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In 2018, the Laparoscopic Approach to Cervical Cancer (LACC) trial was first presented to a shocked audience. This randomized phase III trial of 631 patients with 2009 FIGO stages IA1 (lymph-vascular invasion), IA2, or IB1 (tumor ≤4 cm; no evidence of nodal involvement) disease randomized patients between a laparoscopic radical hysterectomy (minimally invasive surgery, MIS) versus open radical hysterectomy, both with lymph node assessment.

To the dismay of many, the study reported its primary endpoint of disease-free survival (DFS) with a . Indeed, the rate of DFS at 4.5 years was 86% versus 96.5% for MIS and open surgery, respectively.

In a Clinical Trial Update in the Journal of Clinical Oncology, Ramirez et al. presented the and overall survival for the LACC study. As was pointed out in the original publication but is worth repeating, there was no difference in postoperative adjuvant therapy between the two arms of the study, with 28.8% and 27.6% in the MIS and open group receiving additional therapy, respectively.

The rate of DFS at 4.5 years was statistically worse in the MIS group: 85.0% vs 96% (difference of -11.1, 95% CI -15.8 to -6.3, P=0.95 for non-inferiority). Further, MIS was associated with a four times worse DFS than open surgery (HR 3.91, 95% CI 2.02-7.58).

The rate of overall survival (OS) at 4.5 years was 90.6% versus 96.2% in the MIS and open groups and the HR for death from any cause was 2.71 (95% CI 1.32-5.59, P=0.007). The HR for disease-specific survival was similar at 2.64 (95% CI 1.18-5.93, P=0.02).

Hypothesis-generating post-hoc analyses were presented, which include the suggestion that MIS leads to higher rates of recurrences that are peritoneal carcinomatosis 26% versus 0% in MIS compared with the open approach.

Furthermore, the size of the tumor did not seem to negate the detrimental effects of MIS, with a detriment seen even in those tumors < 2 cm and a stronger negative effect for those tumors > 2 cm.

In summary, the final analysis from the LACC trial demonstrates worse DFS, worse OS, and troubling findings of increased recurrences via peritoneal dissemination as compared with a more expected local regional recurrence pattern -- all supporting open radical hysterectomy as the standard of care.

This should be definitive, but questions remain, some of which will require another trial to answer:

1. Recently the of radical versus simple hysterectomy was completed for early-stage cervical cancer, demonstrating no inferiority to simple vs radical hysterectomy as long as a lymph node evaluation is included. Does this trial influence the interpretation of the LACC trial?

Answer: Potentially. The SHAPE trial included carefully selected tumors that were < 2 cm, < 10 mm stromal invasion, and < 50% stromal invasion on MRI. So for tumors that meet this criteria (and these tumors were not separately assessed as a group within LACC) a simple hysterectomy -- preferably open -- may be considered. Even though laparoscopic simple hysterectomy was allowed on the SHAPE trial, further study to assess the safety of this approach for cervical cancer is warranted.

2. Given the strikingly negative results of LACC, why is the ROCC/GOG 3043 study open and enrolling? ROCC () is a randomized non-inferiority trial of robotic versus open radical hysterectomy for early-stage cervical cancer. The primary endpoint is 3-year DFS. The study includes patients with FIGO 2018 stage IA2- IB2 cancers. All patients undergo a preoperative pelvic MRI to confirm that the tumor is < 4 cm and there is lack of parametrial or lymphatic spread. The ROCC study aims to overcome the possible risks of MIS radical hysterectomy that might have led to the harm seen.

• First, the ROCC study does not allow transcervical uterine manipulators, and proper tumor containment is standardized and mandatory. This requirement addresses the higher rate of peritoneal dissemination seen in the MIS arm of LACC and the hypothesis that this may have been driven by uterine manipulators and poor tumor containment.

• Second, the ROCC study was recently amended to allow simple open versus robotic surgery for those tumors meeting the SHAPE criteria, but importantly, maintaining the randomization to open vs MIS, which will allow definitive safety data on surgical approach for these tumors as well.

The importance of the LACC trial cannot be overstated. Many had adopted MIS radical hysterectomy as a standard procedure given the robust data for safety in other tumor types. The LACC trial and its leaders should be commended for completing what was an investigator-initiated trial that changed the management of early-stage cervical cancer – overnight.

The ROCC trial now stands to either confirm LACC or reverse course with incorporation of robotics, tumor containment, and loss of the uterine manipulator in an attempt to restore MIS as an accepted approach.

Kathleen N. Moore, MD, MS, is deputy director and the Virginia Kerley Cade Chair in Developmental Therapeutics, and co-director of the Cancer Therapeutics Program of Stephenson Cancer Center at the University of Oklahoma Health Sciences Center. She is also a member of the Board of Directors of both ASCO and the GOG Foundation.

Read the study here and an interview about it here.