Marko Simunovic

Randomized Controlled Trials of Surgical Interventions

Background and Objectives:Surgical trials pose many methodological challenges often not present in trials of medical interventions. If not properly accounted for, these challenges may introduce significant biases and threaten the validity of the results. Methods:We systematically reviewed the significance of randomized controlled trials in the evaluation of surgical interventions, discussed the methodological challenges encountered in designing and conducting randomized controlled trials of surgical treatments, and proposed possible solutions to overcome these challenges. Conclusions:Many barriers and issues of surgical trials affecting internal validity can be overcome with proper methodology, and in most cases these issues do not restrict their conduct. Researchers should consider their research question carefully and design a surgical trial that contains features appropriate for the question. In doing so, they must ensure that the trial is valid, feasible, and affordable—a difficult feat, but one well worth the challenge.

The relationship between surgical factors and margin status after breast-conservation surgery for early stage breast cancer

BACKGROUND The studys aim was to identify technical factors that are predictive of negative margins after breast-conserving surgery (BCS). METHODS This was a retrospective, cohort study of patients who underwent BCS for early-stage cancer from 2000 to 2002. Pathological and specific surgical factors were compared with margin status. Univariate and multivariate regression analyses were performed. RESULTS Four hundred eighty-nine cases were reviewed. The positive margin rate after the initial surgery was 26%. In univariate analysis, lobular histology, size, grade, multifocality, and the presence of EIC and LVI were associated with positive margins (P < .05). The absence of cavity margin dissection and specimen orientation labeling, the absence of a confirmed diagnosis, and smaller volumes of excision were also associated with positive margins (P < .05). In multivariate analysis, confirmed diagnosis, small tumor size, ductal histology, absence of LVI and multifocality, palpability, cavity margin dissection, and larger volumes of excision were predictors of negative margins. CONCLUSIONS This study shows that specific surgical factors are predictive of margin status. Both tumor and technical factors should be considered when planning BCS.

Hospital procedure volume and teaching status do not influence treatment and outcome measures of rectal cancer surgery in a large general population

A clear benefit of increased hospital procedure volume or teaching hospital status on outcomes of rectal cancer surgery has yet to be shown. Few have examined treatment differences that may lead to varying outcomes. This study assessed the impact of hospital procedure volume and teaching status on both treatment and outcome measures of rectal cancer surgery in a large general population. Data were obtained for 1072 incident cases of rectal adenocarcinoma diagnosed in 1990 from Ontario, Canada, and treated with a major resection. Hospitals were classified by teaching status and procedure volume. Pathology reports were examined for 418 procedures. Abdominoperineal resections accounted for 3 1.0% of all procedures. There were no clinically significant differences in treatment measures, operative mortality, and long-term survival among the hospital groups according to both univariate and multivariate analyses. In conclusion, the absence of a hospital volume or teaching status effect on treatment and outcome measures suggests that for rectal cancer surgery in Ontario, centralization of procedures into high-volume or teaching centers is unlikely to improve surgical quality.

Optimal preoperative assessment and surgery for rectal cancer may greatly limit the need for radiotherapy

Radiation is being used increasingly in the management of patients with rectal cancer. Over the past decade the Basingstoke Colorectal Research Unit has combined precision total mesorectal excision with the highly selective use of preoperative radiotherapy.

An Outbreak of Acute Bacterial Gastroenteritis Is Associated With an Increased Incidence of Irritable Bowel Syndrome in Children

OBJECTIVES:Acute bacterial gastroenteritis is associated with subsequent post-infectious irritable bowel syndrome (PI-IBS) in adults. Less is known about this relationship in children. In May 2000, contamination of municipal water by Escherichia coli 0157:H7 and Campylobacter species caused a large outbreak of acute gastroenteritis in Walkerton, Ontario. We assessed this association among a cohort of children enrolled in the Walkerton Health Study (WHS).METHODS:WHS participants who were under age 16 at the time of the outbreak but who reached age 16 during the 8-year study follow-up were eligible for the pediatric PI-IBS study cohort. Eligibility also required no diagnosis of IBS or inflammatory bowel disease before the outbreak and permanent residency in the Walkerton postal code at the time of the outbreak. Validated criteria were used to classify subjects as having had no gastroenteritis (unexposed controls), self-reported gastroenteritis, or clinically suspected gastroenteritis during the outbreak. From 2002 to 2008, standardized biennial interviews used a modified Bowel Disease Questionnaire to diagnose IBS by Rome I criteria. Risk factors for IBS were identified by logistic regression.RESULTS:In all, 467 subjects were eligible for the pediatric PI-IBS study cohort (47.1% female; mean age 11.6±2.44 years at the time of the outbreak). Of these, 305 were exposed to GE (130 clinically suspected and 175 self-reported) and 162 were unexposed controls. The cumulative incidence of IBS was significantly increased among exposed subjects vs. controls (10.5% vs. 2.5%; odds ratio 4.6, 95% confidence interval (1.6, 13.3)). In an unadjusted risk factor analysis, IBS was associated with a shorter time interval from exposure to assessment of IBS symptoms, female gender, diarrheal illness lasting more than 7 days, weight loss >10 lb, and antibiotic use during the outbreak. In adjusted analyses, both female gender and time interval to assessment of IBS symptoms remained independent predictors of PI-IBS.CONCLUSIONS:Acute bacterial gastroenteritis is associated with subsequent IBS in children as in adults. Risk factors for PI-IBS in children are similar to those identified among adults. Confirmation of these findings in similar cohorts is needed.

An evaluation of the relationship between lymph node number and staging in pT3 colon cancer using population-based data.

PURPOSE: The number of lymph nodes examined has been proposed as a quality benchmark for colon cancer surgery, although it is unknown whether this strategy reduces understaging. METHODS: We identified 11,044 patients who underwent surgery for colon cancer with pT3 wall penetration between 1988 and 2003 from the Surveillance, Epidemiology and End Results cancer registry. We determined the proportion of patients who were node positive for each node count. We used logistic regression to predict the odds of being node positive by node count after adjusting for confounders. We used joinpoint analysis to determine whether there was a consistent relationship between node count and the odds of being node positive. RESULTS: The proportion of patients found to be node positive increased with node count at low counts (≤5–6 nodes), but patients with 7 nodes identified were as likely to be node positive as patients with 30 or more nodes (odds ratio = 0.97; 95% CI = 0.90–1.05). Joinpoint analysis demonstrated a dramatic increase in odds of node positivity with increasing node count to 5 nodes (slope = 0.2; P < .0001). Between 6 and 13 nodes there was a marginal increase in odds of positive nodes (slope = 0.03; P = .006), but when more nodes were evaluated, odds of node positivity actually declined (slope = −0.01; P = .04). CONCLUSIONS: Staging of pT3 colon cancer improves with increasing node count, but only when the node count is low (<5–7 nodes). At higher counts, an increased node count has marginal effects on staging.

Assessing the Volume-Outcome Hypothesis and Region-Level Quality Improvement Interventions: Pancreas Cancer Surgery in Two Canadian Provinces

BackgroundThe volume-outcome hypothesis suggests that if increased provider procedure volume is associated with improved patient outcomes, then greater regionalization to high-volume providers should improve region-level outcomes. Quality improvement interventions for pancreas cancer surgery implemented in year 1999 in Ontario, Canada were designed to regionalize surgery to high-volume hospitals and decrease operative mortality. Similar interventions were not used in Quebec, Canada. We assessed the volume-outcome hypothesis and the impact of the Ontario quality improvement interventions.Materials and MethodsAdministrative databases helped identify pancreatic resections from years 1994 to 2004 and relevant patient and hospital characteristics. Hospitals were high-volume if they provided ≥10 procedures in a given calendar year. Outcomes were regionalization of surgery to high-volume providers and rates of operative mortality.ResultsFrom 1994 to 2004 the percentage of cases in high-volume hospitals increased from 33 to 71% in Ontario and from 36 to 76% in Quebec. Annual rates of operative mortality dropped in Ontario (10.4–2.2% or less) and changed little in Quebec (7.2–9.8%). Changes in measures over time in both provinces were similar before and after year 1999.ConclusionsRegionalization was associated with improved operative mortality in Ontario but not in Quebec, undermining the volume-outcome hypothesis. The Ontario quality improvement interventions likely were of little influence since patterns in regionalization and operative mortality were similar before and after year 1999.

The Importance of Reporting Patient Recruitment Details in Phase III Trials

James R. Wright, Juravinski Cancer Centre at Hamilton Health Sciences, and Department of Medicine, McMaster University, Hamilton, ON, Canada Sarah Bouma, Juravinski Cancer Centre at Hamilton Health Sciences, Hamilton, ON, Canada Ian Dayes and Jonathan Sussman, Juravinski Cancer Centre at Hamilton Health Sciences, and Department of Medicine, McMaster University, Hamilton, ON, Canada Marko R. Simunovic, Juravinski Cancer Centre at Hamilton Health Sciences, and Department of Surgery, McMaster University, Hamilton, ON, Canada Mark N. Levine, Juravinski Cancer Centre at Hamilton Health Sciences, and Departments of Medicine and Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, ON, Canada Tim J. Whelan, Juravinski Cancer Centre at Hamilton Health Sciences, and Department of Medicine, McMaster University, Hamilton, ON, Canada

Development and validation of a risk score for post-infectious irritable bowel syndrome.

OBJECTIVES:Acute gastroenteritis (GE) is an important risk factor for the development of irritable bowel syndrome (IBS). We used observational data from the Walkerton Health Study (WHS) to develop and validate a risk score for post-infectious (PI) IBS.METHODS:Model derivation and validation were based on a split-sample method from a cohort of patients with exposure to GE (n=1,368). Study participants were randomly assigned to the derivation and validation cohorts in a 1:1 ratio. Within the derivation cohort, univariate and multivariable logistic regression were used to identify risk factors associated with IBS. The risk model was then applied to the validation cohort. Overall model performance was assessed using the area under the receiver operating curve (ROC). The risk score was developed using multivariable regression coefficients obtained from the derivation set and validated in the validation set. Classification and regression tree (CART) modeling was used to determine cutoff values for high, intermediate, and low risk based on the total score.RESULTS:Nine variables were identified as important predictors of IBS (gender, age<60, longer duration of diarrhea, increased stool frequency, abdominal cramping, bloody stools, weight loss, fever, and psychological disorders (anxiety and depression)). The discriminatory power of the risk model based on the area under ROC was 0.70 and was similar in the validation set. The risk score model showed good accuracy in both the derivation and validation sets and was able to distinguish among cohorts at low, intermediate, and high risk for developing PI-IBS. Percentages of patients with PI-IBS in the low, intermediate and high risk were 10, 35, and 60% in the derivation cohort and 17, 36, and 62% in the validation cohort.CONCLUSIONS:A simple risk tool that uses demographics and symptoms of acute GE can predict which patients with acute GE are at risk of developing PI-IBS. This tool may be used clinically to assess risk and to guide treatment.

The cluster-randomized Quality Initiative in Rectal Cancer trial: evaluating a quality-improvement strategy in surgery

Background: Following surgery for rectal cancer, two unfortunate outcomes for patients are permanent colostomy and local recurrence of cancer. We tested whether a quality-improvement strategy to change surgical practice would improve these outcomes. Methods: Sixteen hospitals were cluster-randomized to the intervention (Quality Initiative in Rectal Cancer strategy) or control (normal practice) arm. Consecutive patients with primary rectal cancer were accrued from May 2002 to December 2004. Surgeons at hospitals in the intervention arm could voluntarily participate by attending workshops, using opinion leaders, inviting a study team surgeon to demonstrate optimal techniques of total mesorectal excision, completing postoperative questionnaires, and receiving audits and feedback. Main outcome measures were hospital rates of permanent colostomy and local recurrence of cancer. Results: A total of 56 surgeons (n = 558 patients) participated in the intervention arm and 49 surgeons (n = 457 patients) in the control arm. The median follow-up of patients was 3.6 years. In the intervention arm, 70% of surgeons participated in workshops, 70% in intraoperative demonstrations and 71% in postoperative questionnaires. Surgeons who had an intraoperative demonstration provided care to 86% of the patients in the intervention arm. The rates of permanent colostomy were 39% in the intervention arm and 41% in the control arm (odds ratio [OR] 0.97, 95% confidence interval [CI] 0.63–1.48). The rates of local recurrence were 7% in the intervention arm and 6% in the control arm (OR 1.06, 95% CI 0.68–1.64). Interpretation: Despite good participation by surgeons, the resource-intense quality-improvement strategy did not reduce hospital rates of permanent colostomy or local recurrence compared with usual practice. (ClinicalTrials.gov trial register no. NCT00182130.)