7(FIGO I)(FIGO≥II)Odds ratio
8.1 Summarizing discussion and future perspectives
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Endometrial cancer is the most common malignancy of the female genital tract in Western countries, affecting around 1400 new women per year in the Netherlands. After breast, colorectal, and lung cancer, endometrial cancer is the fourth most common invasive tumour in Dutch women and accounts for about 5% of all malignancies.
In general, patients with endometrial carcinoma have a good prognosis, since most patients present with early
stage disease due to early symptoms. Standard treatment consists of total abdominal hysterectomy and bilateral salpingo-oophorectomy with or without lymphadenectomy. Nowadays, laparoscopy has developed into an
important component of the operative gynecological palette, since it is accepted as an alternative to conventional
abdominal surgery for many indications. The perception that laparoscopic procedures are more costly than open procedures has been a major reason for the slow acceptance of laparoscopic surgery. However, in little of these the advantage of laparoscopy over laparotomy has been confirmed in randomized trials. The purpose of this thesis was to evaluate costs and effects of laparoscopic hysterectomy compared to the standard approach by laparotomy in early stage endometrial cancer, in order to find the best treatment strategy for these patients.
Evidence based medicine
Surgical innovation is an important part of surgical practice. Its assessment is complex, but necessary so that introduction of surgical innovations can be derived from evidence-based principles rather than trial and error.1-3 Formal and comparative assessments of procedures have had little role in the surgical process. Assessment of superior effectiveness has become more challenging than in the past. Surgeons have now adopted a more scientific basis to change strategies in patient care, turning to current medical standard for the development of knowledge –evidence based health care.4 Evidence based health care is characterized by the promotion of unbiased, highly reliable types of evidence. There are key study designs in the hierarchy of evidence for surgical decision making. Individual case series are of least value, non-randomized controlled trials and case controlled studies are of somewhat greater value. Retrospective trials without strict admission criteria cannot be used to compare the efficacy of different interventions. The retrospective nature of the data collection makes it difficult to ensure that the comparison groups are similar for all factors except those under investigation. Prospective comparative designs are substantially more useful than case series, which are over-represented in surgical publications. An important driving factor behind non-randomized studies is that they are easier to undertake than randomized controlled trials (RCTs). However, a lack of appropriate planning and poor data quality (i.e., missing data for important risk factors, inconsistencies, absence of key diagnostic and operative details) are common setbacks that tend to undermine the validity of results from non-randomized studies. An RCT remains the best possible study design for the assessment of surgical interventions. Notably, the development and evaluation of a surgical technique proceeds through stages, needing different designs for each stage.3 Despite calls for surgical research to be more rigorous, the overall frequency of surgical RCTs has been consistently low since the 1970s.5 In addition to the paucity of randomized controlled trials, the few published controlled trials do not meet current quality standards for optimal reporting.6 To minimize bias on research findings that are considered relatively established (letter 1 and 2), protocol-driven RCTs without flexibility in design, definitions, outcomes and analytical modes are needed. Therefore, we performed a multi centre RCT comparing two surgical interventions, rigorously set up to diminish bias and taking all these aspects into account. This RCT on laparoscopy versus laparotomy meets
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the recommendations on the evaluation of a surgical innovation.1,3 The protocol of our study was registered in a trial register and published before analyzing the data of the included patients in the RCT (chapter 2). Upfront
registration of randomized trials and the principles of developing and adhering to a protocol are approaches to improve the post-study probability and prevent the problem of publication bias.
In this multi centre RCT, 26 surgeons in 21 centers were included, comparing total laparoscopic hysterectomy (TLH) versus total abdominal hysterectomy (TAH) in early stage endometrial cancer patients (chapter 3). The primary
outcome was major complication rate; secondary outcomes were minor complication rate, treatment-related outcome and quality of life. Based on previous studies, we expected a difference of 15% in major complication rate between TLH and TAH. With a power of 80% and α=0.05, we needed 275 patients to detect this difference. In this study, 283 patients were enrolled of which 187 patients in the TLH arm and 96 in the TAH arm. Different from what we expected, there were no differences in major complication rate and minor complication rate between the laparoscopy group and the laparotomy group, according to the intention-to-treat principles. Conversion to laparotomy occurred in 10.8% of the laparoscopic procedures. A TLH took longer to perform, though a TLH resulted in significant less blood loss, a shorter hospital stay, less pain medication use and an earlier return to daily activities. Although these clinical outcomes are very important to patients, evaluation of surgery needs to be widened to include the patients’ perspective in order to effectively evaluate surgery. No major benefit in quality of life scores derived from self-reported questionnaires between both surgical interventions was observed until 6 months after surgery.
To make rational decisions regarding the acceptance of new treatments into the health service, an economic
evaluation is crucial for efficient use of often limited resources. First, in chapter 4, data of controlled trials were
pooled to assess whether laparoscopic hysterectomy, provides ‘good value for money’ in comparison to the conventional procedure. Analysis was performed on 2,226 pooled patients, of which 1,013 underwent (45.5%) a laparoscopic variant of hysterectomy (LH) and 1,213 (54.5%) an abdominal hysterectomy (AH). The incremental costs (i.e., extra costs per additional effect) for reducing one patient with major complication(s) in the LH group compared to the AH group was $35,750. From this review, it can be suggested that the benefits of a shorter hospital stay in the LH group might compensate for the increased procedure-related costs. Laparoscopic hysterectomy points in the direction of cost-effectiveness. However, given the methodological impediments of the majority of studies included in this review, no firm conclusions can be drawn. Moreover, all these studies were performed in patients with a benign or malignant indication for removal of the uterus, using different variants of laparoscopic techniques. Therefore a broader, societal perspective is needed, including all relevant costs and clinical effects for determining implications for practice. Importantly, randomized controlled trials are the most rigorous way of determining the cost- effectiveness of a treatment avoiding all sorts of bias.7 The aim
of chapter 5 is to evaluate the cost-effectiveness of the two surgical approaches (TLH versus TAH), carried out alongside a multicentre randomized controlled trial, complying with all guidelines.8,9 An economic analysis was conducted in 279 patients (TLH n=185; TAH n=94) over a three months time horizon. Health outcomes were expressed in terms of major complication rate and in terms of utility. TLH is more costly intra-operatively and
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less costly postoperatively in-hospital compared to TAH. Incremental costs per major complication free patient were €-37 in favor of laparoscopy. TLH is cost-effective compared to TAH, based on major complication-free rate as primary measure of effect. Along with future cost saving strategies in laparoscopy, TLH will become even more cost-effective. Therefore and due to comparable safety, TLH should be recommended as the standard surgical procedure in early endometrial cancer, on the condition that the procedure is performed by proven skilled surgeons.
In literature, it is often mentioned that patients with a high BMI and older patients benefit most from TLH. The aim
of chapter 6 is to analyze whether data support this assumption. Data of 283 patients enrolled in the multicenter randomized controlled trial were re-analyzed. First, subgroups of patients were constructed based on age, BMI, co-morbidity, previous laparotomy and FIGO stage and surgical technique (TLH or TAH) as predictors of major complications and conversion from laparoscopy to laparotomy. For each subgroup of patients costs per major complication-free patient were estimated, using incremental cost effect ratios (ICER). Patients with increasing
age and BMI had a higher risk to develop major complications, adjusted for surgical technique (TLH or TAH). Furthermore, patients with increasing BMI and a history of a laparotomy had a higher risk to be converted to laparotomy. In patients with a BMI over 35 kg/m2, 33.3% of all laparoscopic procedures were converted. For patients over 70 years of age and patients with a BMI over 35 kg/m2, incremental costs per major complication- free patients (Δcost/ Δeffect) were €16 (136/8.46) and €54 (-272/-5.07) for TLH compared to TAH, respectively. From these results can be concluded that TLH is cost effective in patients over 70 year of age, but not in patients with a BMI over 35 kg/m2, based on major complication-free rate as a primary measure of effect. In general, TLH should be recommended as the standard surgical procedure in early endometrial cancer, except in patients with a BMI over 35 kg/m2, due to a high conversion rate.
Key points in surgical intervention studies Surgical outcome evaluation
The key questions to address when planning a study on a surgical intervention are: what is the outcome, how should it be measured, who should assess it, and when? In our RCT, the primary outcome was major complication rate as being an indicator of treatment related morbidity. Complications were registered intra- and postoperatively until six weeks after surgery. The major complication rate was standardized in order to be reproducible. The severity of a complication was assessed according to the Common Terminology Criteria of Adverse Events (CTCAE) version 3.0. An independent panel, consisting of three experienced clinicians familiar with laparoscopic surgery differentiated between major and minor complications, based on consensus and assessed whether and to what extend the complication was related to the operative procedure. The panel was given a random sample of complications twice, to assess consistency of judgment.
In addition to the clinical effect measures, a cost evaluation of the new intervention in comparison with the conventional procedure is essential to make a rational decision about implementation of this new intervention.
Surgeon-related factors
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not be fully refined; the subsequent study outcome then reflects the stage of development and learning, and not merely the therapeutic effect of the intervention. Additionally, restricting a new procedure to an RCT might be impractical in the absence of regulation that prevents surgeons offering the intervention to patients outside the trial. The learning curve for a surgical intervention, whereby surgeons acquire expertise, poses an important challenge. Evaluation of a new surgical intervention versus an established procedure has been criticized, owing to a perceived imbalance of experience that favors the established comparator.10 Therefore, instead of comparing the established procedure (TAH) with the learning curve of the new surgical intervention (TLH), we included only gynecological surgeons with experience in laparoscopy, trained and assessed by a visiting gynecological oncologist with experience in laparoscopy. The assessment used preset scores from an Objective Structured Assessment of Technical Skills. The gynecological surgeons were allowed to participate in the study only after achieving, according to the predefined assessment, sufficient laparoscopic skills for performing a TLH. Only one or two surgeons in every centre were trained in TLH to ensure sufficient exposure to laparoscopic procedures per surgeon.
To overcome the problem that the experimental procedure was offered outside the trial, two centers were banned from participation shortly after the beginning of the study, because they did not comply with the randomization procedure.
Complexity of surgical procedures
Whatever evaluation is used, the quality of the intervention needs to be monitored. This means that not only the surgery but also the surgical environment should be taken into account. A surgical intervention consists of several components that cannot be separated (Figure 8.1.1).2This complexity often receives little recognition in the design of surgical studies, which was the case in our study as well. A weak point of our study was the focus on surgical skills only. These supporting components are affected by infrastructure, staffing and local policies. The effect on health service of these components could justify assessment of alternatives.
Figure 8.1.1 Complexity of a surgical intervention
Preoperative and postoperative care Operating theatre Surgical procedure Anaesthesia team Medical team Nursing team Surgeon(s)