Sentinel lymph node biopsy “had similar diagnostic accuracy and prognostic ability as lymphadenectomy in patients with high-grade endometrial cancer at greatest risk for nodal metastases,” according to the SENTOR trial, a prospective cohort study of 156 patients with clinical stage I disease. Using a sentinel lymph node biopsy algorithm and the contemporary tracer indocyanine green, gynecologic oncologists correctly identified more than 96% of patients with node-positive disease and 99% of patients with node-negative disease. “These measures are comparable to those observed for breast cancer and melanoma, for which [sentinel lymph node biopsy] has become the standard of care,” the authors wrote in JAMA Surgery.1
“This has changed our practice,” Sarah E. Ferguson, MD, corresponding author of the SENTOR trial, said in an interview with The ASCO Post. “We used to do complete staging for high grades,” she said, “and now we have changed our practice to offer sentinel lymph node biopsy following the sentinel lymph node biopsy algorithm.” Dr. Ferguson is Professor, Division of Gynecologic Oncology, University Health Network/Sinai Health Systems, Department of Obstetrics and Gynecology, University of Toronto.
“A false-negative rate of less than 4% for any sentinel lymph node protocol would be considered pretty high quality.”— Sarah E. Ferguson, MD
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Based on previous studies, clinicians have used sentinel lymph node biopsy for patients with low-grade stage I endometrial cancer, but those studies “had a relatively small proportion of patients with high-grade disease,” Dr. Ferguson noted. “The concern was that, with high-grade histologies, there may be less predictable pathways and multiple pathways of nodal spread, and that [sentinel lymph node biopsy] may not be accurate enough in high-grade disease compared with low-grade disease, which has a relatively well-described pathway of spread.”
As the investigators stated: “The SENTOR study adds to previous work by being applicable to patients with high-grade endometrial cancer.”
High-Grade Histologies
The study included 126 patients with clinical stage I high-grade histologic subtypes (grade 3 endometrioid, serous, carcinosarcoma, clear cell, undifferentiated or dedifferentiated, and mixed high-grade). Another 30 patients with intermediate-grade endometrial cancer were enrolled in the study before the protocol was amended to include high-grade cancers alone. The median age of patients was 65.5 years.
Patients had no evidence of extrauterine disease and were scheduled for laparoscopic or robotic hysterectomy with an intent to complete staging at three cancer centers in Toronto. “All patients underwent [sentinel lymph node biopsy] followed by lymphadenectomy as the reference standard,” the authors explained. All patients had pelvic lymphadenectomy, and 101 patients (80% of those with high-grade endometrial cancer) also had para-aortic lymphadenectomy.
“Because the sentinel lymph node technique is directed by the fluorescent lymph node, you go where the lymph node is. It is not just about using traditional boundaries.”— Sarah E. Ferguson, MD
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The authors noted: “Operations were completed by 14 fellowship-trained gynecologic oncologists who had participated in a formal peer mentorship instruction program and validation study of [sentinel lymph node biopsy] technique,” which was led by Dr. Ferguson.
Only One False-Negative
“Sentinel lymph node detection rates were 97.4% per patient (95% confidence interval [CI] = 93.6%–99.3%), 87.5% per hemipelvis (95% CI = 83.3%–91.0%), and 77.6% bilaterally (95% CI = 70.2%–83.8%),” the investigators reported. “Of 27 patients (17%) with nodal metastases, 26 patients were correctly identified by the [sentinel lymph node biopsy] algorithm, yielding a sensitivity of 96% (95% CI = 81%–100%), a false-negative rate of 4% (95% CI = 0%–19%), and a negative predictive value of 99% (95% CI = 96%–100%).”
“The high sensitivity rate shows that spread to the lymph nodes isn’t that different in these high-grade populations,” Dr. Ferguson said. “They weren’t having isolated para-aortic lymph node positivity rates.”
“Only one patient in the total cohort (0.6%) was misclassified by [sentinel lymph node biopsy] and deemed to have a false-negative result,” the investigators reported. “This patient had dedifferentiated histologic findings, lymphovascular space invasion, and greater than 50% myometrial invasion on the final pathology report; results of bilateral mapped sentinel lymph nodes were negative, but two right pelvic lymph nodes and two right para-aortic lymph nodes tested positive.”
“There is always going to be a false-negative rate for any diagnostic test,” Dr. Ferguson noted. “A false-negative rate of less than 4% for any sentinel lymph node protocol would be considered pretty high quality.”
Beyond Traditional Boundaries
“The SENTOR study also suggests that [sentinel lymph node biopsy] may improve the detection of nodal metastases in ways not captured by traditional calculations of diagnostic accuracy,” the authors wrote. “Fourteen patients with node-positive disease (52%) had metastatic disease in sentinel lymph nodes only, and 7 cases (26%) were found outside lymphadenectomy boundaries or required immunohistochemistry for diagnosis. These patients would not have been identified by [pelvic lymph node dissection] or [para-aortic lymph node dissection] alone.”
“Because the sentinel lymph node technique is directed by the fluorescent lymph node, you go where the lymph node is. It is not just about using traditional boundaries,” Dr. Ferguson explained. “Certainly, we see lymph nodes in areas that we wouldn’t necessarily remove—for example, we don’t typically remove tricky areas underneath vessels in nodal basins. That in itself is a reason to take up the sentinel lymph node technique. The benefits are really in finding those node-positive patients so we can direct adjuvant therapy to those who would benefit.”
“With this study, using indocyanine green with a high-grade histologic subtype, there is now stronger evidence that using sentinel lymph node biopsy is a safe and accurate staging technique.”— Sarah E. Ferguson, MD
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Indocyanine green is “a more contemporary tracer” than used in some previous studies, Dr. Ferguson noted, and it was “absolutely instrumental” in obtaining the high positivity rate. A previous study by Soliman et al2 was a noninferiority study but showed that “indocyanine green did have much better ability to detect sentinel lymph nodes than blue dye,” Dr. Ferguson said. “With this study, using indocyanine green with a high-grade histologic subtype, there is now stronger evidence that using sentinel lymph node biopsy is a safe and accurate staging technique. And it’s helpful for staging patients in both low-grade and high-grade populations.”
“Indocyanine green is an easier tracer to use,” Dr. Ferguson added. “It visually takes you exactly to seeing the fluorescent node, where you need to remove the node. It for sure helped with the positivity in the studies we have.”
All the patients in the study had been scheduled for laparoscopic or robotic primary hysterectomy with an intent to complete full staging, but Dr. Ferguson said, “there are ways to use indocyanine green in an open case, if for some reason you have to use open surgery. I would argue that as long as you have the equipment to see the fluorescent lymph nodes, it wouldn’t matter whether you had minimally invasive or open surgery.”
Adverse Effects
“Theoretically, [sentinel lymph node biopsy] should reflect the status of the entire nodal basin and provide the pathologic information required to guide decisions on adjuvant therapy while avoiding the heightened risks of intraoperative injury, chronic lymphedema, and other complications associated with complete lymphadenectomy,” the authors wrote. In this study, five patients experienced intraoperative adverse events, but none were during sentinel lymph node biopsy. The intraoperative events included injuries to the bladder, sigmoid colon, and inferior vena cava.
In addition, 26% of the total patients had at least one postoperative event (within 30 days). They included vaginal bleeding, urinary retention, and wound infection. “The majority of these events—almost 90%—were minor,” Dr. Ferguson noted, and did not require intervention.
Surgeons dissected a median of 3 sentinel lymph nodes per patient, compared with a median of 5 para-aortic lymph nodes and 16 pelvic lymph nodes. “Removal of 10 or more pelvic nodes was performed in 134 patients (85%),” the investigators reported. The removal of a large number of lymph nodes has the potential for late effects of lymphedema, Dr. Ferguson noted, but the study did not include long-term follow-up.
Building Confidence
The high sensitivity and negative predictive value rates have motivated Dr. Ferguson and her coauthors to conduct a systematic review of the previous prospective studies and take a closer look at the patients with high-grade stage I endometrial cancer. Combined with patients in the current study, that will total almost 450 patients with high-grade disease, Dr. Ferguson pointed out. “We haven’t published those findings yet,” she said, “but I expect that, because of the large number of patients, the study will result in a high level of confidence in the accuracy of sentinel lymph node biopsy for high-grade clinical stage I endometrial cancer.”
Although sentinel lymph node biopsy has not been incorporated into guidelines for clinical stage I endometrial cancer, “the evidence is becoming pretty strong that this is how we should be surgically staging patients,” Dr. Ferguson stated. She noted that the National Comprehensive Cancer Network does list sentinel lymph node biopsy as an option.
DISCLOSURE: Dr. Ferguson reported no conflicts of interest.
REFERENCES
2. Soliman PT, Westin SN, Dioun S, et al: A prospective validation study of sentinel lymph node mapping for high-risk endometrial cancer. Gynecol Oncol 146:234-239, 2017.
