H. J. Bonjer

Laparoscopic versus open surgery for rectal cancer (COLOR II): short-term outcomes of a randomised, phase 3 trial

BACKGROUND Laparoscopic surgery as an alternative to open surgery in patients with rectal cancer has not yet been shown to be oncologically safe. The aim in the COlorectal cancer Laparoscopic or Open Resection (COLOR II) trial was to compare laparoscopic and open surgery in patients with rectal cancer. METHODS A non-inferiority phase 3 trial was undertaken at 30 centres and hospitals in eight countries. Patients (aged ≥18 years) with rectal cancer within 15 cm from the anal verge without evidence of distant metastases were randomly assigned to either laparoscopic or open surgery in a 2:1 ratio, stratified by centre, location of tumour, and preoperative radiotherapy. The study was not masked. Secondary (short-term) outcomes-including operative findings, complications, mortality, and results at pathological examination-are reported here. Analysis was by modified intention to treat, excluding those patients with post-randomisation exclusion criteria and for whom data were not available. This study is registered with ClinicalTrials.gov, number NCT00297791. FINDINGS The study was undertaken between Jan 20, 2004, and May 4, 2010. 1103 patients were randomly assigned to the laparoscopic (n=739) and open surgery groups (n=364), and 1044 were eligible for analyses (699 and 345, respectively). Patients in the laparoscopic surgery group lost less blood than did those in the open surgery group (median 200 mL [IQR 100-400] vs 400 mL [200-700], p<0·0001); however, laparoscopic procedures took longer (240 min [184-300] vs 188 min [150-240]; p<0·0001). In the laparoscopic surgery group, bowel function returned sooner (2·0 days [1·0-3·0] vs 3·0 days [2·0-4·0]; p<0·0001) and hospital stay was shorter (8·0 days [6·0-13·0] vs 9·0 days [7·0-14·0]; p=0·036). Macroscopically, completeness of the resection was not different between groups (589 [88%] of 666 vs 303 [92%] of 331; p=0·250). Positive circumferential resection margin (<2 mm) was noted in 56 (10%) of 588 patients in the laparoscopic surgery group and 30 (10%) of 300 in the open surgery group (p=0·850). Median tumour distance to distal resection margin did not differ significantly between the groups (3·0 cm [IQR 2·0-4·8] vs 3·0 cm [1·8-5·0], respectively; p=0·676). In the laparoscopic and open surgery groups, morbidity (278 [40%] of 697 vs 128 [37%] of 345, respectively; p=0·424) and mortality (eight [1%] of 699 vs six [2%] of 345, respectively; p=0·409) within 28 days after surgery were similar. INTERPRETATION In selected patients with rectal cancer treated by skilled surgeons, laparoscopic surgery resulted in similar safety, resection margins, and completeness of resection to that of open surgery, and recovery was improved after laparoscopic surgery. Results for the primary endpoint-locoregional recurrence-are expected by the end of 2013. FUNDING Ethicon Endo-Surgery Europe, Swedish Cancer Foundation, West Gothia Region, Sahlgrenska University Hospital.

Surgical stress response and postoperative immune function after laparoscopy or open surgery with fast track or standard perioperative care: a randomized trial.

Objective: To evaluate the effect of laparoscopic or open colectomy with fast track or standard perioperative care on patients immune status and stress response after surgery. Methods: Patients with nonmetastasized colon cancer were randomized to laparoscopic or open colectomy with fast track or standard care. Blood samples were taken preoperatively (baseline), and 1, 2, 24, and 72 hours after surgery. Systemic HLA-DR expression, C-reactive protein, interleukin-6, growth hormone, prolactin, and cortisol were analyzed. Results: Nineteen patients were randomized for laparoscopy and fast track care (LFT), 23 for laparoscopy and standard care (LS), 17 for open surgery and fast track care (OFT), and 20 for open surgery and standard care (OS). Patient characteristics were comparable. Mean HLA-DR was 74.8 in the LFT group, 67.1 in the LS group, 52.8 in the OFT group, and 40.7 in the OS group. Repeated-measures 2-way analysis of variance (ANOVA) showed this can be attributed to type of surgery and not aftercare (P = 0.002). Interleukin-6 levels were highest in the OS group. Repeated-measures 2-way ANOVA showed this can be attributed to type of surgery and not aftercare (P = 0.001). C-reactive protein levels were highest in the OS group. Following repeated-measures 2-way ANOVA, this can be attributed to type of surgery and not aftercare (P = 0.022). Growth hormone was lowest in the LFT group. Following repeated-measures 2-way ANOVA, this can be attributed to type of aftercare and not to type of surgery (P = 0.033). No differences between the groups were seen regarding prolactin or cortisol. No differences in (infectious) complication rates were observed between the groups. Conclusions: This randomized trial showed that immune function of HLA-DR in patients undergoing laparoscopic surgery with fast track care remains highest. This can be attributed to type of surgery and not aftercare. These results may indicate a reason for the accelerated recovery of patients treated laparoscopically within a fast track program as described in the LAparoscopy and/or FAst track multimodal management versus standard care (LAFA-Trial) (www.trialregister.nl, protocol NTR222).

Cytoreductive surgery and HIPEC for peritoneal metastases combined with curative treatment of colorectal liver metastases: Systematic review of all literature and meta-analysis of observational studies.

OBJECTIVE Assess the overall outcome in colorectal cancer (CRC) patients that present with a combination of peritoneal metastases (PM) and liver metastases (CRLM) after curative resection and hyperthermic intraperitoneal chemotherapy (HIPEC) in the current literature. METHODS A systematic literature search according to the PRISMA guidelines was conducted using the PubMed database of the U.S. National library of Medicine using the keywords: colorectal cancer, liver metastasis, extra-hepatic, peritoneal metastases, peritoneal carcinomatosis, cytoreductive surgery (CRS), HIPEC and combinations hereof. Papers focussing on CRS and HIPEC for PM combined with curative treatment of CRLM were included, provided sufficient information on survival outcomes could be extracted. Duplicate publications were excluded. Meta-analysis was performed using the method described by Tierney et al. RESULTS After screening and full-text assessment of 39 papers, six articles were included containing data on combined PM and CRLM in patients treated with curative resection of both sites and HIPEC or early postoperative intraperitoneal chemotherapy (EPIC). Three articles provided enough statistical information for meta-analysis. Pooled hazard ratio (HR) was extracted from survival curves and was 1.24 (CI 0.96-1.60). A comparison was made with patients presenting with isolated PM undergoing CRS and HIPEC and with patients with disseminated disease undergoing (modern) systemic chemotherapy. CONCLUSIONS In the absence of randomized controlled studies, we found in this systematic review and meta-analysis of patients with a combination of colorectal metastases in the liver as well as in the peritoneum show a trend towards a lower overall survival after curative resection and HIPEC, when compared to patients with isolated peritoneal metastases after CRS and HIPEC (pooled HR1.24, CI 0.96-1.60). However, patients with metastatic CRC show a tendency towards increased median overall survival after CRS and HIPEC combined with resection of liver metastases when compared to treatment with modern systemic chemotherapy.

Laparoscopic vs transverse incision right colectomy for colon carcinoma

Aim  We investigated whether laparoscopic right colectomy has short‐term and/or oncological advantages compared with transverse incision right colectomy.

Selective Decontamination of the Digestive Tract in Gastrointestinal Surgery: Useful in Infection Prevention? A Systematic Review

IntroductionGastrointestinal surgery is associated with a high incidence of infectious complications. Selective decontamination of the digestive tract is an antimicrobial prophylaxis regimen that aims to eradicate gastrointestinal carriage of potentially pathogenic microorganisms and represents an adjunct to regular prophylaxis in surgery.Material and MethodsRelevant studies were identified using bibliographic searches of MEDLINE, EMBASE, and the Cochrane database (period from 1970 to November 1, 2012). Only studies investigating selective decontamination of the digestive tract in gastrointestinal surgery were included.ResultsTwo randomized clinical trials and one retrospective case–control trial showed significant benefit in terms of infectious complications and anastomotic leakage in colorectal surgery. Two randomized controlled trials in esophageal surgery and two randomized clinical trials in gastric surgery reported lower levels of infectious complications.ConclusionSelective decontamination of the digestive tract reduces infections following esophageal, gastric, and colorectal surgeries and also appears to have beneficial effects on anastomotic leakage in colorectal surgery. We believe these results provide the basis for a large multicenter prospective study to investigate the role of selective decontamination of the digestive tract in colorectal surgery.

Tailoring heated intraperitoneal mitomycin C for peritoneal metastases originating from colorectal carcinoma: a translational approach to improve survival

Background:Patients with peritoneal metastases (PMs) originating from colorectal carcinoma (CRC) are curatively treated by cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) with mitomycin C (MMC). We aim to improve patient selection for HIPEC by predicting MMC sensitivity.Methods:The MMC sensitivity was determined for 12 CRC cell lines and correlated to mRNA expression of 37 genes related to the Fanconi anaemia (FA)–BRCA pathway, ATM–ATR pathway and enzymatic activation of MMC. Functionality of the FA–BRCA pathway in cell lines was assessed using a chromosomal breakage assay and western blot for key protein FANCD2. Bloom syndrome protein (BLM) was further analysed by staining for the corresponding protein with immunohistochemistry (IHC) on both CRC cell lines (n=12) and patient material (n=20).Results:High sensitivity correlated with a low BLM (P=0.01) and BRCA2 (P=0.02) at mRNA expression level. However, FA–BRCA pathway functionality demonstrated no correlation to MMC sensitivity. In cell lines, weak intensity staining of BLM by IHC correlated to high sensitivity (P=0.04) to MMC. Low BLM protein expression was significantly associated with an improved survival in patients after CRS and HIPEC (P=0.04).Conclusions:Low BLM levels are associated with high MMC sensitivity and an improved survival after HIPEC.

Avances en cirugía del cáncer de recto: recorrido histórico y nuevas perspectivas después del estudio COLOR II

Rectal cancer treatment has significantly changed during the past two centuries. Development of new surgical techniques and introduction of (neo) adjuvant therapies have contributed to the improved prognosis of rectal cancer and reduced morbidity rates. The first technically successful excision of rectal cancer was performed by LisFranc in 1826. It was a primitive procedurewithout anesthesia or hemostasis and the patient did not survive. In those days operative mortality rates of 20% and local recurrence rates of 80% were reported. In 1908 Miles published the concept of cylindrical lymphatic spread of cancer cells. He recommended more extensive mesenteric lymphadenectomy combinedwith resection of the anus and rectum in order to prevent recurrence. With the introduction of this radical ‘abdominoperineal resection’ (APR), Miles established the basis for modern rectal cancer surgery. Because the APR resulted in creation of a permanent colostomy, considered a great disadvantage for the patients, halfway through the twentieth century the focus shifted toward sphincter-sparing procedures and the ‘anterior resection’ (AR) became the standard treatment for mid and high rectal cancer. Subsequently, in the 1970s the restoration of bowel continuity after AR was introduced. In order to decrease anastomotic leakage rates and pelvic sepsis, adjustments were made such as creation of a colonic J-pouch anastomosis or diverting ileostomy. However, both the APR and AR included blunt dissection of the rectum along the presacral fascia with a cone-wise development of the most distal part of the rectum. This blunt technique resulted in high rates of involved circumferential resection margins (CRMs), which predisposes to local recurrence, and local recurrence rates up to 40%were reported. In 1982 Heald et al. introduced the technique of total mesorectal excision (TME), in which sharp excision of the complete mesorectum en bloc with the tumor to the level of the levator muscles was performed following the anatomical planes. Thismore extensive excision resulted in significant decrease of involved CRMs and decreased local recurrence rates to 3.7% at 5-years postoperatively. In the 1980s it was hypothesized that less surgical trauma would not only improve postoperative recovery, moreover it would result in less tumor recurrence and therefore improved survival. Following laparoscopic resection of the gallbladder and appendix, laparoscopic colorectal surgery was first described by Jacobs et al. For colon cancer, evidence was obtained that laparoscopic surgery was safe, causing less postoperative pain, shorter hospital stay, and resulting in comparable survival rates compared with open colectomy. However, rectal cancer surgery is considered technically more challenging than colon surgery, mainly because of the limited workspace in the lower pelvis and fibrosis of the tissue as a result of neoadjuvant radiotherapy. Recent studies showed improved short-term outcomes as well as comparable oncological outcomes after laparoscopic TME for rectal cancer compared with open TME. However, these studies included small numbers of patients. The largest randomized trial comparing laparoscopic and traditional open resection for rectal cancer is the COLOR II trial. It was undertaken in 30 hospitals in 8 countries and 1044 patients were included. Short-term outcomes showed less blood loss, less pain and shorter hospital stay after laparoscopic resection with comparable quality of the resected specimen as in open surgery. Recently, the COLOR II study group published their long-term outcomes and reported that laparoscopic surgery c i r e s p . 2 0 1 6 ; 9 4 ( 1 ) : 1 – 3

Short-term outcomes of transanal completion total mesorectal excision (cTaTME) for rectal cancer: a case-matched analysis

BackgroundLocal excision of early rectal tumors as a rectal preserving treatment is gaining popularity, especially since bowel cancer screening programs result in a shift towards the diagnosis of early stage rectal cancers. However, unfavorable histological features predicting high risk for recurrence within the “big biopsy” may mandate completion total mesorectal excision (cTME). Completion surgery is associated with higher morbidity, poorer specimen quality, and less favorable oncological outcomes compared to primary TME. Transanal approach potentially improves outcome of completion surgery for rectal cancer. The aim of this study was to compare radical completion surgery after local excision for rectal cancer by the transanal approach (cTaTME) with conventional abdominal approach (cTME).MethodsAll consecutive patients who underwent cTaTME for rectal cancer between 2012 and 2017 were case-matched with cTME patients, according to gender, tumor height, preoperative radiotherapy, and tumor stage. Surgical, pathological, and short-term postoperative outcomes were evaluated.ResultsIn total, 25 patients underwent completion TaTME and were matched with 25 patients after cTME. Median time from local excision to completion surgery was 9 weeks in both groups. In the cTaTME and cTME groups, perforation of the rectum occurred in 4 and 28% of patients, respectively (p = 0.049), leading to poor specimen quality in these patients. Number of harvested lymph nodes was higher after cTaTME (median 15; range 7–47) than after cTME (median 10; range 0–17). No significant difference was found in end colostomy rate between the two groups. Major 30-day morbidity (Clavien–Dindo≥ III) was 20 and 32%, respectively (p = 0.321). Hospital stay was significantly longer after cTME.ConclusionTaTME after full-thickness excision is a promising technique with a significantly lower risk of perforation of the rectum and better specimen quality compared to conventional completion TME.

eHealth program to empower patients in returning to normal activities after general surgical and gynecological procedures: Intervention Mapping as a useful method for further development (Preprint)

Background Support for guiding and monitoring postoperative recovery and resumption of activities is usually not provided to patients after discharge from the hospital. Therefore, a perioperative electronic health (eHealth) intervention (“ikherstel” intervention or “I recover” intervention) was developed to empower gynecological patients during the perioperative period. This eHealth intervention requires a need for further development for patients who will undergo various types of general surgical and gynecological procedures. Objective This study aimed to further develop the “ikherstel” eHealth intervention using Intervention Mapping (IM) to fit a broader patient population. Methods The IM protocol was used to guide further development of the “ikherstel” intervention. First, patients’ needs were identified using (1) the information of a process evaluation of the earlier performed “ikherstel” study, (2) a review of the literature, (3) a survey study, and (4) focus group discussions (FGDs) among stakeholders. Next, program outcomes and change objectives were defined. Third, behavior change theories and practical tools were selected for the intervention program. Finally, an implementation and evaluation plan was developed. Results The outcome for an eHealth intervention tool for patients recovering from abdominal general surgical and gynecological procedures was redefined as “achieving earlier recovery including return to normal activities and work.” The Attitude-Social Influence-Self-Efficacy model was used as a theoretical framework to transform personal and external determinants into change objectives of personal behavior. The knowledge gathered by needs assessment and using the theoretical framework in the preparatory steps of the IM protocol resulted in additional tools. A mobile app, an activity tracker, and an electronic consultation (eConsult) will be incorporated in the further developed eHealth intervention. This intervention will be evaluated in a multicenter, single-blinded randomized controlled trial with 18 departments in 11 participating hospitals in the Netherlands. Conclusions The intervention is extended to patients undergoing general surgical procedures and for malignant indications. New intervention tools such as a mobile app, an activity tracker, and an eConsult were developed. Trial Registration Netherlands Trial Registry NTR5686; http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=5686

eHealth program to empower patients in returning to normal activities after colorectal surgical procedures: a mixed method process evaluation alongside a randomized controlled trial (Preprint)

Background Long-term recovery takes longer than expected despite improved surgical techniques and Enhanced Recovery After Surgery programs. An electronic health (eHealth) care program (“ikherstel”) was developed to partially substitute perioperative care for patients undergoing colorectal surgical procedures. Successfully tested eHealth programs are not always implemented in usual care, and it is, therefore, important to evaluate the process to optimize future implementation. Objective The aim of this study was to evaluate whether the eHealth intervention was executed as planned. Methods A mixed-methods process evaluation was carried out alongside a multicenter randomized controlled trial (RCT). This evaluation was performed using the Linnan and Steckler framework for the quantitative part of this study, measuring the components reach, dose delivered, dose received, fidelity, and participants’ attitudes. Total implementation scores were calculated using the averaging approach, in which the sum of all data points is divided by the number of data points and the total adherence to the protocol is measured. For the qualitative part, the Unified Theory of Acceptance and Use of Technology framework was used. The quantitative data were based on participants’ questionnaires, a logistic database, a weblog, and participants’ medical files and were obtained by performing semistructured interviews with participants of the RCT. Results A total of 151 participants of 340 eligible patients were included in the RCT, of which 73 participants were allocated to the intervention group. On the basis of the quantitative process data, total implementation scores for the website, mobile app, electronic consult, and activity tracker were 64%, 63%, 44%, and 67%, respectively. Participants in the qualitative part experienced the program as supportive and provided guidance on their recovery process after colorectal surgery. Most frequently mentioned barriers were the limited interaction with and feedback from health care professionals and the lack of tailoring of the convalescence plan in case of a different course of recovery. Conclusions The intervention needs more interaction with and feedback from health care professionals and needs more tailored guidance in case of different recovery or treatment courses. To ensure a successful implementation of the program in daily practice, some adjustments are required to optimize the program in a blended care form. Trial Registration Netherlands Trial Registry NTR5686; http://www.trialregister.nl/trialreg/admin/rctview.asp?TC= 5686 (Archieved by WebCite at http://www.webcitation.org/75LrJaHrr)