18: Endometrial cancer

Endometrial cancer

Stephanie V. Blank and Zachary P. Schwartz

Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, NYU Langone Medical Center, New York, NY, USA

Clinical questions

  1. In women with low grade endometrial cancer (population), what is the evidence for and against (comparison) lymph node dissection (intervention) in relation to prognosis (outcome)?

Approximately 2.8% of women will develop endometrial cancer over their lifetimes; this represents a rate of about 25 per 100 000 women per year. Of these newly diagnosed endometrial cancers, an estimated 67% will be localized to the uterus [1]. Additionally, an estimated 75% of all endometrial cancers are low grade [2]. In the case of patients diagnosed with endometrial cancer, the standard method of staging and treatment is total hysterectomy, bilateral salpingo‐oophorectomy, peritoneal cytology and pelvic and para‐aortic lymph node dissection [3]. While few would argue about the role of removal of uterus, tubes, and ovaries, there remains great debate as to the role for and necessity of lymph node dissection in patients with low risk endometrial cancer.

The argument supporting lymph node dissection rests on the following principles:

  1. 1. The belief that the risk of nodal metastases in these patients warrants the dissection:

Creasman’s landmark study found an estimated rate of lymph node metastases in patients who are clinically low grade of upwards of 9% [4], but notably, there were no lymph node metastases in patients with tumors invading less than one third of the myometrium. Mariani et al. which established the “Mayo Criteria” for identifying low‐risk endometrial cancer cases noted that in even low‐risk endometrial cancer cases, the risk of nodal metastasis was seen in up to 5% of cases [5]. These percentile risks are felt to be high enough by some to warrant this process.

  1. 2. The possibility that the cancer will be upgraded or upstaged when the uterus is removed:

In a prospective randomized study by Benedetti et al., patients with low‐grade endometrial cancer were assigned to either receive complete pelvic lymphadenectomy or no lymphadenectomy at all. This study found that, indeed, those with complete pelvic lymphadenectomies had improved surgical staging, with significantly more patients found to have nodal metastasis, thereby upstaging their clinical low‐grade status [6]. Finding this higher stage status is important because it has large implications for potential need for and exposure to adjuvant therapies.

  1. 3. The belief that there is inherent therapeutic benefit to nodal dissection among these patients:

This benefit is twofold: (i) nodal dissection allows select patients to potentially avoid treatment and the adverse effects of such treatment when nodes are negative and (ii) an upgraded staging based on positive nodes identifies patients who would benefit from adjuvant therapy.

The treatment distinction between patients with positive nodes versus those with negative nodes is based on the idea that patients with positive lymph nodes are immediately placed within an advanced stage requiring chemotherapy. They therefore get appropriate treatment based on that knowledge. On the other hand, a patient with no positive nodes has the potential to be followed with surveillance alone. This is based on Gynecologic Oncology Group 99 study by Keys et al. which evaluated patients who had complete surgical staging, including pelvic and para‐aortic lymph node dissections and were without evidence of lymph node metastases. These patients were placed in low, intermediate, and high‐risk groups based on age, histology, depth of invasion, and lymphovascular space invasion. Those in the intermediate and high‐risk groups were randomized to either no treatment or whole pelvic radiation therapy. While no statistically significant difference was noted in expected four year survival between the two groups, there was a significant difference in evidence of pelvic and vaginal recurrences after treatment (12% in no treatment versus 3% in treatment arm, Relative hazard: 0.42, p = 0.007) [7]. This conclusion was again supported by the Post‐Operative Radiation Therapy in Endometrial Carcinoma (PORTEC) trial in 2000 which found patients with low grade endometrial cancer randomized to either radiation or placebo had similar five year overall survival (81% vs. 85%, p = 0.31) but had a decrease in locoregional recurrence (4% vs. 14%, p = <0.001) [8]. Thus, with surgical staging, the patient is able to be definitively placed within a low, intermediate, and high risk group and be given the opportunity for treatment that decreases overall locoregional recurrence of disease.

The counter argument to lymphadenectomy is based upon the idea that despite the possibility of upstaging patients with this procedure, patients have no difference in progression for free or overall survival despite lymphadenectomies [6, 9]. In Benedetti et al. study mentioned above, 514 patients with Stage I endometrial carcinoma were randomized to receive pelvic lymphadenectomy vs. no lymphadenectomy. Despite finding increased evidence of nodal metastasis in patients having undergone pelvic lymphadenectomy versus those that didn’t (13.3% vs. 3.2%, p = 0.001), there was no notable difference in five‐year disease free survival and overall survival (81% vs. 85.9% and 81.7 vs. 90.0%, respectively). Of note, the treatments were not standardized in these trials, thereby limiting the interpretation of the role of lymphadenectomy.

The landmark, international, randomized ASTEC trial further helped support this conclusion [9]. This study randomized 1408 women with suspected low‐grade endometrial cancer confined to the uterus to either total abdominal hysterectomy, bilateral salpingo‐oophorectomy, washings, and palpation of para‐aortic lymph nodes compared to the same procedure, but with added pelvic lymph node dissection and possible para‐aortic lymph node dissection based on the discretion of the surgeon. The study then took a step further than the Benedetti et al. study and controlled for post‐surgery treatment by randomizing those patients with intermediate or high‐risk cancer into the whole pelvic radiation versus no radiation, with both groups being able to possibly receive vaginal vault radiation therapy. In the end, after controlling for baseline characteristics and pathology details, the study found that Hazard Ratio for overall survival was 1.04 (0.74–1.45; p = 0.83) and for recurrence free survival was 1.25 (0.93–1.66; p = 0.14). Thus, the conclusions of this study demonstrated no difference in survival or recurrence of disease whether or not lymph node dissection was performed.

Now, while this ASTEC trial was strongly powered and had the strength of being randomize‐controlled, many aspects have been called into question. Often cited concerns regarding this study include selection bias based on the European locale of the study and the ability of the surgeon to decide on whether or not para‐aortics were performed as well as inappropriate randomization within the radiation treatment arms [3, 10]. European guidelines rarely require para‐aortic lymph node dissections [11] and given that this study was performed entirely within Europe, it is suggested that surgical inexperience with full staging would bias the practitioner against said staging. Additionally, and perhaps one of the most controversial aspects of this study, is that survival was evaluated after patients received radiation treatment randomization. In this study, those who were randomized to receive radiation were only those who were deemed intermediate or high‐risk cancer patients based on uterine pathology only. There was no consideration of lymph node status. In addition, by the nature of this randomization, approximately 50% of patients with intermediate or high‐risk cancers did not receive whole pelvic radiation. Thus, the outcomes of the patients receiving lymphadenectomies could very much be confounded by whether or not they received appropriate adjuvant therapy. Additionally, there is no way to tell whether lymphadenectomies would change outcomes with adjuvant therapy because lymphadenopathy was not considered in triaging patients to treatment.

Lymph node dissection in patients with low‐grade endometrial cancer remains controversial. Lymph node dissection introduces surgical risks including lymphedema and damage to major nerves and blood vessels [12]. But, regarding oncologic outcomes, studies either suggest that this process has no benefit or some. There is little to suggest that it has a negative impact on oncologic outcomes, but cost and impact on quality of life (for which there is a paucity of data) must be considered. At present, there is not an evidence‐based answer to this clinical question.

Some have recommended sentinel lymph node dissection for low grade endometrial cancer as a means to obtain the prognostic and treatment‐driving information that comes from pathologic evaluation of the lymph nodes all while minimizing the morbidity associated with full lymph node dissections [13]. Studies have suggested that using this methodology, despite its diminished invasiveness does not negatively impact the disease free survival, progression free survival and overall survival when comparing low‐grade disease [14, 15]. These studies are small however and there is very little long‐term follow‐up as yet. As such, lymph node evaluation via complete staging remains the standard of care.

  1. 2. In women with endometrial cancer (population) what is the evidence regarding minimally invasive surgery (intervention) in relation to adequacy of surgery, quality of life and oncologic outcomes (outcome)?

The surgical management of early stage endometrial cancer has, historically, been limited to laparotomy, total abdominal hysterectomy, bilateral salpingo‐oophorectomy and lymph node dissection [3]. In the early 1990s, however, small case studies started to establish laparoscopy as a safe, effective mode of surgical staging of endometrial cancer [16, 17]. Since then, multiple studies continued to support the efficacy, safety and beneficial outcomes of minimally invasive surgical techniques in early clinical stage endometrial cancers. These minimally invasive techniques include laparoscopic staging with total laparoscopic hysterectomy or laparoscopic assisted vaginal hysterectomy and, more recently, robotic assisted laparoscopic approaches.

Since the establishment of laparoscopy as a viable surgical staging tool, multiple prospective studies – many randomized – have evaluated just how effective this tool is in staging endometrial cancer [1823]. Holub et al. [18] in 2002 is an example of one such study that evaluated 92 women who completed laparoscopically assisted vaginal hysterectomy as well as bilateral salpingo‐oophorectomy, and lymph node dissection compared to an abdominal approach control group of 24 patients. They found an increase in time for laparoscopy (an average of 38 more minutes, p = <0.0001) but importantly they also found a significantly shorter hospital course (an average of 3.6 days shorter, p = <0.0001) for laparoscopy compared to laparotomy. They also found no statistically significant difference in complications, estimated blood loss, and number of lymph nodes removed.

Malur et al. [24] similarly evaluated patients undergoing laparoscopically assisted vaginal hysterectomy, bilateral salpingo‐oophorectomy and lymph node dissection (assuming tumor was more than 1/3 invaded through the myometrium). They compared 37 patients via laparoscopy versus 33 patients via laparotomy. They similarly found a statistically significant decline in length of stay, blood loss, and length of time until first bowel movement. They also noted no statistically significant difference in disease recurrence or long‐term survival over a three year period.

Further studies looked at laparoscopy alone as a methodology for hysterectomy, bilateral salpingo‐oophorectomy and lymph node dissections. Important studies such as Kuoppala et al. [19] and Malzoni et al. [25] compared patients with laparoscopy (n = 40 and n = 81, respectively) alone versus laparotomy (n = 40 and n = 78, respectively). Like previous studies mentioned above, both studies found a statistically significant increase in the duration of surgery but they also noted a significant decline in blood loss and length of post‐operative hospitalization. In the Kuoppala et al. study they interestingly found a statistically higher number of lymph nodes removed in the laparoscopic group. Survival and recurrence, however, wasn’t compared in this trial between the two groups so the significance of the increased number of nodes is hard to interpret. The Malzoni et al. group did compare rates of recurrence, overall survival rates and disease free survival. They had a median duration of follow‐up of 38.5 months. They found no statistically significant difference in rates of recurrence in laparoscopy versus laparotomy (8.6% vs. 11.5%), rates of overall survival (93.2% vs. 91.1%, p = 0.31), or disease free survival (91.4% vs. 88.5%, p = 0.28). Thus, both studies demonstrated surgical benefits of laparoscopy over laparotomy and Malzoni et al. found that despite this surgical benefit, there was no decline in survival or recurrence outcomes.

Now, while the above‐mentioned studies have all importantly demonstrated the merits of laparoscopic surgery in clinically early stage endometrial cancer, all of these studies have had small cohorts of participants. As such, the laparoscopy (LAP2) trial by Walker et al. [21] was designed to further evaluate these methodologies on a larger scale. This landmark trial randomized 2616 patients into laparoscopic (n = 1682) and open laparotomy (n = 920) groups. Both groups underwent total hysterectomy, bilateral salpingo‐oophorectomy, pelvic cytology, and pelvic and para‐aortic lymph node dissections. This study found a longer median operative time in laparoscopy compared to laparotomy (204 vs. 140 min, p < 0.001) but, as with previous smaller studies, they found fewer post‐operative adverse events in laparoscopic cases (14% vs. 21%) and hospitalizations greater than two days were significantly less in laparoscopic cases (52% vs. 94%, p < 0.0001). Interestingly, they found that surgeons were unable to remove both pelvic and para‐aortic lymph nodes in 8% of laparoscopic cases, as opposed to only 4% in open cases (p < 0.0001). This did not seem to affect outcomes, however, with no notable difference in the detection of advanced stage disease between groups, which occurred in 17% of patients in both groups (p = 0.841).

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Jul 19, 2020 | Posted by in GYNECOLOGY | Comments Off on 18: Endometrial cancer
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