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 reports no financial relationships relevant to this field of study.
Synopsis: LAP2 was a randomized, Phase 3 trial to evaluate and compare the modality of surgical staging (laparoscopy vs laparotomy) in endometrial cancer. The primary endpoint was assessing non-inferiority of laparoscopy relative to laparotomy on recurrence-free survival. Although the estimated recurrence rates and 5-year overall survival were nearly identical between the arms, the noninferiority objective (i.e., the statistical proof that the laparoscopic approach is not inferior to laparotomy in terms of overall survival) was not met.
Source: Walker JL, et al. Recurrence and survival after random assignment to laparoscopy versus laparotomy for comprehensive surgical staging of uterine cancer: Gynecologic Oncology Group LAP2 study. J Clin Oncol 2012;30:695-700.
LAP2 was a phase 3 clinical trial to assess the non-inferiority of laparoscopy compared with laparotomy for recurrence of uterine cancer after surgical staging. Eligible patients had clinical stage I-IIA disease, were histologically either adenocarcinoma or sarcoma, and were randomly allocated (2 to 1) to laparoscopy (n = 1696) or laparotomy (n = 920). Patients in both arms were to have a standard surgical staging: hysterectomy, salpingooophorectomy, pelvic cytology, and pelvic and paraortic lymphadenectomy. The primary endpoint was noninferiority of recurrence-free interval defined as no more than a 40% increase in the risk of recurrence with laparoscopy compared with laparotomy (upper limit hazard ratio: 1.4). Over a median follow-up of 59 months, there were 309 recurrences (210 laparoscopy, 99 laparotomy) and 350 deaths (229 laparoscopy, 121 laparotomy). The estimated 3-year recurrence rates were 11.4% and 10.2% for laparoscopy and laparotomy, respectively (90% lower bound, -1.28; 95% upper bound, 4.0). The estimated hazard ratio for laparoscopy relative to laparotomy was 1.14 (90% lower bound, 0.92; 95% upper bound, 1.46), falling short of the protocol-specified definition of noninferiority. The estimated 5-year overall survival was almost identical in both arms at 89.8%. Multivariate analysis identified age, surgical stage, cell type, myometrial invasion, and lympho-vascular invasion as independent factors influencing recurrence; however, there was no difference by surgical approach among these factors. The authors concluded that the study, which previously had reported the superiority of laparoscopic surgical management on short-term safety and length-of-stay endpoints, did not meet its noninferiority endpoint. However, the quantified risks were small, providing accurate information for decision making for women with uterine cancer.
The standard operative procedure for patients with primary endometrial cancer is hysterectomy, bilateral salpingoophorectomy, and surgical staging including assessment of the pelvic and paraortic lymph nodes. Traditionally, this has been done via exploratory laparotomy (ceiliotomy), where access to pelvic and abdominal areas is generally assured. However, more than 20 years ago, each of the critical steps in surgical staging for this disease was found to be feasible via minimally invasive surgical (MIS) techniques.1,2 Over these past 2 decades, the standard approach has increasingly been replaced by laparoscopy and robotic endoscopy.3 Critics argued that compromised procedures due to patient (e.g., body habitus limiting exposure), surgeon (e.g., loss of tactile feedback and limited capability to assess the high paraortic nodes), and technical (e.g., potential for aerosolization of tumor cells by CO2) factors would increase the likelihood of recurrence and lower survival in patients undergoing the MIS approach.4-7 LAP2 initially was launched to assess morbidity and mortality of MIS in endometrial cancer staging, but was amended in 2001 to also address the noninferiority of MIS relative to laparotomy. The trial was designed with a 2:1 randomization and established confidence limits for noninferiority based on an anticipated recurrence rate in the laparotomy arm of 15%. The statistics are important in understanding the “accurate” interpretation of the study. As strictly demonstrated, the lower limit of the confidence interval assessing inferiority crosses 1.0. This would, under normal circumstances, reject the null hypothesis of inferiority for MIS, concluding that there was not a substantial increase in recurrence for the MIS approach. However, because the observed recurrence rate was substantially lower than anticipated, the upper limit of this same confidence interval crosses 1.4, which under the initial assumptions would have rejected the alternate hypothesis (that is, MIS is noninferior to laparotomy). So in an argument, both conclusions could be supported, and strictly speaking, the study’s conclusions are ambiguous. Fortunately, the actual differences in recurrence rate, site of recurrence, 3-year recurrence risk, 5-year overall survival, and just about every other metric are nominal and “practically” identical. This colossal effort on behalf of the Gynecologic Oncology Group is to be commended as the history of completing this trial with all of the excitement for MIS at the time was a challenge. Currently, the MIS approach is preferred particularly in patients who have very high body mass index, as the operative and postoperative morbidity can be substantially ameliorated. However, when the surgical output is compromised by the approach, it cannot be justified.