What is the evidence based surgical approach for hysterectomy in low and high risk apparent early stage endometrial cancer?
What is the evidence based surgical approach for hysterectomy in low and high risk apparent early stage endometrial cancer?
The standard management of patients with endometrial cancer is removal of the uterus, tubes and ovaries with pelvic and paraaortic lymphadenectomy, as necessary, for staging and management planning. This procedure has traditionally been performed by laparotomy. While there is no doubt about its efficacy, there have been concerns about the incidence of surgical morbidity and quality of life issues related to open hysterectomy through laparotomy, which has raised interest in minimally invasive techniques.
With the introduction of any new surgical technique, the feasibility, safety, and efficacy must be compared with the current standard surgical approach. Analysis of cost effectiveness and evaluation of impact on patient quality of life is also important. A number of retrospective analyses, single institution prospective studies and meta-analyses have been reported in the literature. However, these have generally involved small patient numbers, were subject to selection bias and offered short duration follow up only.
Recently, the results of three large multi-institution randomised controlled trials (RCTs) have become available with information on feasibility, safety, benefits and impact on quality of life, when surgery for endometrial cancer is performed by laparoscopy compared with laparotomy.
Since the introduction of laparoscopic hysterectomy more than 20 years ago, new technologies and increasing operator experience has led to a reduction in the rate of intraoperative conversion from a laparoscopic approach to laparotomy. This is reflected in the literature when reviewing conversion rates for laparoscopic procedures to laparotomy for endometrial cancer. Rates of conversion vary widely between different studies, likely due to varied experience between centres in laparoscopic surgery, and due to varied inclusion and exclusion criteria applied to patients enrolled in these studies.
The US Gynaecologic Oncology Group (GOG) recently published an RCT comparing laparoscopy to laparotomy in 2616 patients with newly diagnosed FIGO Stage I to IV endometrial cancer (GOG Study LAP2). The laparoscopic arm included patients undergoing laparoscopically assisted vaginal hysterectomy (LAVH), total laparoscopic hysterectomy (TLH), and rarely, robotic procedures. A conversion rate of 25% was reported. Common reasons cited for conversion were: the need to perform aortic node dissection irrespective of intra-operative findings, metastatic disease (unknown preoperatively), and risk factors such as (morbid) obesity resulting in poor exposure, and increasing age. Fifty-seven per cent of patients with a BMI > 40 kg/m2 required conversion, compared to only 17.5% of patients with a BMI <25 kg/m2. Despite this high conversion rate, a benefit was still seen in terms of lower rates of postoperative complications (grade 2 or greater), and shorter hospital stay.
The Laparoscopic Approach to Carcinoma of the Endometrium (LACE) Trial is an RCT involving centres in Australia, New Zealand and Hong Kong. In contrast to the LAP2 study, this group reported a 2.4% conversion rate, which even included patients converted from the total abdominal hysterectomy (TAH) to the TLH group because of patient preference. This conversion rate is extremely low when compared to other studies reporting rates between 4% and 10.8%.
The low conversion rate seen in the LACE trial is likely to be due to several factors. There were strict eligibility criteria for both patients and surgeons. Only patients with stage I endometrial cancer, ECOG of <2, CT suggesting an absence of extra-uterine disease, uterine size <10 weeks, and who were medically fit were eligible. Lymph node dissection was not performed if the tumours were well or moderately differentiated and invaded into less than the inner half of the myometrium or if the patients were medically unfit. As a result of those criteria, only 52% of LACE patients had pelvic or paraaortic lymph node dissection. In addition, surgeons underwent a rigorous accreditation process to ensure procedural competence.
In 2010, Mourits et al. published a prospective randomised trial involving 283 patients in 21 centres in the Netherlands assessing safety of laparoscopic versus open hysterectomy in patients with stage I endometrial cancer or complex atypical hyperplasia. All surgeons were experienced in laparoscopic surgery, and a conversion rate of 10.8% was recorded.
Conversion to laparotomy increases with co-morbidities (including morbid obesity) and increasing stage of disease. Consideration of medical conditions such as severe cardiopulmonary disorders precluding steep Trendelenburg positioning in particular need to be considered when contemplating a laparoscopic approach..
Performance of pelvic lymph node dissection
While there is ongoing debate as to the role and extent of lymphadenectomy required in the management of endometrial cancer (see section on Lymphadenectomy), a number of studies have confirmed that laparoscopic lymphadenectomy is feasible. In the GOG LAP 2 trial, paraaortic nodes were successfully retrieved in 94% of laparoscopic procedures, compared with 97% of procedures performed by laparotomy. A number of RCTs comparing laparoscopy versus laparotomy did not detect any difference in number of nodes harvested, although the studies were not powered to detect a difference.
Published studies show that laparoscopic surgery of endometrial cancer involves a longer operating time compared to laparotomy. This has been confirmed by RCTs to be statistically significant. In general, the three RCT’s showed that operating times for laparoscopic approach are 1.27 to 1.62 times longer than for laparotomy.
Intra-operative adverse events
Laparoscopic management of endometrial cancer appears comparable to the open approach in regards to the incidence of intra-operative complications. Retrospective and single institution studies suggest less tissue trauma and blood loss compared to open procedures. These findings have been confirmed in the recently performed RCTs.
The Dutch Trial found no significant difference in major intra-operative complication rates when comparing the laparoscopic to an open approach. However, TLH was associated with significantly less blood loss. No pelvic lymph node sampling was performed in this trial. The LAP2 trial also reported no differences in intra-operative adverse event rates between the laparoscopic and open arms (p=0.106). In the LACE trial was no difference in intra-operative adverse events between the laparoscopic and open arms. 2.9% of patients sustained a vaginal injury in the TLH arm compared to none in the open arm.
Postoperative adverse events
A heterogeneous group of RCTs enrolling patients with different eligibility criteria have shown a significant advantage of laparoscopy over laparotomy in regards to the incidence of post-operative surgical adverse events.
While there was no significant difference in post-operative complication rates reported by Mourits et al., half as many serious adverse events were seen in the TLH group compared to the TAH group in the LACE study. In both the LACE and LAP2 trials, post-operative adverse events were classified using the Common Toxicity Criteria for Adverse Events (CTCAE) (VER3).
The LAP2 study found CTCAE equal to or greater than grade 2 (moderate to severe adverse events) were more common in the open group compared to laparoscopic group (21% versus 14%, p<0.004). This was due mainly to an increase in post operative ileus and arrhythmia in the laparotomy group. An increase in post operative adverse events was also seen in the LACE trial (53.8% versus 42.8%, p=0.004). In LACE, the difference was mainly due a large difference in the wound infection/dehiscence rate (30.9% in the open group versus 8% on the laparoscopic group).
Quality of life (QOL)
An intention to treat analysis of patients in the LAP2 study found patients in the TLH arm had significantly better QOL, fewer physical symptoms, less pain and pain related interference with functioning, better physical functioning and emotional state, earlier resumption of normal activities, earlier return to work, and better body image compared to those assigned to laparotomy when assessed at six weeks post surgery. However, differences in body image and return to work were modest, and adjusted Functional Assessment of Cancer Therapy –General (FACT-G) scores did not meet minimally important difference. At six months, there were no statistically significant differences in QOL measures other than body image, which was improved in the laparoscopy arm.
By comparison, the LACE study, which used the same QOL instruments as used in the LAP2 study (FACT-G), found QOL significantly better in the laparoscopy arm during the early post operative period and maintained to six months. Reasons for this difference are likely to be due to the high number of conversions to laparotomy in the LAP2 study, and perhaps the lower proportion of patients receiving pelvic lymph node dissection in the LACE trial TLH arm when compared to patients enrolled in the LAP2 study.. Also, the statistical approach differed slightly. In LACE patients preoperative QOL scores were compared to their postoperative scores (patients acted as their own controls). In contrast, LAP2 compared the QOL scores of a large number of patients within a specified time period.
Length of hospital stay
Older retrospective, and more recent randomised trials, confirm that patients undergoing laparoscopic procedures for endometrial cancer have a shorter length of stay (LOS) despite longer operating times. Even with a 25% conversion rate in the LAP2 trial, median length of stay was still significantly lower in the laparoscopic group compared with the open arm, with 52% of patients assigned to the (intention to treat) laparoscopy arm requiring more than two days in hospital, compared to 94% of patients assigned to the laparotomy arm (P<0.0001). The most likely explanation is the significantly reduced risk of postoperative surgical adverse events as these patients experience the longest LOS.
Prospective single institution studies comparing LAVH to the open approach, as well as the LAP2 RCT, have shown patients experience less pain, and less need for analgesic medications when their procedure is performed laparoscopically as compared by laparotomy.) The LAP2 Study assessed pain severity and pain interference with quality of life (QOL) prior to surgery, and at one, three and six weeks, and six months after surgery. Pain severity scores were lower in the laparoscopy group at one week, but not at three and six weeks or six months.
In the Dutch trial there was no significant difference in reported pain between the two surgical treatment arms but significantly less pain medication was used in the laparoscopic group compared to the laparotomy group (p>0.0001).
Financial costs and cost effectiveness
Studies on cost effectiveness have had differing conclusions, depending on what costs are included. Scribner et al. compared laparoscopy to laparotomy in a non-randomised retrospective study concluding that although early discharge occurs, longer surgical time and higher anaesthetic costs offset this gain, and total costs do not differ statistically. Another retrospective study found that overall costs in the laparoscopic group were significantly lower when the reduction in number of post-operative complications is accounted for. An economic analysis of a multi-centre prospective randomised trial found that laparoscopic management of endometrial cancer was cost effective when compared to laparotomy based on major complication free rate as a measure of effect. TLH was more costly intra-operatively, but less costly post-operatively in hospital compared to TAH.
Disease-free and overall survival
Currently good quality data on disease-free and overall survival for patients undergoing a laparoscopic procedure for endometrial cancer is not available. Survival data for the LAP2 trial has been presented in abstract form showing that survival curves were overlapping, thus indicating no difference in disease-free or overall survival. Survival data from the LACE trial will become available in 2014 and no survival analysis is planned for the Dutch study. It seems likely that the laparoscopic approach to endometrial carcinoma will prove to be safe, but until more data are available, no firm conclusions about the oncological safety of laparoscopic approach can be made.
TLH in the morbidly obese patient
Obesity is a well-recognised risk factor for endometrial cancer and poses significant challenges to the performance of safe surgery by any technique.
In the past, morbidly obese patients were excluded from having a TLH because of concerns regarding ventilation during general anaesthetic (particularly in the steep Trendelenburg position), obtaining surgical access, achieving pneumoperitoneum successfully, port placement, visibility into the pelvis, and lymph node sampling in this patient group.
Some studies have shown an increased conversion rate in obese patients and decreased success in obtaining pelvic and paraaortic lymph nodes. Other retrospective studies (with small patient numbers) suggest that with appropriate preparation and experienced surgeons and anaesthetists, laparoscopic procedures for endometrial cancer can be performed safely in the morbidly obese, with conversion rates comparable to women with lower BMIs. Some studies even suggest superiority of a laparoscopic approach in regards to surgical complications over an open procedure in the morbidly obese.
Unfortunately, little is known about how these adverse effects can be overcome to safely complete laparoscopic surgery in morbidly obese patients.
While there are particular technical issues associated with a laparoscopic approach in morbidly obese patients, this is the cohort of patients who potentially would benefit most from early mobilisation and the reduced wound complications conferred by a laparoscopic approach.
TLH in the elderly
Another cohort that may specifically benefit from a laparoscopic approach is elderly patients. With increased age, co-morbidities are more common, and there is a higher risk of post-operative cardiac and respiratory complications, an increased risk of thrombo-embolic events, longer hospitalisation and greater loss of QOL in the post surgical period. One small retrospective study showed that older patients (mean age 75 years) undergoing laparoscopic surgery for endometrial cancer had less intra-operative and post-operative complications than those having open surgery, resulting in an earlier return to normal function post-operatively.
Evidence summary and recommendations
|Rates of conversion from laparoscopy to laparotomy depend on the laparoscopic expertise of the surgeon and the requirement to complete a pelvic and/or aortic lymph node dissection.||II, III-3||, , , , |
|Laparoscopic pelvic and para-aortic lymphadenectomy is feasible with comparable numbers of lymph nodes being obtained by either method. Lymphadenectomy may not be feasible in morbidly obese patients.||II, III-3||, , , , , , , |
|Intra-operative surgical Adverse Events (AEs) are not increased with laparoscopic management of endometrial cancer. Post-operative surgical AEs are significantly less common with laparoscopic surgery.||II||, , |
|Operative times are longer with laparoscopy than procedures performed by laparotomy for the management of endometrial cancer.||II||, , , |
|Patients undergoing laparoscopic management of endometrial cancer:
(a) Have shorter hospital stay,
|II, III-2||, , , , |
|(b) Experience less pain, and use less pain medication,||II, III-3||, , , |
|(c) Have improved surgical recovery, and quality of life in both the short and the long term to six months||II, III-3||, |
|Laparoscopic approach to the management of endometrial cancer is as cost effective as laparotomy.||II, III-2, III-3||, , |
|Data from retrospective series demonstrate equivalence in disease-free and overall survival of patients undergoing laparoscopic management of endometrial cancer compared to patients undergoing laparotomy. RCT survival data are awaited.||III-2, III-3||, |
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