Transforming Outcomes in Colorectal Surgery Danique J.I. Heuvelings
Transforming Outcomes in Colorectal Surgery Danique J.I. Heuvelings
Copyright 2024 Danique Heuvelings All rights reserved. No part of this thesis may be reproduced, distributed or transmitted in any form or by any means, without the prior written permission of the author or when applicable, publishers of the included scientific papers. ISBN: 978-94-6506-658-5 Printed by: Ridderprint, ridderprint.nl Layout and design: Tara Schollema, persoonlijkproefschrift.nl Cover design: Catharine Labarca Parts of the studies in this thesis were financially supported by the American Society of Colon and Rectal Surgeons (ASCRS), European Association for Endoscopic Surgery (EAES), Stichting Jules Coenegracht Sr., and KWF Kankerbestrijding. Publication of this thesis was financially supported by Maastricht University, Maastricht University Medical Center+, De Nederlandse Vereniging voor Evolutionaire Chirurgie (NVEC), LIMIS Development BV, and Quest Medical Imaging (Olympus). The work presented in this thesis was performed within NUTRIM School of Nutrition and Translational Research in Metabolism.
Transforming Outcomes in Colorectal Surgery PROEFSCHRIFT voor het behalen van de graad van Doctor aan de Universiteit Maastricht, in opdracht van de Rector Magnificus, Prof. Dr. Pamela Habibović, overeenkomstig met het besluit van het College van Decanen, te verdedigen in het openbaar op vrijdag 20 december 2024 om 16u00 door Danique Joep Ingrid Heuvelings geboren op 13 november 1996 te Roosendaal
Promotor Prof. Dr. Nicole D. Bouvy, Universiteit Maastricht Copromotores Dr. Stephanie O. Breukink, Universiteit Maastricht Dr. Mahdi Al-Taher, Tawam Hospital United Arab Emirates Dr. Patricia Sylla, The Mount Sinai Hospital New York City Beoordelingscommissie Prof. Dr. Geerard L. Beets, Universiteit Maastricht (voorzitter) Prof. Dr. Wim G. van Gemert, Universiteit Maastricht Dr. Denise E. Hilling, Erasmus Universiteit Rotterdam Dr. Sven D. Mieog, Universiteit Leiden Prof. Dr. Rutger M. Schols, Vrije Universiteit Brussel en Universiteit Maastricht
TABLE OF CONTENTS Chapter 1 Introduction and outline of the thesis 9 Part I Increasing international consensus on current evidence and reporting of anastomotic leaks after colorectal cancer surgery Chapter 2 Quality of reporting on anastomotic leaks in colorectal trials: A systematic review 25 Chapter 3 International Consensus on Reporting Anastomotic Leaks after colorectal cancer surgery: The CoReAL reporting framework 61 Chapter 4 Proposal of a Reporting and Data System for Colorectal Anastomotic Leakage (CAL-RADS): A study protocol for a categorical CT assessment scheme 89 Part II Improving bowel perfusion assessment to reduce the risk of anastomotic leaks Chapter 5 Simultaneous fluorescence imaging of bowel perfusion and ureter delineation using methylene blue: a demonstration in a porcine model 101 Chapter 6 Quantitative analysis of intestinal perfusion with indocyanine green (ICG) and methylene blue (MB) using a single clinically approved fluorescence imaging system: a demonstration in a porcine model 121 Chapter 7 Real-time intestinal perfusion assessment for anastomotic site selection using Laser Speckle Contrast Imaging: verification in a porcine model 137 Chapter 8 Real-time quantification of Laser Speckle Contrast Imaging during intestinal laparoscopic surgery: successful demonstration in a porcine intestinal ischemia model 153 Part III Patients’ perspectives on colorectal anastomotic leaks Chapter 9 Impact of anastomotic leakage after colorectal cancer surgery on quality of life: A systematic review 175 Chapter 10 The patient perspective on colorectal anastomotic leaks: A qualitative study 205 Part IV Prevention of metachronous peritoneal metastases after colorectal cancer surgery Chapter 11 DNA and RNA alterations associated with colorectal peritoneal metastases: A systematic review 229 Chapter 12 Predictive genetic biomarkers for the development of peritoneal metastases in colorectal cancer 275 Chapter 13 Evaluation of the effect of an intraperitoneal cytostatic-loaded supramolecular hydrogel on intestinal anastomotic healing in an animal model 297
Part V Summary, discussion, future perspectives, and impact Chapter 14 Summary, general discussion and future perspectives 319 Chapter 15 Impact paragraph 347 Chapter 16 Dutch summary | Nederlandse samenvatting 355 Part VI Appendices Acknowledgments | Dankwoord 368 Scientific output 374 About the author 376
1 CHAPTER GENERAL INTRODUCTION
10 Chapter 1 COLORECTAL CANCER Colorectal cancer (CRC) ranks as the third most prevalent cancer globally, comprising around 10% of all cancer cases. Moreover, it stands as the second primary cause of cancer-related deaths worldwide 1. The primary approach for curative treatment of CRC involves surgical removal of the tumor and adjacent lymph nodes. Choice of the best surgical procedure depends on the tumors’ location and patients’ condition, but often involves the creation of a primary anastomosis. The emphasis on improving patient outcomes in colorectal surgery has emerged as a central focus in medical research and clinical care. It is crucial to implement strategies to prevent associated complications to mitigate the impact of CRC surgery and improve patients’ outcomes. The most feared complication after colorectal surgery is anastomotic leakage (AL). It is known that AL patients have a worse overall survival and poorer oncological outcomes, especially after rectal cancer surgery 2-4. Besides, the most important and ultimately life-threatening feature of CRC is the ability to still metastasize after curative surgery. These so-called metachronous metastases have the poorest outcomes when they spread to the peritoneum, as treatment options are limited 5. Minimizing the risk to prevent both AL and PM after colorectal surgery is essential as their development can lead to cancer progression, decreased quality of life, and poorer prognosis. As prevention is better than cure, taking proactive measures to minimize risks through meticulous surgical techniques, appropriate perioperative care, and early detection strategies can significantly improve patient outcomes and reduce the need for more complex and aggressive treatments later on. ANASTOMOTIC LEAKAGE Background AL represents the most common major complication following colorectal resections. Severity of AL spans from minor defects with no evident extravasation of air or fluid to significant dehiscence, with or without localized abscess, phlegmon, and diffuse purulent and/or fecal peritonitis 6, 7. These leaks can manifest early or late postoperatively, taking the form of fistulae, anastomotic strictures, chronic sinuses, or abscess cavities 7, 8. The clinical impact of AL varies from minimal or no symptoms, particularly in diverted patients, to substantial morbidity and mortality arising from abdominal and/or pelvic sepsis 9. AL also exerts a detrimental influence on oncological outcomes, functional results, and quality of life due to the necessity for reoperation, permanent diversion, or delayed ostomy reversal 9-12. Difficult etiology and heterogeneous presentation of AL is reflected by its wide reported incidence rates, ranging from 2% to 25% 10-12. Reporting of AL Despite the growing number of literature that delves into the occurrence, origins, risk factors, treatment methods, and short/long-term consequences of AL after colorectal
11 General introduction surgery, interpreting the findings remains challenging due to significant heterogeneity in AL reporting 13. This variation not only impacts reported incidence rates in clinical registries but also undermines the reliability of reported outcomes among colorectal surgery patients. Examination of an extensive colorectal dataset in the Netherlands has suggested a potential underestimation of AL rates following colorectal cancer resections in international literature 9. The audit suggests that AL may intricately be involved in up to 23% of low anterior resections, especially when considering both acute and delayed leaks, as well as leaks that may manifest asymptomatically in patients with fecal diversion. This underscores the imperative need for a standardized and widely acknowledged definition of AL in colorectal surgery, as the absence of such a consensus limits the meaningfulness of comparing outcomes across wordwide medical centers. The lack of uniformity in AL definitions also hampers efforts to identify and categorize risk factors, standardize treatment protocols, and implement quality improvement initiatives with the objective to reduce AL occurrences. Furthermore, the lack of consensus also influences surgical trials investigating AL rates, particularly when AL is specified as the primary endpoint. In 2010, the International Study Group of Rectal Cancer (ISREC) published a consensus on definition and grading AL, particularly in the context of anterior resection for rectal cancer, which stands out as the most frequently referenced and has garnered support through validation 14. However, despite its acknowledgment, this definition has not garnered widespread endorsement from surgical societies or widespread adoption among practicing surgeons. Although several consensus guidelines and position statements aiming to establish standardized definitions of AL 8, 13-15, a universally accepted definition remains elusive. Yet, consensus on the radiologic definition or standardized assessment of CT-scans is also still lacking 13, 15. Risk factors for AL Although the creation of an anastomosis is a surgical technique, numerous patient related risk factors linked to a higher risk of the development of AL have been identified, offering opportunities for improved prevention and early detection of this significant complication. Nonmodifiable factors, including male gender, comorbidities, and the tumor’s proximity to the anal verge, are among these contributors that can be assessed before surgery. Modifiable risk factors encompass smoking, alcohol consumption, obesity, neoadjuvant treatment, and the use of certain drugs 16. Beside preoperative patients factors, intraoperative factors may also play a rol. The most important one is adequate blood perfusion, which is widely recognized as a crucial factor for the successful healing of the anastomosis and thereby reducing the risk of AL 17. Bowel perfusion assessment Adequate anastomotic perfusion is important for anastomotic healing, as good blood flow promotes tissue viability, cellular metabolism, and collagen synthesis, all of which are critical 1
12 Chapter 1 for the formation of a strong and durable anastomosis. Insufficient perfusion can lead to tissue ischemia, delayed wound healing, and ultimately an increased risk of anastomotic breakdown and leakage 18. Hence, there is a rising interest in employing real-time perfusion assessment techniques to aid in surgical decision-making and enhance outcomes. Through the identification of tissue areas exhibiting compromised perfusion, surgeons can potentially steer clear of establishing an anastomosis in those regions, opting instead for tissues with more favorable perfusion. The most common intraoperative adjunct to assess bowel perfusion is by using near-infrared fluorescence angiography (NIRF). In short, a fluorophore is intravenously injected and, upon excitation at a specific wavelength, emits light at another specified wavelength (typically infrared) immediately following vessel division and/or completion of the anastomosis 17. Using an optic dye like indocyanine green (ICG) have proved to be effective for bowel perfusion assessment and AL reduction after colorectal surgery 19-22. As this technology enhances intraoperative decision-making by guiding surgeons to optimize perfusion and minimize the risk of AL, optimalisation of fluorescence imaging with new and better camera systems, development new optical dyes, quantification methods and assessing outcomes in large trials, is very popular in fluorescence-guided surgery research. Besides, near infrared fluorescence imaging can be used to visualize other structures too, like lymph nodes and the ureter, and might be helpful for multiple purposes during surgery. Another technique that has emerged as promising modality for real-time assessment of bowel perfusion is laser speckle contrast imaging (LSCI). It is a non-invasive imaging technique that assesses blood flow dynamics by exploiting the speckle pattern created when coherent light interacts with moving objects, in particular red blood cells 23. Previous research indicates that LSCI can achieve real-time intraoperative visualization of intestinal micro perfusion deficits, allowing for accurate prediction postoperative ischemic complications 24, 25. Therefore, LSCI can be a useful tool to mitigate ischemia-related complications such as AL and improve patients’ outcomes after CRC surgery. With this revealing capacity, it is important to perform additional preclinical validation, quantification, and feasibility assessment of LSCI to facilitate its potential in surgical decision-making when constructing colorectal anastomoses. Long-term oncological outcomes Already 15 years ago, an analysis of patients who did develop AL after lower anterior resections (LAR) for rectal cancer, showed that overall survival was reduced, but oncologic outcomes were not significantly influences by AL 26. Later, a meta-analysis on this topic concluded that AL was associated with high local recurrence and poor survival (both overall and cancer-specific), but not with distant recurrence after anterior resections 27. More recent studies showed that rectal cancer patients who developed AL after anterior resection or laparoscopic total mesorectal excisions (TME) had an increased risk of local recurrence, and even a decrease in overall survival, cancer-specific survival, and disease-free survival 2-4. In
13 General introduction contrast, some studies did not find these significantly higher recurrence rates 28, 29. For colonic resections, a systematic review including 69,047 patients in which 2,555 patients developed AL, found that AL was significantly associated with impaired overall survival, disease free survival and cancer specific survival, but not with higher recurrence rates 30. These similar findings were also published later on by a study including both colon and rectal cancer patients 31. They showed that long-term oncological outcomes were negatively influenced by the occurrence of AL after rectal cancer surgery, but not for colon cancer; although the authors stated this was probably due to low power of this study. A recent large retrospective Dutch population-based study including 65,299 colon cancer patients and 22,855 rectal cancer patients stated that AL had a stage-dependent negative impact on survival, but no independent association with disease recurrence after CRC resection 32. Although oncological outcomes are not always significantly influenced by the occurrence of a leak, we know that survival rates are impaired for CRC patients after AL. Yet, it is necessary to avoid any further risk of poorer oncological and survival outcomes, which can be achieved by risk reduction of recurrence/metastatic spread after curative CRC surgery. PERITONEAL METASTASES Background Peritoneal metastases (PM), commonly referred to as peritoneal carcinomatosis, signify the dissemination of metastatic lesions across the peritoneal surface within the abdominal cavity. These deposits possess the capability to infiltrate abdominal organs and structures, frequently leading to complications such as bowel obstruction, ureteral obstruction, and malignant ascites 33. They may be identified either during the initial treatment of the primary tumor (referred to as synchronous PM) but also through follow-up assessments after primary surgery (referred to as metachronous PM) 34. The incidence of metachronous PM is estimated in 4–12% of patients who undergo curative resection for colon cancer and in 2–19% of patients who undergo curative resection for rectal cancer 35, with an estimated average of 5% in all colorectal patients 33. Although recurrence as PM seems to be a rare event in CRC patients after curative resection, consequences are notably significant. It is generally considered as a palliative situation when extensive spread is present as the typical life expectancy following diagnosis of PM spans from six to twelve months if no intervention takes place 36-38. The limited efficacy of routine imaging techniques often leads to a failure in detecting PM, attributed to their small size and the inherently low contrast resolution of soft tissue in which they manifest. Consequently, their true incidence is probably underestimated, which is also reflected by autopsy reports 5, 33, 35, 39. 1
14 Chapter 1 Treatment options Only a selection of physically fit patients with limited colorectal PM (based on a low peritoneal cancer index (PCI) score) are considered eligible for current available treatment options 33. The most common applied treatment is the surgical removal of all visible tumor deposits which is called cytoreductive surgery (CRS), followed by the application of heated chemotherapy in the abdominal cavity, known as hyperthermic intraperitoneal chemotherapy (HIPEC). Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is also increasingly investigated as a palliative treatment option for patients 40. Nonetheless, the exposure of tumor cells to the cytostatic drug remains restricted in both HIPEC and PIPAC, diminishing the therapeutic effectiveness 41. Subsequently, minimally invasive alternatives that are applicable to a larger selection of patients with prolonged exposure of the cytostatic to the cancer cells are currently investigated. Recently, new research has been done to develop such a new minimally invasive treatment for PM, namely intraperitoneal administration of a cytostatic-loaded supramolecular hydrogel 41-43. These previous investigations demonstrated enhanced survival among animals subjected to mitomycin C (MMC)-loaded hydrogels in a PM model. Given the promising nature of these findings, there arises not only potential interest in employing this approach as a therapeutic intervention but also in considering its application as a prophylactic intervention during primary surgery to mitigate the likelihood of metachronous PM in at-risk patients. It is therefore important to further investigate this hydrogel in colorectal surgery setting. Risk factors and prevention Given that the prospects for preventing metachronous peritoneal metastases (PM) are more encouraging than for synchronous PM, previous research on risk factors for metachronous PM is more comprehensive 33. Various studies indicate that independent risk factors for metachronous PM include advanced tumor stages, infiltration of the radial margin, elevated preoperative tumor markers, emergency surgery, a primary tumor in the colon rather than the rectum, and the presence of free intraperitoneal cancer cells both before and/or after the resection of the primary tumor 33, 44, 45. Currently, these clinical risk factors do not function as a landmark to apply certain prophylactic treatments. In recent years, there has been a growing recognition of the potential role of biomarkers in disease course prediction and not only offering a promising avenue for early detection, but also for potential preventive interventions 46. The role of biomarkers may play an interesting role in the prevention of metachronous colorectal PM. If specific biomarkers, based on DNA/RNA alterations identified in the primary colorectal tumor during curative surgery, could characterize colorectal PM patients that have a higher risk of developing metachronous PM, these patients may benefit from preventive treatments regimes.
15 General introduction AIMS AND OUTLINE OF THIS THESIS By examining innovative approaches and intercontinental expert opinions, this thesis aims to shed light on promising avenues that contribute to improved patient outcome after CRC surgery. While this thesis may not offer unequivocal solutions to the aforementioned discussion points, it does present novel perspectives within four distinct areas; evidence overview and reporting of colorectal AL, improvement of bowel perfusion assessment, impact of colorectal AL on patients, and prevention of metachronous PM. PART I: Increasing international consensus on current evidence and reporting of anastomotic leaks after colorectal cancer surgery Aims - To increase insight in how AL is currently reported in high level evidence literature; - T o provide an overview of evidence-based statements regarding AL and a subsequent reporting framework that can be used to standardize AL reporting in the future; - To create a radiological scoring system that can be used to standardize the assessment of AL on computerized tomography (CT) scans in the future. The first part of this thesis focuses on the reporting of AL after CRC surgery. Chapter 2 is a systematic review that focuses on the use of different AL definitions in high-level evidence literature (randomized controlled trials, systematic reviews, and meta-analyses) and additional reported elements that are related to AL. In this chapter, we also highlight the importance of standardized reporting of AL. Subsequently, Chapter 3 reflects an international consensus project, in which the overview of current evidence regarding colorectal AL is presented, followed by a reporting framework to standardize reporting of colorectal AL after oncological surgery. As radiological assessment of AL plays a key role in the diagnostic phase, Chapter 4 displays a study protocol for the development of a radiological scoring system that can be used to assess AL on CT-scans and to radiologically report its assessment in a standardized way. Part II: Improving bowel perfusion assessment to reduce the risk of anastomotic leaks Aims - To study the feasibility and quantification of intestinal perfusion and ureter visualization with indocyanine green (ICG) and methylene blue (MB) using a new near-infrared fluorescence imaging system; - T o study the feasibility and quantification of intestinal perfusion during surgery with laser speckle contrast imaging (LSCI). 1
16 Chapter 1 Part II of this thesis provides insights into bowel perfusion assessment to reduce the risk of AL. Chapter 5 is a feasibility study in a porcine model which evaluates a new imaging system that is able to visualize both MB and ICG. This study illustrates the use of MB for both ureter visualization and bowel perfusion assessment. Subsequently, Chapter 6 is a quantification analysis in which MB and ICG are compared in a porcine model using ischemic bowel loops. Chapter 7 highlights the clinical implications of LSCI by performing a porcine experiment on anastomotic site selection. In this study, we demonstrate how LSCI can provide valuable real-time feedback on intestinal tissue perfusion during surgery. Chapter 8 is a preclinical validation of LSCI for bowel perfusion assessment in a porcine model. In this quantification study, we perform a correlation analysis between laser speckle units and local lactate levels in ischemic bowel loops and assess inter-observer variability. PART III: Patients’ perspectives on colorectal anastomotic leaks Aims - T o create an overview of the current knowledge of the impact on Quality of Life (QoL) of patients after colorectal AL; - T o obtain a more in-depth understanding of patients’ experiences after AL. The third part of this thesis gives insights into the patients’ perspective on AL after CRC surgery. Chapter 9 is a systematic review that provides an overview of current literature on the impact on the QoL of patients after AL. In this chapter, we also give additional recommendations on how to improve future AL research in relation to QoL. In Chapter 10, a qualitative interview study provides an insight into patients’ experiences after developing an AL. In addition to summarizing the identified interview themes, we emphasize the key factors highlighted by patients that can directly enhance clinical practice and improve patient outcomes. PART IV: Prevention of metachronous peritoneal metastases after colorectal cancer surgery Aims - T o create an overview of the current knowledge on predictive biomarkers in primary colorectal tumors for PM; - T o identify predictive biomarkers in primary colorectal tumors for metachronous PM; - To evaluate the safety of intraperitoneal cytostatic-loaded supramolecular hydrogel administration after the creation of a colon anastomosis. Part IV of this thesis describes potentials to reduce the risk of developing PM by considering prophylactic interventions in patients who are at risk. Chapter 11 provides an overview of current knowledge on specific biomarkers in the primary colorectal tumor that could
17 General introduction serve as a prediction tool to estimate the risk of distant peritoneal spread. Chapter 12 is an explorative study in which primary colorectal tumor samples are analyzed to identify specific DNA and/or RNA that may predict metachronous PM after curative resection. As intraperitoneal administration of cytostatic loaded hydrogels is a promising preventive strategy for patients who have a high risk of developing metachronous PM, we evaluate the safety of a certain intervention in Chapter 13. This evaluation describes the effect of an intraperitoneal mitomycin-loaded hydrogel on anastomotic healing in a rodent model, based AL scores, adhesion scores and microscopic evaluation. PART V: Summary, discussion and impact This thesis is completed by a summary, general discussion and additional future perspectives in Chapter 14. Chapter 15 provides an impact paragraph, followed by the Dutch summary of this thesis in Chapter 16. 1
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19 General introduction Endoscopic Surgery (EAES) consensus on Indocyanine Green (ICG) fluorescence-guided surgery. Surg Endosc 2023, 37:1629-48. [23] Heeman W, Steenbergen W, van Dam G, Boerma EC: Clinical applications of laser speckle contrast imaging: a review. J Biomed Opt 2019, 24:1-11. [24] Heeman W, Wildeboer ACL, Al-Taher M, Calon JEM, Stassen LPS, Diana M, Derikx JPM, van Dam GM, Boerma EC, Bouvy ND: Experimental evaluation of laparoscopic laser speckle contrast imaging to visualize perfusion deficits during intestinal surgery. Surg Endosc 2023, 37:950-7. [25] Kojima S, Sakamoto T, Nagai Y, Matsui Y, Nambu K, Masamune K: Laser Speckle Contrast Imaging for Intraoperative Quantitative Assessment of Intestinal Blood Perfusion During Colorectal Surgery: A Prospective Pilot Study. Surg Innov 2019, 26:293-301. [26] Den Dulk M, Marijnen C, Collette L, Putter H, Påhlman L, Folkesson J, Bosset J-F, Rödel C, Bujko K, Van De Velde C: Multicentre analysis of oncological and survival outcomes following anastomotic leakage after rectal cancer surgery. Journal of British Surgery 2009, 96:1066-75. [27] Wang S, Liu J, Wang S, Zhao H, Ge S, Wang W: Adverse Effects of Anastomotic Leakage on Local Recurrence and Survival After Curative Anterior Resection for Rectal Cancer: A Systematic Review and Meta-analysis. World J Surg 2017, 41:277-84. [28] Bao QR, Pellino G, Spolverato G, Restivo A, Deidda S, Capelli G, Ruffolo C, Bianco F, Cuicchi D, Jovine E, Lombardi R, Belluco C, Amato A, La Torre F, Asteria C, Infantino A, Contardo T, Del Bianco P, Delrio P, Pucciarelli S: The impact of anastomotic leak on long-term oncological outcomes after low anterior resection for midlow rectal cancer: extended follow-up of a randomised controlled trial. International Journal of Colorectal Disease 2022, 37:1689-98. [29] Ma L, Pang X, Ji G, Sun H, Fan Q, Ma C: The impact of anastomotic leakage on oncology after curative anterior resection for rectal cancer: A systematic review and meta-analysis. Medicine (Baltimore) 2020, 99:e22139. [30] Bashir Mohamed K, Hansen CH, Krarup PM, Fransgård T, Madsen MT, Gögenur I: The impact of anastomotic leakage on recurrence and longterm survival in patients with colonic cancer: A systematic review and meta-analysis. Eur J Surg Oncol 2020, 46:439-47. [31] Koedam TW, Bootsma BT, Deijen CL, van de Brug T, Kazemier G, Cuesta MA, Fürst A, Lacy AM, Haglind E, Tuynman JB: Oncological outcomes after anastomotic leakage after surgery for colon or rectal cancer: increased risk of local recurrence. Annals of surgery 2022, 275:e420e7. [32] Arron MNN, Greijdanus NG, Bastiaans S, Vissers PAJ, Verhoeven RHA, Ten Broek RPG, Verheul HMW, Tanis PJ, van Goor H, de Wilt JHW: Long-Term Oncological Outcomes After Colorectal Anastomotic Leakage: A Retrospective Dutch Population-based Study. Ann Surg 2022, 276:882-9. [33] Simkens GA, Rovers KP, Nienhuijs SW, de Hingh IH: Patient selection for cytoreductive surgery and HIPEC for the treatment of peritoneal metastases from colorectal cancer. Cancer Manag Res 2017, 9:259-66. [34] Bakkers C, Lurvink RJ, Rijken A, Nienhuijs SW, Kok NF, Creemers GJ, Verhoef C, Lemmens VE, van Erning FN, De Hingh IH: Treatment Strategies and Prognosis of Patients With Synchronous or Metachronous Colorectal Peritoneal Metastases: A Population-Based Study. Ann Surg Oncol 2021, 28:9073-83. [35] Klaver YL, Lemmens VE, Nienhuijs SW, Luyer MD, de Hingh IH: Peritoneal carcinomatosis of colorectal origin: Incidence, prognosis and treatment options. World J Gastroenterol 2012, 18:5489-94. [36] Koppe MJ, Boerman OC, Oyen WJ, Bleichrodt RP: Peritoneal carcinomatosis of colorectal origin: incidence and current treatment strategies. Ann Surg 2006, 243:212-22. [37] Maggiori L, Elias D: Curative treatment of colorectal peritoneal carcinomatosis: current status and future trends. Eur J Surg Oncol 2010, 36:599-603. [38] Jayne DG, Fook S, Loi C, Seow-Choen F: Peritoneal carcinomatosis from colorectal cancer. Br J Surg 2002, 89:1545-50. [39] Simkens GA, Wintjens A, Rovers KP, Nienhuijs SW, de Hingh IH: Effective Strategies to Predict Survival of Colorectal Peritoneal Metastases Patients Eligible for Cytoreductive Surgery and HIPEC. Cancer Manag Res 2021, 13:5239-49. [40] Lurvink RJ, Rovers KP, Nienhuijs SW, Creemers GJ, Burger JWA, de Hingh IHJ: Pressurized intraperitoneal aerosol chemotherapy with oxaliplatin (PIPAC-OX) in patients with colorectal peritoneal metastases-a systematic review. J Gastrointest Oncol 2021, 12:S242-s58. [41] Wintjens A, Liu H, Fransen PKH, Lenaerts K, van Almen GC, Gijbels MJ, Hadfoune M, Boonen BTC, Lieuwes NG, Biemans R, Dubois LJ, Dankers PYW, de Hingh I, Bouvy ND: Treating colorectal peritoneal metastases with an injectable cytostatic loaded supramolecular hydrogel in a 1
20 Chapter 1 rodent animal model. Clin Exp Metastasis 2023, 40:243-53. [42] Wintjens A, Simkens GA, Fransen PKH, Serafras N, Lenaerts K, Franssen G, de Hingh I, Dankers PYW, Bouvy ND, Peeters A: Intraperitoneal drug delivery systems releasing cytostatic agents to target gastro-intestinal peritoneal metastases in laboratory animals: a systematic review. Clin Exp Metastasis 2022, 39:541-79. [43] Wintjens A, Fransen PKH, Lenaerts K, Liu H, van Almen GC, van Steensel S, Gijbels MJ, de Hingh I, Dankers PYW, Bouvy ND: Development of a Supramolecular Hydrogel for Intraperitoneal Injections. Macromol Biosci 2023:e2300005. [44] Pedrazzani C, Turri G, Marrelli D, Kim HJ, Park EJ, Spolverato G, Foppa C, Spinelli A, Pucciarelli S, Baik SH, Choi GS: Prediction of Metachronous Peritoneal Metastases After Radical Surgery for Colon Cancer: A Scoring System Obtained from an International Multicenter Cohort. Ann Surg Oncol 2022, 29:7896-906. [45] Tsai TY, You JF, Hsu YJ, Jhuang JR, Chern YJ, Hung HY, Yeh CY, Hsieh PS, Chiang SF, Lai CC, Chiang JM, Tang R, Tsai WS: A Prediction Model for Metachronous Peritoneal Carcinomatosis in Patients with Stage T4 Colon Cancer after Curative Resection. Cancers (Basel) 2021, 13. [46] Ogunwobi OO, Mahmood F, Akingboye A: Biomarkers in Colorectal Cancer: Current Research and Future Prospects. Int J Mol Sci 2020, 21.
21 General introduction 1
PART I INCREASING INTERNATIONAL CONSENSUS ON CURRENT EVIDENCE AND REPORTING OF ANASTOMOTIC LEAKS AFTER COLORECTAL CANCER SURGERY
Dis Colon Rectum. Epub 2024 Aug 7. 2024 Nov 1;67(11):1383-1401. doi: 10.1097/DCR.0000000000003475. 2 CHAPTER QUALITY OF REPORTING ON ANASTOMOTIC LEAKS IN COLORECTAL CANCER TRIALS: A SYSTEMATIC REVIEW Danique J.I. Heuvelings Omar Mollema Sander M.J. van Kuijk Merel L. Kimman Marylise Boutros Nader Francis Nicole D. Bouvy Patricia Sylla On behalf of the CoReAL collaborative
26 ABSTRACT Background. Although attempts have been made in the past to establish consensus regarding the definitions and grading of the severity of colorectal anastomotic leakage, widespread adoption has remained limited. Objective. A systematic review of the literature was conducted with the objective of examining the various elements used to report and define anastomotic leakage in colorectal cancer resections. Data sources and study selection. A systematic review, using the PubMed, Embase, and Cochrane Library Database, of all published randomized controlled trials, systematic reviews, and meta-analyses containing data related to adult patients undergoing colorectal cancer surgery and reporting anastomotic leakage as a primary or secondary outcome, with a definition of anastomotic leakage included. Outcomes. Definitions of AL, clinical symptoms, radiological modalities and findings, findings at reoperation, as well as grading terminology or classifications for AL. Results. Of the 471 articles reporting anastomotic leakage as a primary or secondary outcome, a definition was reported in 95 studies (45 randomized controlled trials, 13 systematic reviews, and 37 meta-analyses), involving a total of 346,140 patients. Of these 95 articles, 68% reported clinical signs and symptoms of AL, 26% biochemical criteria, 63% radiological modalities, 62% radiological findings, and 13% findings at re-intervention. Only 45% (n=43) of included studies reported grading of anastomotic leakage severity or leak classification, and 41% (n=39) included a timeframe for reporting. Limitations. There was a high heterogeneity between the included studies. Conclusion. This evidence synthesis confirmed incomplete and inconsistent reporting of anastomotic leakage across the published colorectal cancer literature. There is a great need for the development and implementation of a consensus framework for defining, grading, and reporting anastomotic leakage. Keywords. Anastomotic leakage; consensus; colorectal surgery; systematic review; definitions, severity grading, reporting.
27 Quality of reporting on anastomotic leaks in colorectal trials: A systematic review INTRODUCTION Despite advances in preoperative risk assessment, operative techniques and strategies, and postoperative care, the incidence of anastomotic leakage (AL) after colorectal cancer (CRC) surgery has not improved over the recent decades; with an incidence of 1.5 to 23% and with mortality rates as high as 16%-29% 1-5. AL negatively impacts oncological outcomes, functional outcomes, and quality of life due to reoperation, permanent diversion, or delayed ostomy reversal 2, 3, 5. In addition, AL leads to increased hospital costs adding to the overall economic burden associated with CRC surgery 6. AL can present as small defects without air or fluid extravasation or large defects with or without localized abscess, phlegmon, and/or peritonitis 7, 8. The clinical impact of AL varies from minimal or no symptoms to substantial morbidity and mortality from abdominal and/or pelvic sepsis 9. Clinical studies where AL serves as a primary endpoint are often difficult to compare given considerable heterogeneity in the definition, severity grading, and diagnostic modalities used to assess AL. Despite efforts to create a validated consensus definition and severity grading system by the International Study Group of Rectal Cancer (ISREC) in 2010; this has not been widely adopted in clinical practice 10-12. A survey study among Dutch and Chinese colorectal surgeons highlighted ongoing lack of national and international agreement on definitions of AL 13. Hence, several definitions of AL continue to be used in studies, with most controversy surrounding the radiological criteria considered diagnostic of AL. A panel of eight senior US surgeons attempted to reach consensus on the definition of AL, specifically evaluating clinical and radiological criteria 14. Consensus could only be achieved in a few specific cases for both a radiological and clinical description, and only for specific types of interventions. The development of an internationally accepted standardized framework for defining, reporting and, grading colorectal AL is needed to facilitate earlier identification, reporting and treatment of AL in order to reduce short and long-term sequelae. A widely implemented standardized framework could serve as a template for clinical trials where the incidence of AL is used as a clinical end point. This systematic review aimed to gain insight into the different elements contributing to the general definition and reporting of AL in the literature. The findings of this study will serve as the basis of an ongoing project to develop a framework for reporting and grading AL after CRC surgery (Consensus Reporting of colorectal Anastomotic Leaks; CoReAL). METHODS This systematic review was reported according to the guidelines of the “Preferred Reporting Items for Systematic Reviews and Meta-Analyses” (PRISMA) 15. The protocol has been prospectively registered at PROSPERO ID 454660. 2
28 Chapter 2 Search and Information Sources A literature search was performed on November 4, 2022 in the PubMed, Embase, and the Cochrane Library Database using MeSH-, Emtree-, and free terms (Supplementary 1). Reference lists of all publications were searched for additional studies. The cross-referencing method was continued until no further relevant publications were identified. Selection Process Inclusion and exclusion criteria Randomized controlled trials (RCTs), systematic reviews (SRs), and meta-analyses (Mas) containing data related to adult (>18 years) patients with CRC and in which AL was a primary or secondary outcome, were considered eligible. Studies published before 2000 (date of the first systematic review concerning AL definitions), other publication types and articles not in English or Dutch were excluded. Articles were excluded if AL was not a primary or secondary outcome as stated in the methods section, no AL definitions were stated in the study, or patients were not undergoing oncological procedures. Study selection All search results were imported into a web tool designed for SRs (Rayyan) 16. Firstly, all duplicates were removed. Secondly, the screening of studies for eligibility was independently performed by 2 reviewers (DH, OM), using the predefined in- and exclusion criteria in two phases. In the first phase, articles were screened based on title and abstract. Disagreements between reviewers were resolved by initial discussion to create consensus and/or by one of the senior authors (NB). As part of the second phase, full texts were assessed. If the eligibility criteria were met after full-text screening by both reviewers, article inclusion followed. All references were stored in the Endnote Reference Management Tool. Data Items and Collection Process Two reviewers (DH, OM) independently extracted data from text, tables, and figures in a standardized, predefined datasheet. Data extraction for each article included first author, year of publication, country, study design, number of patients, number of studies in case of a SR or MA, study aims, surgical details, definitions or criteria used for AL assessment (clinical, biochemical, radiologic criteria and/or finding during reoperation), all definitions of AL, clinical symptoms associated with definitions of AL, radiological modalities and findings used in the diagnosis of AL, findings at reoperation for AL, as well as grading terminology or classifications for AL. We ensured definitions and reporting elements were not doublecounted by cross-referencing RCTs included in systematic reviews. When systematic reviews provided their own AL definitions without detailing those from included studies, we treated these as separate entries. This method maintained data integrity. Data acquired through the outlined search strategy was summarized in tables.
29 Quality of reporting on anastomotic leaks in colorectal trials: A systematic review Study Risk of Bias Assessment To assess the methodological quality of the included studies, the risk of bias was independently assessed by 2 reviewers (DH, OM). RCTs were assessed using the RoB2 tool, while (systematic) reviews and meta-analyses were assessed using the ROBIS tool 17, 18. All types of bias were evaluated and judged as low-, moderate-, or high risk resulting in an overall bias judgement. The bias was visualized using the Risk-of-bias visualization (Robvis) tool 19. RESULTS Study Selection The electronic search yielded 1,792 studies after removing duplicates and publications before 2000. After screening abstracts, 644 potentially eligible studies remained, based on the predefined inclusion and exclusion criteria. Full-text assessment from 134 studies was not possible (i.e., no full-texts available, or retracted articles), whereafter 511 articles remained eligible. Reference checking resulted in 13 additional studies, resulting in 524 studies for full-text assessment. Fifty-three studies did not meet inclusion criteria; the remaining 471 studies reported AL as a primary or secondary outcome. Of these, 376 did not report a definition of AL, which resulted in the inclusion of 95 studies. The study selection process is summarized in Figure 1. Study characteristics The 95 studies included 45 RCTs, 13 SRs, and 37 meta-analyses (MAs) published between 2000 and 2022. The main characteristics of the included studies are summarized in Table 1. 2
30 Chapter 2 Figure 1. Flow diagram of selections process based on the PRISMA 2020 guidelines.
31 Quality of reporting on anastomotic leaks in colorectal trials: A systematic review Table 1. Characteristics of included studies Author Year Country Study design Number of patients* Number of studies Aim of the study Type of resections included Alekseev et al. 20 2020 Russia RCT 380 N/A To evaluate the usefulness of ICG FA in reducing AL in patients undergoing a stapled colorectal anastomosis. (L)AR with TME, left colectomy Altomare et al. 21 2021 Italy RCT 54 N/A To compare incidence of AL and severity of postop complications in patients undergoing LAR with diverting stoma or LAR with reinforcement of the anastomosis without diverting stoma. LAR with TME Ansari et al. 22 2017 Australia RCT 326 N/A To compare acute adverse events and postoperative complication rates in a randomized trial of short-course versus longcourse preoperative radiotherapy. APR, (L)AR, Hartmann procedures Badawi et al. 23 2015 Saudi Arabia SR 6921 31 To review risk factors for and protective strategies against AL following minimally access surgery for CRC. (L)AR Bakker et al. 24 2017 The Netherlands RCT 402 N/A To evaluate the efficacy of the C-seal device in reducing AL following stapled colorectal anastomoses. All types of colorectal resections with stapled anastomoses Balciscueta et al. 25 2020 Switzerland SR and MA 1267 4 To evaluate the incidence of AL rate following laparoscopic rectal surgery following one vs two stapler firings for rectal transection. AR Bao et al. 26 2022 Italy RCT follow-up 311 N/A To evaluate overall survival, disease-free survival, and local and distant recurrence in patients with AL following LAR. LAR 2
32 Chapter 2 Table 1. Continued Author Year Country Study design Number of patients* Number of studies Aim of the study Type of resections included Blanco-Colino et al. 27 2018 Spain SR and MA 1302 5 To evaluate AL rates using ICG fluorescence imaging vs standard surgical care in CRC surgery. LAR with TME, right colectomy, left colectomy, sphincter-saving resection Boelens et al. 28 2014 The Netherlands RCT 123 N/A To investigate whether early enteral nutrition (EEN), as a bridge to a normal diet, can reduce postoperative ileus. LAR, APR, Hartmann procedure Bretagnol et al. 29 2010 France RCT 178 N/A To assess postoperative outcomes in patients undergoing sphincter-saving rectal resection for cancer without preoperative MBP. Mesorectal excision, sphinctersaving resection Brisinda et al. 30 2009 Italy RCT 77 N/A To compare surgical outcomes of end-to-end and end-to-side anastomosis after AR for T1 – T2 rectal cancer. AR with TME or PME Brown et al. 31 2001 Singapore RCT 59 N/A To assess the effect of prophylactic drainage after LAR when anastomoses are located below the peritoneal reflection. LAR with total- or wide mesorectal excision Bülow et al. 32 2006 Denmark RCT 194 N/A To compare AL rates after AR with a loop ileostomy vs transanal stenting vs both vs neither. Anterior resection Cong et al. 33 2015 China SR 16178 37 To evaluate AL requiring laparotomy and the associated rate of diverting stoma in initial AR for rectal cancer. (ultra)LAR, sphincter-saving resection Cong et al. 34 2014 China SR and MA 24232 39 To evaluate AL requiring reoperation and compare mortality in patients with AL relative to overall postoperative mortality after AR for rectal carcinoma. AR
33 Quality of reporting on anastomotic leaks in colorectal trials: A systematic review Table 1. Continued Author Year Country Study design Number of patients* Number of studies Aim of the study Type of resections included Cong et al. 35 2013 China SR 24288 70 To evaluate the pooled incidence and severity of AL and determine the average rate of AL for each grade after AR for rectal cancer. AR, (ultra)LAR, sphincter-saving resection Maggiore et al. 36 2018 Egypt RCT 57 N/A To compare the short-term operative as well as oncologic outcomes of robotic-assisted and laparoscopic rectal cancer resections AR, (ultra)LAR, APR Debakey et al. 37 2022 China SR and MA 1556 7 To evaluate the TDT effect on AL prevention. Laparoscopic rectal resections Deng et al. 38 2020 Italy RCT 252 N/A To evaluate the usefulness of intraoperative assessment of anastomotic perfusion using ICG angiography in patients undergoing leftsided colon or rectal resection with colorectal anastomosis. LAR, left colectomy Emile et al. 39 2022 Egypt SR and MA 8786 27 To assess changes in surgical plan based on ICG fluorescence angiography on the rates of AL. All types of colorectal procedures Finochi et al. 40 2020 France MA 5115 12 To compare postoperative outcomes between patients undergoing rectal cancer resection performed by totally laparoscopic approach compared to those who underwent intraoperative conversion. APR, sphinctersaving resection Floodeen et al. 41 2013 Sweden RCT 45 N/A To compare patients with symptomatic AL following LAR for cancer diagnosed during the initial hospital stay with those in whom leakage was diagnosed after hospital discharge. LAR Fujii et al. 42 2018 Japan RCT 331 N/A To clarify whether the IMA should be tied at the origin (high tie) or distal to the left colic artery (low tie) in relation to AL. AR 2
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