The Current Status of Lymphadenectomy in the Management of Endometrial Cancer

Abstract

The International Gynocologic Cancer Society is a biannual meeting for those multidiscipline physicians who are involved in research and the clinical care of women with a gynecologic cancer. Approximately 3000 physicians from all geographic areas attended and heard presentations covering all aspects of gynecologic cancer.

One of the main topics of discussion at the International Gynocologic Cancer Society (IGCS) was the current status of lymphadenectomy (LA) in the management of endometrial cancer. This was highlighted by a debate between major contributors to the literature on this subject. The debate began with a brief historical review of LA by William Creasman, Medical University of South Carolina, SC, USA, who also served as moderator. Data from the 1950s suggest that the rate of metastases to the lymph nodes was as high as 28% [1]. Why this information had not been incorporated into the management of endometrial cancer subsequent to that time remains a mystery. In the 1970s, a pilot project of the Gynecologic Oncology Group (GOG) was undertaken to evaluate pelvic and para-aortic lymph node status at the time of a hysterectomy and bilateral salpingo-oophorectomy [1]. Current practice at that time involved treating endometrial cancer by removing the uterus and adnexal, usually accompanied with pre- or post-operative radiation therapy. The pilot project noted 11% of women with clinical Stage I cancer (1971, International Federation of Gynecology and Obstetrics [FIGO] staging) had metastasis to the pelvic nodes and 10% in the para-aortic area of those whose nodes were removed [2]. This study led to a group-wide study by the GOG, in which over 1000 women were surgically evaluated with pelvic LA (PLA) and para-aortic LA (PALA), in addition to the standard hysterectomy and bilateral salpingo oophorectomy. This study confirmed the pilot study with regards to lymph node metastasis. In addition, metastases were dependent on grade and depth of invasion. As expected, increased recurrence and death from disease correlated with lymph node metastasis. It was also determined that there were low- and high-risk groups of patients in regards to lymph node metastases [3]. These as well as other studies substantiated the fact that both pelvic and para-aortic lymph nodes were at risk for metastases in endometrial cancer. These data, in 1988, led FIGO to change endometrial cancer staging to a surgical one instead of clinical. These studies confirmed the fact that LA can be diagnostic, which is extremely important in optimizing individual care. It did raise questions: can LA also be therapeutic? Do all women with endometrial cancer need LA? What is the adequacy of LA? And having this information, what is the optimal postop therapy if any?

A retrospective study attempted to address the therapeutic question. In a retrospective review of over 400 women with Stage I and II endometrial cancer treated at the University of Alabama, Birmingham, approximately a half had lymph nodes removed and the other had a hysterectomy and bilateral salpingo oophorectomy [4]. They identified both a low- and high-risk group of patients. In both the low- and high-risk groups, those who had lymph nodes removed had a better survival than those who did not have nodes removed. They further evaluated the patients with regard to whether or not radiation therapy was given postoperatively and their LA status. In both high- and low-risk groups those who had LA but did not receive postoperative radiation, had a better survival than those who did not have an LA but did receive postoperative radiation therapy. This study brought into question the efficacy of postop radiation therapy, which was standard therapy at that time in many women.

Chan, in reporting the Surveillance, Epidemiology and End Results (SEER) data from the USA identified over 13,000 women who had lymph nodes evaluated to varying degrees [5]. He noted that even with positive nodes the survival increased if multiple nodes were removed. For instance, if one node was removed and it contained a metastasis, survival was 51%; however, if at least 20 lymph nodes were removed the survival was 83%. This high significance remained, even when at least five lymph nodes contained a metastasis and at least 20 lymph nodes were also removed (21% survival if only 6–10 lymph nodes were removed, and more than five were positive vs 61% if 20 lymph nodes were removed). This suggests a therapeutic benefit with the removal of multiple nodes, which may remove micrometastasis. This significance remained when multivariate analysis was performed.

A study from Japan (SEPAC study) was published in early 2010 [6]. This was a study of PLA versus PALA in endometrial cancer. It was not a randomized study; one hospital only removed pelvic nodes and the other hospital removed both pelvic and para-aortic lymph nodes. LA was certainly adequate for using the number of lymph nodes removed as a parameter. Survival was significantly better (p > 0.001) in those women receiving the PLA and PALA. This association appeared in intermediate-and high-risk patients but not in low-risk patients. In a multivariate analysis PLA plus PALA reduced the risk of death compared with PLA only. In the high-risk group, chemotherapy plus PLA plus PALA patients had a better survival than chemotherapy plus PLA only. PLA plus PALA and adjuvant chemotherapy were independently associated with improved survival.

Two prospective studies were presented as part of the debate by their senior authors in Prague, Czech Republic. A Study in the Treatment of Endometrial Cancer (ASTEC) was presented by Henry Kitchener from the University of Manchester (Manchester, UK) [7]. In a large multicentric study, 1408 patients were randomized to abdominal hysterectomy, bilateral salpingo-oophorectomy with or without PLA. A median follow-up of 37 months was obtained. There was no difference in survival between the two groups. This was an intent-to-treat study and has been criticized regarding a relatively large noncompliance with regard to LA as well as subsequent therapy. In the LA arm, almost half had no nodes or a small number (≤9) removed. This study was further complicated by the fact that many of these patients were secondarily randomized into a postoperative radiation study, not taking into consideration surgical findings. PALA was not the standard management although some patients had these nodes removed.

The second study was presented by Pierluigi Benedetti Panici from the University of Rome (Rome, Italy) [8]. This Italian study randomized 514 Stage I patients to systematic PLA or no LA. Although 13.3% of patients in the LA arm had known metastasis versus 3.2% in the no-LA arm, there was no difference in recurrence or overall survival. The protocol required a minimum of 20 lymph nodes to be removed; however, the LA was limited to the pelvis although PALA could be removed at the discretion of the surgeon. Postoperative radiation was left to the discretion of the treating physician. Adjuvant therapy was similar in the two groups. Whether or not this had an effect on survival is unknown since this was not standardized.

Karl Podratz of the Mayo Clinic, MN, USA, presented their data with regard to the adequacy of the LA. As an advocate of thorough LA including paaraortic to the renal vessels, he compared his population to the ASTEC study. His patients were divided into low, intermediate/high and advanced endometrial categories as defined by the ASTEC study. The medium number of nodes removed were 47 (33 pelvic and 14 para-aortic) in the Mayo study compared with 12 in the ASTEC trial. Known metastasis in Group 1, 2 and 3 were 2, 8 and 21% in the ASTEC trial compared with 4, 21 and 48% in the Mayo cohort. Only three out of 54 positive cases (5.6%) had para-aortic involvement in the ASTEC study. By contrast, utilizing systematic PALA in 61% of positivenode patients in the Mayo series, para-aortic involvement was 54, 60 and 63% in Group 1, 2 and 3 respectively in the Mayo study. The extent of thoroughness of the LA is apparent.

Other studies were presented at the IGCS, which also addressed the extent of LA. Koc reported on 78 patients who had both upper and lower regions of the para-aortic regions evaluated [9]. LA positivity was 14% in the upper region and 6.4% in the lower region of the paraaortic. In 27% of patients with lymph-node involvement in the upper region, no metastases were noted in the pelvis. In 9% of patients with metastasis to the upper region and at 20% with lymph node involvement in the lower region, myometrial invasion was not present.

Shan evaluated 501 patients who had PLA [10]. Of the 205 patients who also had PALA, 31 (15%) had nodal metastasis, 12 (5.9%) with pelvic metastasis, 12 with pelvic and para-aortic metastasis and seven (3.4%) with isolated para-aortic metastasis. The remaining patients experienced no metastasis.

In 128 patients El-Balat found lymph-node metastasis in 27 (21%) patients after a systematic pelvic plus PALA [11]. A total of 14 patients (10%) had positive pelvic plus para-aortic metastasis, six (4.7%) had positive para-aortic nodes only and seven (5.5%) patients had only pelvic lymph node metastasis. Only 41.1% of affected PALA were above the inferior mesenteric artery.

Suzuki reviewed a subset of the Survival Effect of Para-aortic Lymphadenectomy in Endometrial Cancer (SEPAL) study and identified 215 patients with high-risk, early-stage and advanced-stage endometrial cancer for which 125 had PLA plus PALA and 90 underwent only PLA [12]. Postoperatively all patients were recommended to receive either radiation or chemotherapy. Survival was significantly better in the PLA plus PALA group compared with the PLA group (p = 0.0006). Multivariate analysis confirmed that age, histology, lymph node metastasis, type of LA and type of adjuvant therapy were independent prognostic factors.

Summary

Although LA continues to be controversial for some, over the last 30 years our knowledge of the lymph node involvement in endometrial cancer and how that information can be used to benefit our patients has increased. From the data presented at the debate, as well as from other studies, it appeared that LA in endometrial cancer is an important part of the surgical procedure. It is certainly diagnostic. There does appear to be therapeutic benefit if adequate PLA and PALA are done. Two questions remain: do all patients require lymphadenopathy? The data suggest ‘low-risk’ patients do not. Unfortunately low risk has not been adequately defined for all although increasing data would probably lead to a consensus in the near future.

The second question is who if anyone needs adjuvant therapy? The main benefit of LA is to identify those women who may be candidates for adjuvant therapy. The early quoted GOG study found approximately one-quarter of patients thought to have early-stage disease had disease outside of the uterus. Likewise patients can be identified who may have been historically treated with radiation therapy, and appear to not need subsequent therapy, thereby saving expensive therapy with its inherent morbidity. Prospective studies have shown that postoperative radiation does not improve survival. Many investigators are currently engaged in studies to determine appropriate therapy in selected patients after surgical staging.