluate the impact of timing of surgery after chemoradiotherapy (CRT) on short- and long-term outcomes. METHODS: Patients were selected from a collaborative rectal cancer research project including 71 Dutch centres, and were subdivided into two groups according to time interval from the start of preoperative CRT to surgery (< 14 and >/= 14 weeks). RESULTS: From 2095 registered patients, 475 patients received preoperative CRT. MRI restaging was performed in 79.4% of patients, with a median CRT-MRI interval of 10 weeks (interquartile range [IQR] 8-11) and a median MRI-surgery interval of 4 weeks (IQR 2-5). The CRT-surgery interval groups consisted of 224 (< 14 weeks) and 251 patients (>/= 14 weeks), and the long-interval group included a higher proportion of cT4 stage and multivisceral resection patients. Pathological complete response rate (n = 34 [15.2%] vs. n = 47 [18.7%], p = 0.305) and CRM involvement (9.7% vs. 15.9%, p = 0.145) did not significantly differ. Thirty-day surgical complications were similar (20.1% vs. 23.1%, p = 0.943), however no significant differences were found for local and distant recurrence rates, disease-free survival, and overall survival. CONCLUSIONS: These real-life data, reflecting routine daily practice in The Netherlands, showed substantial variability in the use and timing of restaging MRI after preoperative CRT for rectal cancer, as well as time interval to surgery. Surgery before or after 14 weeks from the start of CRT resulted in similar short- and long-term outcomes.

Aim A Snapshot study design eliminates changes in treatment and outcome over time. This population based Snapshot study aimed to determine current practice and outcome of rectal cancer treatment with published landmark randomized controlled trials as a benchmark.Method In this collaborative research project, the dataset of the Dutch Surgical Colorectal Audit was extended with additional treatment and long-term outcome data. All registered patients who underwent resection for rectal cancer in 2011 were eligible. Baseline characteristics and outcome were evaluated against the results of the Dutch TME trial and the COLOR II trial from which the original datasets were obtained.Results A total of 71 hospitals participated, and data were completed for 2102 out of the potential 2633 patients (79.8%). Median follow-up was 41 (interquartile range 25-47) months. Overall circumferential resection margin (CRM) involvement was 9.3% in the Snapshot cohort and 18.5% in the Dutch TME trial. CRM positivity after laparoscopic resection was 7.8% in the Snapshot and 9.5% in the COLOR II trial. Three-year overall local recurrence rate in the Snapshot was 5.9%, with a disease-free survival of 67.1% and overall survival of 79.5%. Benchmarking with the randomized controlled trials revealed an overall favourable long-term outcome of the Snapshot cohort.Conclusion This study showed that current rectal cancer care in a large unselected Dutch population is of high quality, with less positive CRM since the TME trial and oncologically safe implementation of minimally invasive surgery after the COLOR II trial.

Aim A Snapshot study design eliminates changes in treatment and outcome over time. This population based Snapshot study aimed to determine current practice and outcome of rectal cancer treatment with published landmark randomized controlled trials as a benchmark.Method In this collaborative research project, the dataset of the Dutch Surgical Colorectal Audit was extended with additional treatment and long-term outcome data. All registered patients who underwent resection for rectal cancer in 2011 were eligible. Baseline characteristics and outcome were evaluated against the results of the Dutch TME trial and the COLOR II trial from which the original datasets were obtained.Results A total of 71 hospitals participated, and data were completed for 2102 out of the potential 2633 patients (79.8%). Median follow-up was 41 (interquartile range 25-47) months. Overall circumferential resection margin (CRM) involvement was 9.3% in the Snapshot cohort and 18.5% in the Dutch TME trial. CRM positivity after laparoscopic resection was 7.8% in the Snapshot and 9.5% in the COLOR II trial. Three-year overall local recurrence rate in the Snapshot was 5.9%, with a disease-free survival of 67.1% and overall survival of 79.5%. Benchmarking with the randomized controlled trials revealed an overall favourable long-term outcome of the Snapshot cohort.Conclusion This study showed that current rectal cancer care in a large unselected Dutch population is of high quality, with less positive CRM since the TME trial and oncologically safe implementation of minimally invasive surgery after the COLOR II trial.

Occult nodal tumour cells should be categorised as micrometastasis (MMs) and isolated tumour cells (ITCs). A recent meta-analysis demonstrated that MMs, but not ITCs, are prognostic for disease recurrence in patients with stage I/II colon cancer. The objective of this retrospective multicenter study was to correlate MMs and ITCs to characteristics of the primary tumour, and to determine their prognostic value in patients with stage I/II colon cancer. One hundred ninety two patients were included in the study with a median follow up of 46 month (IQR 33-81 months). MMs were found in eight patients (4.2%), ITCs in 37 (19.3%) and occult tumour cells were absent in 147 patients (76.6%). Between these groups, tumour differentiation and venous or lymphatic invasion was equally distributed. Advanced stage (pT3/pT4) was found in 66.0% of patients without occult tumour cells (97/147), 72.9% of patients with ITCs (27/37), and 100% in patients with MMs (8/8), although this was a non-significant trend. Patients with MMs showed a significantly reduced 3 year-disease free survival compared to patients with ITCs or patients without occult tumour cells (75.0% versus 88.0% and 94.8%, respectively, p = 0.005). When adjusted for T-stage, MMs independently predicted recurrence of cancer (OR 7.6 95% CI 1.5-37.4, p = 0.012). In this study, the incidence of MMs and ITCs in patients with stage I/II colon cancer was 4.2% and 19.3%, respectively. MMs were associated with an reduced 3 year disease free survival rate, but ITCs were not

Background Neoadjuvant chemoradiotherapy (CRT) has been proven to increase local control in rectal cancer, but the optimal interval between CRT and surgery is still unclear. The purpose of this study was to analyse the influence of variations in clinical practice regarding timing of surgery on pathological response at a population level. Methods All evaluable patients who underwent preoperative CRT for rectal cancer between 2009 and 2011 were selected from the Dutch Surgical Colorectal Audit. The interval between radiotherapy and surgery was calculated from the start of radiotherapy. The primary endpoint was pathological complete response (pCR; pathological status after chemoradiotherapy (yp) T0 N0). Results A total of 1593 patients were included. The median interval between radiotherapy and surgery was 14 (range 6–85, interquartile range 12–16) weeks. Outcome measures were calculated for intervals of less than 13 weeks (312 patients), 13–14 weeks (511 patients), 15–16 weeks (406 patients) and more than 16 weeks (364 patients). Age, tumour location and R0 resection rate were distributed equally between the four groups; significant differences were found for clinical tumour category (cT4: 17·3, 18·4, 24·5 and 26·6 per cent respectively; P = 0·010) and clinical metastasis category (cM1: 4·4, 4·8, 8·9 and 14·9 per cent respectively; P < 0·001). Resection 15–16 weeks after the start of CRT resulted in the highest pCR rate (18·0 per cent; P = 0·013), with an independent association (hazard ratio 1·63, 95 per cent confidence interval 1·20 to 2·23). Results for secondary endpoints in the group with an interval of 15–16 weeks were: tumour downstaging, 55·2 per cent (P = 0·165); nodal downstaging, 58·6 per cent (P = 0·036); and (near)-complete response, 23·2 per cent (P = 0·124). Conclusion Delaying surgery until the 15th or 16th week after the start of CRT (10–11 weeks from the end of CRT) seemed to result in the highest chance of a pCR.

This thesis focuses on the surgical treatment of patients with Crohn’s disease. Part I describes and evaluates multiple treatment methods of perianal fistulas in patients with Crohn’s disease, especially the ligation of the intersphincteric fistula tract procedure and the advancement flap procedure. Multiple clinical outcome parameters as well as radiological healing after these surgical closure procedures were evaluated. Furthermore, outcome parameters after short-term anti-TNF therapy combined with surgical closure were directly compared to medical therapy only as treatment of Crohn’s perianal fistulas in the PISA-II trial; a patient preference randomised controlled trial. Both 18 month and long-term outcomes are described. Also, fistula characteristics on MRI after surgical closure and the relationship between those characteristics to patients’ clinical outcomes were evaluated, and it was evaluated whether certain MRI features could be used to predict clinical outcome in patients after surgical closure. Part II of this thesis focuses on multiple (new) surgical treatment strategies for different problems of Crohn’s disease. Important dilemmas for medically refractory or complex Crohn’s disease are discussed. Furthermore, a novel treatment method using the Semiflex Dome System, a catheter set for vacuum therapy of perianal abscesses and fistulas is described. Lastly, in order to make management of the complex problem of the chronically failing pouch more comprehensible and make results between different centres more comparable, a new classification system for the surgical treatment of the chronically failing ileo-anal pouch is suggested in this thesis.

This dissertation examines the innovations in the surgical treatment of the chronic intestinal disease ulcerative colitis (UC). There is a range of medical therapies that a patient with UC can use to reduce symptoms and/or colonic disease. In case medication lacks efficacy, surgical treatment may be an option or, in some cases, necessary. The first part of my dissertation focuses on the role of the appendix in UC. Over the past decades, research has shown that removing the appendix protects against developing UC. For this reason, appendectomy as a therapy for UC has been examined. Promising results have been described thus far. This dissertation supports the findings of previous research; appendectomy can reduce the severity of UC and/or delay a potential later colectomy. Approximately half of the patients who underwent an appendectomy showed long-term improvement in disease activity of the intestinal wall. This dissertation also contributes to the identification of patients with an inflamed appendix through endoscopy and/or ultrasound examination. Patients with an inflamed appendix seem to benefit more from an appendectomy. If neither medication nor appendectomy mitigates UC, the ultimate surgical intervention for refractory UC is removal of the entire colon, including the rectum (proctocolectomy). A new rectum can be created out of small intestine tissue, known as a pouch. This complex operation is called a proctocolectomy with ileal pouch-anal anastomosis (IPAA). IPAA surgery is known to be a complicated procedure. This dissertation maps out common causes of pouch failure and the best intra- and postoperative approach to reduce and treat complex long-term complications, particularly pouch failure. In conclusion, this dissertation paves the way for the surgical approach to UC.

Ulcerative colitis is a burdensome chronic inflammatory bowel disease that has a serious impact on the lives of mainly young adults. Fortunately, the medical and surgical treatment of ulcerative colitis is a continuously developing field. The aim of this thesis was to contribute to improvements in the surgical treatment and outcomes of patients with ulcerative colitis. Part I of this thesis focusses on the surgical management of ulcerative colitis in the biological era, indication shift for colectomy from therapy refractory disease to colorectal cancer and postoperative outcomes following ileal pouch–anal anastomosis (IPAA). In Part II, the effect of a laparoscopic appendectomy on the disease course of patients with ulcerative colitis and the potential underlying mechanisms between the appendix and ulcerative colitis are addressed.

Colorectal surgery still has a relatively high risk for complications. Especially anastomotic leakage is associated with high morbidity, mortality and costs. This thesis aimed to show the effect of quality improving interventions to lower complication rates after colorectal surgery and identify interventions that can be easily implemented in community hospitals with direct impact on surgical outcome. In the first part of this thesis we show that the introduction of a relatively simple set of clinical measures reduced postoperative complications. In a second study we show that screening for frailty, and consequently postoperative medium care observation of frail patients led to a significant decrease in complication rates and was cost efficient. The second part focuses on diagnostic instruments to detect or rule out anastomotic leakage to achieve early reinterventions and thereby reducing mortality. In our study we investigate the accuracy of CT scanning and show that rectal contrast improves the accuracy of detecting anastomotic leakage significantly. We also investigate the predictive value of C-reactive protein for anastomotic leakage and describe how it can best be used. The third part concentrates on benign colon polyps that are too large or complex to remove during endoscopy. Our studies show that the number of patients referred for an oncological resection due to benign polyps tripled after introduction of the screening program in 2014, but complication and mortality risk after surgery are the same as for oncological patients. We show that laparoscopic wedge excision, as an alternative, could be a safe, less invasive option.

De ziekte van Crohn is een inflammatoire darmziekte, waarbij de ziekte zich kan uitbreiden tot buiten de darm. Hierdoor kunnen perianale complicaties ontstaan, zoals peri-anale of rectovaginale fisteling. Een zeldzame complicatie is het “uitzaaien” van de ziekte van Crohn (metastatische Crohn), waarbij de ziekte actief is in wonden in de huid zonder dat er een verbinding bestaat met de darm. Al deze complicaties zijn lastig te behandelen, waarbij succespercentages van huidige behandeling (medicamenteus dan wel chirurgisch) tegenvallen. Hyperbare zuurstoftherapie is een behandeling waarbij 100% zuurstof wordt toegediend onder een verhoogde omgevingsdruk. Hierdoor neemt de partiële zuurstofdruk in weefsels in het lichaam toe, wat een effect heeft op o.a. inflammatie en wondgenezing. De behandeling wordt wereldwijd en in Nederland al toegepast voor een aantal ziektebeelden (zoals diabetische ulcera, bestralingsschade of koolstofmonoxide), en in de literatuur bestaan ook aanwijzingen dat behandeling een positief effect kan hebben op perianale complicaties van de ziekte van Crohn. In dit proefschrift worden de uitkomsten van de behandeling van patiënten met peri-anale fistels, rectovaginale fistels en metastatische ziekte van Crohn met hyperbare zuurstoftherapie beschreven. Daarnaast wordt gekeken naar een MRI-index als uitkomstmaat voor het meten het resultaat van behandeling van perianale fistels, en wordt een overzicht gegeven van de verschillende manieren waarop in het verleden placebotherapie is gegeven in randomised controlled trials met hyperbare zuurstoftherapie.

This thesis describes the implementation and scale up of video consultation at a tertiary referral center. Before video consultation can be implemented and used sustainably in healthcare, it is vital to involve patients and address their needs and requirements of receiving care over a video connection. Therefore the aim of this thesis was to provide the most optimal implementation strategy for video consultation in healthcare based on scientific research. We have researched patient- and provider needs in order to understand their preferences when it comes to digital care. Next, patient- and provider satisfaction with video consultation was evaluated when compared to both physical as telephone consultation. Based on this strategy video consultation was implemented at the surgical outpatient clinic. During the COVID-19 pandemic we were able to scale-up to all outpatient departments. Again, patient and provider satisfaction and willingness to use video consultation was evaluated. Both technical as workflow aspects of the scale up are described in detail. This thesis indicates that the use of video consultation for outpatient care appointments is feasible, and accepted by both patients as well as providers without a detriment to the quality of care provided. There are still a few difficulties that hamper the structural use of video consultation in clinical practice today. But as soon as “Why?” becomes, “Why did we not do this before?”, we can work towards a climate in which receiving care at the right moment, at the right place can be supported by the convenience of digital care.

Dit proefschrift laat zien hoe uitdagend het kan zijn om de chirurgische behandeling van inflammatoire darmziekten (IBD) te verbeteren op nationaal en internationaal niveau. Hoofdstuk 1 omvat de PISA- RCT waarin de huidige drie behandelingen voor perianale Crohnse fistels met elkaar worden vergeleken (seton drainage vs. Anti-TNF en chirurgisch sluiten). Het bleek dat seton drainage geassocieerd was met meer reïnterventies, waardoor langdurige seton drainage niet langer moet worden geadviseerd als enige behandeling voor perianale Crohnse fistels. Ook is er gekeken of het randomiserende karakter van de PISA-studie invloed heeft gehad op het aantal deelnemende patiënten en op de studie-uitkomsten. Een alternatieve studieopzet is een partially randomised patient preference trial (RPPT), waarin patiënten kunnen worden geïncludeerd op basis van randomisatie en op basis van hun eigen behandelvoorkeur. De RPPT lijkt een goed alternatief voor studies waarin medicamenteuze met chirurgische behandelingen worden vergeleken. In tegenstelling tot oncologische resectie, wordt tijdens darmresecties bij IBD-patiënten alleen het macroscopische aangedane stuk darm gereseceerd. In dit proefschrift is de invloed van inflammatie in de resectiemarges en in het mesenterium bij ileocoecaalresecties bekeken. Het reseceren van een ruimer stuk ileum of mesenterium lijkt niet zinvol. Veelal wordt in ziekenhuizen prioriteit gegeven aan oncologische zorg ten faveure van benigne ziektebeelden zoals IBD. Echter een langere wachttijd tot IBD operaties resulteert in veel ziekte-gerelateerde complicaties. Ten aanzien van de chirurgische techniek is onderzocht dat een transanale ileo-anale pouch bij colitis ulcerosa patiënten een veilige procedure is. Het vroeg sluiten van een pouch naadlekkage met behulp van endosponge therapie resulteert in het behoudt van pouchfunctie. Tot slot, kwam in het laatste hoofdstuk aan het licht dat patiënten met rectumstomp inflammatie vaker pouchitis hebben. Mogelijk ligt een agressiever colitis ulcerosa-fenotype hieraan ten grondslag. In conclusie, chirurgie kan eerder en vaker worden toegepast in de multidisciplinaire behandeling van IBD.

This thesis describes multiple surgical treatment options in patients with ulcerative colitis (UC) and perianal Crohn’s disease (CD). An appendectomy is suggested to have a beneficial effect on UC, however, some recently published data reported an increased risk of colorectal cancer (CRC). Part I confirms that a higher proportion of colectomies after appendectomy in UC is undertaken for CRC, but less for active colitis. We found an 84% decrease in colectomies and a delay in surgery. Furthermore, an appendectomy resulted in a clinical response in 46%, and 25% were in endoscopic remission after 4 years. Since the colon is longer in situ, the risk of CRC remains, which emphasises the importance of endoscopic surveillance. Part II describes the results after restorative proctocolectomy and ileal pouch-anal anastomosis. Our research demonstrated that both techniques of double-end ileosigmoidostomy and end ileostomy with closed rectal stump are safe and effective. With respect to small bowel obstruction, the modified 2-stage IPAA seems the safest. In case of anastomotic leakage, long-term pouch function can be preserved with endo-sponge assisted early surgical closure. Part III evaluates treatment options for high perianal fistulas in CD. We found that the knotless SuperSeton is a feasible novel technique which significantly improves fistula related quality of life. Definitive closure of the perianal fistulas can be achieved by the endorectal advancement flap and ligation of the intersphincteric fistula tract with comparable success and recurrence rates. Finally, the different treatment options were head-to-head compared in the randomised PISA-trial, which showed inferior outcomes for chronic seton drainage.

Although the vermiform appendix was generally regarded to be an evolutionary remnant, a substantial body of evidence has accumulated supporting its role in the development and course of UC. This thesis aims to investigate what the role of the appendix is in IBD, evaluate the natural history of UC, and demonstrate risk factors for postoperative complications after pouch surgery. Clinical studies were systematically reviewed and meta-analysed. The majority of the studies showed a significant inverse association between an appendectomy and the development of UC. Some studies found that previous appendectomy patients had a lower relapse rate, less steroid use and a decreased risk of colectomy. Furthermore, evidence elaborated in this thesis support the idea that a defective function and interaction with gut flora in the appendix play an essential role in the aetiology and probably also in the onset of UC. One third of UC patients with left-sided disease extended proximally during 10 years of follow up. The cumulative colectomy rate did not decrease over time. Anastomotic leakage represents a major early complication after IPAA surgery, which can lead to pouch dysfunction or pouch failure. Long-term disease course and the concurrent combination of steroid and anti-TNF treatment before IPAA surgery were independent risk factors for anastomotic leakage in IBD patients that underwent a proctocolectomy. Being overweight and high ASA score were independent risk factors in patients that underwent a completion proctectomy and IPAA at a later stage. These risk factors enable a tailored approach in patients undergoing IPAA surgery.

For localized colorectal cancer (CRC), lymph node metastases are the most powerful prognostic factor for disease specific and overall survival. In the first part of the thesis, we explore the prognostic role of lymph nodes in patients with stage I/II colon cancer. In these patients, nodal metastases are not detected with conventional pathological examination. Additional immunohistochemistry in the sentinel lymph node can reveal isolated tumour cells and micrometastasis. Studies in this thesis show that patients with micrometastasis have an increased risk of disease recurrence. Isolated tumour cells are not associated with worse prognosis. We also describe a positive correlation between lymph node size, lymph node harvest and prognosis. The second part of the thesis addresses several aspects of a multi-modality approach in the treatment of CRC. The aim of curative surgery for CRC is radical resection of the tumour. This can be difficult when tumours are large and advanced, or when emergency surgery is required because of obstructive tumours. In addition, microscopic tumour seeding within the peritoneal cavity might occur unnoticed. In these situations, surgical treatment alone is not sufficient to cure the patient and a multimodality approach should be applied. We analyzed the chance of a pathological complete tumour response after neoadjuvant chemoradiotherapy (CRT) for rectal cancer and calculated the optimal timing of surgery after (CRT). In addition, we describe the long term oncological follow up of patients that have been treated for obstructive colon cancer, and describe how adjuvant intraperitoneal chemotherapy might prevent the outgrow of peritoneal metastasis.

Kijkoperaties van de dikke darm leiden op de lange termijn tot minder littekenbreuken en minder (complicaties van) verklevingen in de buik. Sanne Bartels beschrijft de effecten van kijkoperaties van de dikke darm. Het was al bekend dat er ten opzichte van standaardchirurgie voordelen zijn op de korte termijn, zoals een sneller herstel, een kortere ligduur, minder wondinfecties en kleinere littekens. Het is bekend dat de vaak jonge vrouwelijke patiënten die een ileo-anale pouchoperatie via een grote incisie in de buik ondergaan bij colitis ulcerosa (ontstekingen van de dikke darm) minder kans hebben op een zwangerschap na de operatie door verklevingen aan de eileiders. Na een kijkoperatie werden deze patiënten sneller en vaker zwanger.

Bij de behandeling van borstkanker is het de standaardpraktijk: checken of de ‘schildwachtklier’ die bij de tumor hoort, vrij is van kwaadaardige cellen. Edwin van der Zaag pleit ervoor dezelfde procedure te volgen bij darmkanker. Chirurgen doen er volgens hem goed aan bij het wegnemen van een stuk darm met tumoren te checken welke lymfeklier de zogenoemde ‘schildwachtklier’ is die bij de tumor hoort. Daarna is het aan de patholoog om te beoordelen of deze vrij is van tumorcellen. Als eventuele vervolgbehandelingen worden afgestemd op de bevindingen in de schildwachtklier is veel winst te behalen, denkt Van der Zaag. Van de patiënten die worden geopereerd aan kanker in de dikke darm of de endeldarm, en die volgens de huidige procedure schone lymfeklieren hebben, krijgt ongeveer dertig procent toch weer kanker. Kijk je via de schildwachtprocedure, dan blijkt dertig procent van degenen met veronderstelde schone klieren toch tumorcellen in de schildwachtklier te hebben.