Minimally Invasive Surgery for Endometrial Cancer: The Horse Is Already out of the Barn

The number of surgeries being performed using minimally invasive approaches has increased dramatically during the last two decades. Unlike new drugs, which require clinical trials and US Food and Drug Administration approval, surgical innovations are often developed and adopted with less stringent requirements to demonstrate their benefits, risks, and incremental costs. Prospective comparisons of novel surgical techniques to their more established counterparts are essential to prove that they add value. For benign surgeries such as hysterectomy and cholecystectomy, comparative studies of minimally invasive and open surgery need only examine outcomes over a few months. In contrast, when minimally invasive surgery is used in treating cancer, outcomes must be tracked for several years to ensure that cure rates are not compromised. In view of the potential advantages of minimally invasive surgery, the Gynecologic Oncology Group (GOG) performed a large prospective trial from 1996 to 2005 that included more than 2,600 women with clinically early-stage endometrial cancer. Subjects were randomized in a 2:1 ratio to laparoscopic versus open hysterectomy, bilateral salpingo-oophorectomy, and pelvic and aortic lymph node sampling. The first report from the study (Laparoscopic Surgery or Standard Surgery in Treating Patients With Endometrial Cancer or Cancer of the Uterus [LAP2]) confirmed the presumed short-term advantages of laparoscopy, including shorter hospital stays, fewer perioperative complications, reduced blood loss, and improved body image. Laparoscopic surgery took longer and there was a 26% conversion rate to laparotomy, with obesity being the strongest risk factor, but metastatic disease was identified in 17% of patients in both groups. This provided reassurance that an initial laparoscopic approach does not compromise surgical staging. In the article that accompanies this editorial, Walker et al report recurrence and survival outcomes of the LAP2 study. Recurrence rates at 3 years after surgery were 11.39% in the laparoscopy group and 10.24% in the open surgery group (hazard ratio for laparoscopy 1.14; 95% CI, 0.92 to 1.46). Although the difference in 3-year survival was small, the trial was deemed inconclusive because laparoscopy could not be demonstrated with 95% confidence to have a hazard ratio below the predetermined threshold of 1.4 for noninferiority. In beginning to interpret this study, in which the statistical results were inconclusive, we need to look more closely at its design and limitations. One of the disadvantages of noninferiority studies is that it may be difficult to determine the appropriate upper boundary for noninferiority when the study is designed. The 1.4 hazard ratio boundary chosen by the GOG equated to a 5.3% increase in recurrence at 3 years from 15% to 20.3%. No rationale was provided for this threshold, but avoiding a 5% increase in recurrence risk is probably a reasonable clinical end point. However, if a slightly higher threshold had been chosen, these same data may have been reported as having successfully demonstrated noninferiority. Two factors reduced the ability of this study to provide a conclusive result. First, recurrence and survival were not included as end points when the study was originally designed. As a result, 23% of patients had less than 3 years of follow-up. Second, recurrence rates were lower than the initially projected rate of 15%. These issues resulted in the study being underpowered relative to what was anticipated. This is a bit disappointing in the context of one of the largest studies of endometrial cancer the GOG has ever performed, but in our opinion, these data provide reassurance that laparoscopic surgery is a reasonable, safe, and effective approach in the management of apparent early-stage endometrial cancer. On the basis of the LAP2 study one can reasonably conclude that there is not a substantial increase in recurrence rates with laparoscopic surgery. However, because the study did not achieve noninferiority, it is important to not dismiss the possibility that a small difference may actually exist. Other trials of minimally invasive surgery are ongoing, and although they are not identical in study design to LAP2, it is hoped that these will provide additional reassurance. In addition, gynecologic oncologists should continue to consider ways in which minimally invasive surgery for endometrial cancer can be conducted to minimize the potential for dissemination of disease. Although it may be difficult to develop a strong evidence base to support specific techniques, it is reasonable to advocate practices that are consistent with the basic principles of cancer surgery. Recurrences of cancer in abdominal wall port sites were noted when laparoscopy was first used in the management of abdominal cancers. There was concern that increased intra-abdominal pressure with carbon dioxide gas might facilitate seeding of tumor in the abdomen or in port sites. However, no differences in overall patterns of recurrence were seen between laparoscopic and open surgery in the LAP2 study. Incisional recurrences were rare, and among the four such recurrences in the laparoscopic arm, three were in patients whose cancers had already been found to have spread outside the uterus. JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L S VOLUME 30 NUMBER 7 MARCH 1 2012