Efficacy of Systemic Pelvic Lymph Node Dissection in the Treatment of Endometrial Cancer (MRC ASTEC Trial): A Randomized Study
BACKGROUND:Hysterectomy and bilateral salpingo-oophorectomy (BSO) are the standard surgeries for stage I endometrial cancer. Systemic pelvic lymphadenoadenectomy has been used to determine the presence of extrauterine disease and as a means of treatment; However, randomized trials are needed to assess treatment effects. The ASTEC surgical trial investigated whether pelvic lymphadenectomy could improve survival in women with endometrial cancer.
METHODS:A total of 1408 women with histologically confirmed endometrial cancer from 85 centers in four countries, preoperatively deemed confined to the uterine corpus, were randomized to standard surgery (hysterectomy and BSO, peritoneal irrigation, and para-aortic lymph node palpation; n=704) or standard surgery plus lymphadenectomy (n=704). The primary outcome measure was overall survival. To control postoperative treatment, women with early-stage disease at moderate or high risk of recurrence were randomized (independent of lymph node status) to participate in the ASTEC radiation therapy trial. The analysis was performed on an intention-to-treat basis. This study is registered under the ISRCTN 16571884.
RESULTS:After a median follow-up period of 37 months (IQR 24-58), 191 women (88 in the standard surgery group and 103 in the lymph node dissection group) died, with a risk ratio (HR) of 1.16 (95% CI 0.87-1.54; p=0.31), with an absolute difference of 1% (95% CI -4 to 6) in 5-year overall survival. Twenty-five women died or relapsed (107 in the standard surgery group and 144 in the lymph node dissection group), with a hazard ratio of 1.35 (1.06 to 1.73; p=0.017), with an absolute difference of 6% (1-12) in 5-year recurrence-free survival. After adjusting for baseline features and pathologic details, the HR for overall survival was 1.04 (0.74-1.45; p=0.83) and the HR for recurrence-free survival was 1.25 (0.93-1.66; p=0.14).
INTERPRETATION:Our findings suggest that pelvic lymphadenectomy has no benefit in terms of overall survival or recurrence-free survival in patients with early-stage endometrial cancer. Pelvic lymph node dissection is not recommended as a routine treatment other than in clinical trials.
introduce
Endometrial cancer is currently the most common gynecologic malignancy in Western Europe and North America. It affects around 6,400 women each year in the UK, 181,500 in the EU and 40,100 in North America. More than 90% of cases occur in women over 50 years of age, with an average age of 63 years. Between 1993 and 2001, there was a 19% increase in incidence in older women (60-69 years) in the UK. It is the seventh leading cause of cancer deaths among women in Western Europe, accounting for 1-2% of all cancer deaths. About 75% of women survive for 5 years. Such a high survival rate is attributed to the fact that most women are diagnosed early after postmenopausal bleeding.
At diagnosis, about three-quarters of women's disease is confined to the corpus of the uterus. Standard radical surgeries include hysterectomy and bilateral salpingo-oophorectomy (BSO). Most tumors are endometrioid; Other histological types include serous, mucous, clear cell, and mixed epithelium. With the exception of clear cell and serous tumors, which are often considered grade 3, endometrial tumors are classified as well-differentiated (grade 1), moderately differentiated (grade 2), and poorly differentiated (grade 3). Endometrial cancer spreads outside the uterus by direct penetration of the myometrium, extends to the cervix, and most commonly metastasizes to pelvic lymph nodes and, less commonly, to para-aortic lymph nodes. Pelvic lymph node metastases occur in about 10% of women with clinical stage I (i.e., confined to the corpus of the uterus). In stage I disease, lymph node involvement occurs in 3-5% of women with well-differentiated tumors and superficial muscular invasion. In women with poorly differentiated tumors and deep myometrial invasions, this rises to about 20%.
In Europe, the traditional treatment for patients with stage I is surgery, and for patients whose pathologic features indicate an increased risk of lymph node metastasis, surgery is often combined with adjuvant radiotherapy. Tumor type, grade, and depth of muscle invasion are key prognostic factors for recurrence and are used to assess the risk of recurrence and the need for adjuvant therapy. A systematic review and meta-analysis of 1770 patients in four randomized trials and data from the ASTEC/EN.5 radiotherapy trial suggest that adjuvant radiotherapy slightly reduces the risk of isolated pelvic recurrence (2.9%), but there is no evidence that it affects overall or disease-specific survival.
Since 1988, the International Federation of Obstetrics and Gynecology (FIGO) has required comprehensive and systematic pelvic and para-aortic lymph node dissection for staging of endometrial cancer. It has been proposed that if lymph node dissection does not show signs of disease in the lymph nodes, adjuvant radiotherapy can be avoided and treatment morbidity reduced. However, there is little evidence of a therapeutic benefit of lymphadenectomy on survival. Lymph node dissection is widely performed in North America and Australia, and is supported by non-randomized studies and case series showing an association between lymph node dissection and improved survival. However, other observational studies have not shown any such benefit. ASTEC (Endometrial Cancer Treatment Study) aims to evaluate the therapeutic benefits of lymph node dissection for endometrial cancer, independent of the effect of adjuvant radiotherapy.
ASTEC consists of two separate randomized trials designed to answer questions about surgery and radiation therapy. Surgical trials have investigated whether pelvic lymph node dissection can improve survival in patients with endometrial cancer, which was previously thought to be confined to the uterine body. The radiation therapy trial explored whether adjuvant external beam radiation therapy (EBRT) can improve survival in patients with intermediate- and high-risk early-stage endometrial cancer. In this paper, we report the results of surgical randomization.
discuss
This randomized trial showed no evidence of benefit from systemic lymphadenectomy on overall survival, disease-specific survival, and recurrence-free survival in patients with endometrial cancer. This study is one of the largest reported surgical trials of gynecologic cancers. We searched to identify other published randomised trials of lymph node dissection for endometrial cancer and searched the Cochrane database for systematic reviews of randomised and observational studies. No results were found, but a randomized trial (smaller than ASTEC) has just been reported confirming that lymphadenectomy is not associated with a survival benefit in patients with endometrial cancer.
The proportion of women with pelvic lymph node metastases in ASTEC (9%) is consistent with the proportion in the gynecologic oncology group (GOG) in surgical studies of disease spread. ASTEC's trial design succeeded in randomizing participants to postoperative EBRT regardless of lymph node status, resulting in an even proportion of women receiving radiation therapy in both groups. Otherwise, lymph node dissection may result in more women in the lymph node dissection group being classified as having advanced disease, resulting in more women in this population undergoing postoperative EBRT. As a result, any effect that is beneficial to the lymph node dissection group is enhanced. Although more women received EBRT in the standard surgery group than in the lymph node dissection group, with the exception of the low-risk early subgroup, the difference was not significant. In addition, a greater proportion of node-positive women in the lymph node dissection group underwent EBRT (which may have been beneficial for lymph node dissection), albeit in smaller numbers. However, given the results of a systematic review and meta-analysis of 1770 women from four randomized trials7, and now data from the ASTEC/EN.5 radiotherapy trial, these results suggest that even if a small benefit of radiotherapy can be ruled out (5-year overall survival rate of more than 3%), this slight imbalance in the use of EBRT is not statistically and clinically significant.
Several observational studies comparing the outcomes of women who underwent systemic lymph node dissection with those who did not have systemic lymph node dissection, some of which supported lymph node dissection for all grades of tumour, another study supported lymph node dissection for G3 grade tumours, and some concluded that the benefit depended on the number of lymph nodes removed. However, these studies on the benefits of treatment should be interpreted with caution as they are prone to bias because of systemic differences between women who underwent and did not undergo lymphadenectomy, including comorbidities and obesity that may be associated with poor survival. In addition, in non-randomized studies, the proportion of women with node-positive unsurgical staged occult stage III disease was consistently higher than that of women classified as stage I with node-negative and reduced risk of recurrence after lymph node dissection (staging migration). Large cancer registries are invaluable for monitoring trends in cancer incidence and outcomes, formulating hypotheses and planning the delivery of cancer services, but they are not reliable for assessing treatment outcomes. Analysis of large observation cohorts means that small associations may be important, but they can easily arise from very slight biases and should not be misconstrued as measuring the immediate effects of an intervention.
There are currently no nationally or internationally accepted guidelines for lymph node dissection to determine whether lymph node dissection is adequate in terms of lymph node count, so no specific guidelines are provided in this protocol. The number of lymph nodes determined may depend on the physical characteristics of the woman, the thoroughness of the surgery, and the pathological examination of the tissue. ASTEC has successfully compared systemic lymphadenectomy with the more conservative standard surgical methods for women who only present with potentially positive lymph nodes on palpation. The median lymph node count in the lymph node dissection group was about the same as that of a large single-institution case series in the US, in which 11 lymph nodes were removed, and a study using data from a large observational database, in which the median number of lymph nodes removed was between 7 and 12.
We were unable to perform an unbiased analysis of the results based on the number of lymph nodes removed in individual patients, as we had to break random comparisons, which also had the problem of selection bias (although there were fewer staging shifts). However, we were able to perform exploratory analyses comparing standard surgery and lymph node dissection in different centers with different numbers of routinely dissected lymph nodes. The results of this analysis suggested, if anything, that the lymph node dissection group had worse outcomes when more lymph nodes were removed than in the standard surgery group. This finding, along with the trend towards a slightly higher rate of recurrence in the lymph node dissection group, may be important, although the reasons for this are not yet apparent. While some lymph node sampling was performed in the standard surgery group, only 35 (5%) women had their lymph nodes removed, and 26 of them had no more than 4 lymph nodes removed. This small amount of non-adherence may slightly skew the point estimate of HR (i.e., lymphadenectomy has no effect), but the treatment effect must be very large for this small amount of non-adherence to affect the overall outcome.
A limitation of this study is that the lymph node dissection prescribed in the protocol is not comprehensive and does not include all pelvic and para-aortic lymph nodes. When ASTEC was conceived, systemic lymph node dissection (i.e., lymph node dissection rather than sampling) was considered a potential treatment procedure that could be performed within the hospital limits of women treating women with endometrial cancer, and for women who needed the procedure, including those who were unable to undergo surgery due to obesity and who were difficult to undergo more extensive surgery. More extensive lymph node dissection may significantly increase treatment-related morbidity and mortality. Data from sentinel lymph nodes give us insight into the overall picture of lymphatic drainage patterns in endometrial cancer and may guide future surgical research. Improvements in imaging technology can also make it easier to select high-risk women, so that a wider range of lymph node dissections can be performed for a subgroup of women with a higher likelihood of lymph node metastases and a wider range of surgical viables (fewer comorbidities, including obesity).
The overall incidence was low, but we noted a substantial increase in the incidence of lymphedema in the lymphadenectomy group compared with standard surgery. Clinicians may not notice or report milder cases because all reported cases of lymphedema are moderate and severe.
We acknowledge that only 191 deaths were recorded, despite the fact that ASTEC was a very large trial. Will you miss out on a small but important therapeutic effect? Recurrence-free survival was the strongest outcome measure (251 events). A lower 95% CI of 0.93 for recurrence-free survival-adjusted HR (Table 8) implies a benefit of 1.5% (adjusted) at 5 years. Therefore, we can reliably rule out a 5-year recurrence-free survival improvement of 1.5% or greater with lymphadenectomy.
ASTEC is important for both clinical practice and future trials. The trade-offs of risks and benefits of systemic lymphadenectomy are not favourable to this intervention, and there is no clear evidence of benefit in terms of overall or recurrence-free survival and increased risk of lymphedema. While the results do not negate the use of lymphadenectomy for surgical staging to determine the need for adjuvant therapy, our results suggest that lymphadenectomy has no therapeutic effect on its own and therefore cannot be used as a stand-alone treatment procedure. Some argue that surgical staging allows for the most rational use of adjuvant radiotherapy, reserved for women with proven extrauterine disease. In this way, the long-term effects associated with radiotherapy can be reduced without affecting survival. This claim may be oversimplifying the evidence, as results from the GOG99 study showed that radiation therapy still had a role in preventing pelvic recurrence when women were randomly assigned to surgically staged and node-negative women, although there was no evidence of a difference in overall survival (recurrence rate was 12% in the non-radiotherapy group versus 3% in the radiotherapy group, relative risk 0.42 [90% CI 0.25–0.73]; p=0.007）。 21 The estimated overall 4-year survival rate was 86% in the non-radiotherapy group and 92% in the radiotherapy group (relative risk 0.86 [90% CI 0.57–1.29]; p=0.56）。 This finding suggests that adjuvant therapy decisions for intermediate- and high-risk disease should be independent of lymph node status.
In conclusion, this large randomized trial suggests that routine systemic pelvic lymphadenectomy is not recommended for women undergoing primary surgery for stage I endometrial cancer outside of clinical trials unless surgical staging directly affects adjuvant therapy. Surgical interventions should be evaluated through randomized trials, and surgical staging as part of a management strategy is no exception.
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