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Lymphadenectomy in Early-stage Endometrial Cancer?
Abstract & Commentary
By Robert L. Coleman, MD, Professor, University of Texas; M.D. Anderson Cancer Center, Houston, is Associate Editor for OB/GYN Clinical Alert.
Dr. Coleman is a retained consultant for GlaxoSmithKline, Eli Lilly Co., Abbott Laboratories, Sanofi-Aventis, and Pfizer; and serves on the speakers bureau for OrthoBiotech.
Synopsis: The intrinsic therapeutic value of lympha-denectomy for endometrial cancer has been debated since pathological-based staging was introduced in 1988. The ASTEC trial is the second and largest phase III study to address this hypothesis and, while acknowledging the procedure is the most precise to determine disease extent, the results suggests the procedure is of little or no benefit in and of itself.
Source: Kitchner H, et al. Efficacy of systematic pelvic lymphadenectomy in endometrial cancer (MRC ASTEC trial): A randomised study. Lancet 2009;373:125-136.
The standard primary surgical intervention for early-stage uterine cancer is hysterectomy, usually with removal of the adnexa. The role of other tissue evaluation, such as cytology and lymphatic survey, is to identify the presence of extrauterine disease. Heretofore, the therapeutic impact of routine lymphadenectomy on overall survival in this disease has been the subject of non-randomized prospective and retrospective comparisons. The ASTEC (A Surgical Trial in Endometrial Cancer) trial was conducted to address this hypothesis in a phase III randomized setting. In this multi-institutional trial, 1408 women with histologically proven endometrial cancer considered preoperatively to be confined to the uterine corpus were randomly allocated to either hysterectomy and bilateral salpingo-oophorectomy (BSO) or the same procedure with pelvic lymphadenectomy. Peritoneal cytology and palpation of the paraortic lymphatics were allowed in both groups. Risk strata were assigned postoperatively based on uterine findings (independent of node status). Those with intermediate risk for extrauterine disease were secondarily randomized to adjuvant pelvic radiotherapy or observation. Vaginal brachytherapy was administered at the discretion of the treating physician, as was the therapy for low-risk and high-risk disease. These latter two groups were not controlled for type of adjuvant therapy.
The primary objective of the study was overall survival (OS) and was powered to detect a 10% increase in the 5-year survival rate (from 80% to 90%). In the intent-to-treat analysis for OS, the hazard ratio (HR) was 1.16 (confidence interval, 0.86-1.54; P = 0.31); a similar finding was observed for the adjusted relapse-free survival (RFS; HR, 1.04; CI, 0.74-1.45; P = 0.83), although, there was superiority in RFS for standard surgery before making the adjustments for baseline characteristics and pathology details. Surgical complications were uncommon in both groups, but more frequently observed in those with more extended surgery. The investigators concluded that the procedure of lymphadenectomy did not improve OS or RFS in women undergoing hysterectomy for suspected early-stage endometrial cancer and, as such, they could not recommend the procedure as routine practice outside clinical trials.
The long-awaited final results of this important clinical trial are no doubt going to be met with strong criticism and commentary as they are carefully dissected over the next several months. In 1988, the staging algorithm for endometrial cancer was adjusted to consider surgical-pathological findings at extirpation, which included lymphadenectomy. The primary reason for this alteration came in response to a number of large clinico-pathological observational studies that demonstrated a relationship between depth of myometrial invasion and grade to the probability of extrauterine (predominately lymphatic) disease.1 Early on, strategies to intraoperatively determine in whom lymphatic dissection should be performed were championed, but were generally found to be of poor reproducibility. This led to the "staging for all" position and was supported by non-randomized data suggesting a therapeutic advantage for systematic lymphadenectomy.2 For the most part, the change in staging paradigm proved to be prognostic as well as informative, and clinicians found that the added information of extrauterine disease of merit in determining postoperative therapy. However, the direct impact of lymphadenectomy had not been subject to rigorous investigative hypothesis testing. The ASTEC trial suggests the procedure itself may not be associated with direct therapeutic benefit. Unfortunately, this is only part of the story, as the trial did not address the utility of lymphadenectomy to identify those patients in whom specific therapy should be administered, it did not control for adjuvant care in either low-risk or high-risk cases, and it considered only pelvic nodes dissection. An imbalance of patients in the lymphadenectomy trial was noted with higher rates of stage IC and non-endometrioid histology, which could have imbalanced the risk for death between the arms despite the randomizations. In addition, the allowance of "inspection" of the paraortics did lead to a number of patients in the control cohort being identified with "high-risk" disease.
Despite the obvious variances, the trial is supported by a second and independently conducted randomized phase III trial recently reported (CONSORT trial), which demonstrated the same effect on OS and RFS.3 In contrast to ASTEC, this randomized trial of 514 patients did not control for postoperative adjuvant therapy. While findings from these trials may be at odds with our underlying bias, the real pitfall may be more realistically attributed to the disease population studied. In both trials, and as often observed in adjuvant therapy studies, the expected survival is quite high and very difficult to improve upon. In addition, nearly a third of patients succumb to non-disease-related events, such as heart disease. Careful construction of a study with appropriate controls for risk strata and adjuvant therapy will need to be performed to address the hypothesis of therapeutic lymphadenectomy in early-stage uterine cancer.