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NEW ORLEANS -- Women undergoing radical hysterectomy for early cervical cancer had a significantly higher risk of disease recurrence and worse long-term survival with minimally invasive surgery (MIS), including robotic-assisted procedures, two separate studies showed.

The number of disease recurrences after laparoscopic or robotic-assisted procedures was almost four times higher than the number of recurrences after open surgery, although the absolute numbers were small: 27 recurrences versus seven in more than 600 patients. The difference translated into a hazard ratio for disease-free survival (DFS) of 3.74 (at 4.5 years) for MIS versus open surgery.

Significantly more patients who had conservative surgery died during a median follow-up of 2.5 years: 19 versus three with open surgery. Although the absolute numbers remained small, the difference meant that women who had MIS were six times as likely to die during the follow-up period, Pedro T. Ramirez, MD, of the University of Texas MD Anderson Cancer Center in Houston, reported here at the Society of Gynecologic Oncology annual meeting.

"Disease-free survival at 4.5 years for minimally invasive radical hysterectomy was inferior compared to the open approach," Ramirez said in conclusion. "Minimally invasive radical hysterectomy was associated with higher rates of locoregional recurrence. Results of [this] trial should be discussed with patients scheduled to undergo radical hysterectomy."

A second study reported at the meeting yielded a similarly unexpected result: almost a 50% higher risk of dying within 4 years of surgery with minimally invasive hysterectomy compared with open surgery. The retrospective analysis, based on two national databases, revealed a statistically significant trend toward declining survival as adoption of MIS increased, said J. Alejandro Rauh-Hain, MD, also of MD Anderson.

Cautious Assessment

Having had 2 weeks to review the two studies, the study's discussant, Shitanshu Uppal, MD, of the University of Michigan in Ann Arbor, said he had already progressed through the "five stages of grief" in reaction to the unexpected results: "I've gone through denial and anger. I couldn't bargain, and depression wasn't an option, so I think I'm getting to the acceptance thing."

Uppal said he did not dispute the data and agreed with Martinez' conclusion that the results must be discussed with patients. However, he noted several limitations of the international phase III trial. Because of slow patient enrollment, the trial ended in a futility analysis of 631 patients, instead of the planned 740. A fair amount of key histopathologic data remained unknown, including tumor size in a third of cases. The minimally invasive arm tilted heavily toward traditional laparoscopic surgery as opposed to robotic-assisted (84% versus 16%).

With regard to the retrospective analysis, Uppal encouraged continued monitoring of survival data for the more recent years of the study period, looking for potential alternative explanations for the declining survival and to confirm the association with MIS.

He also presented data in response to his rhetorical question: "What will happen if we abandoned minimally invasive surgery?" Referring to the National Inpatient Sample for 2015, he noted that a return to open surgery for all patients would result in 85 additional complications, 70 transfusions, and approximately two deaths per 1,000 cases per year. Another of uptake of minimally invasive hysterectomy suggested that an additional six lives per 1,000 cases per year would be saved by increased uptake versus open surgery.

Using the lower estimate for deaths would result in 2.60 lives saved per 1,000 cases with open surgery versus a net loss of 1.25 lives with the higher estimate, as LACC data suggested 4.75 lives would be saved per 1,000 cases if minimally invasive surgery were abandoned.

Randomized Trial

The had a primary endpoint of DFS at 4.5 years. The study was statistically powered as a noninferiority trial, and the investigators tested the hypothesis that MIS would lead to a DFS rate within 7.2% of that associated with open surgery. To help ensure standardization of care, participating centers submitted 10 MIS cases to a central review committee in advance, as well as two unedited videos of MIS procedures. MIS included total laparoscopic and robotic-assisted procedures.

Eligible patients had stage IA1 to IB1 squamous, adenocarcinoma, or adenosquamous cervical cancer. Enrollment started in June 2008 and ended in June 2017 when the data and safety monitoring committee performed an interim analysis and identified a safety issue associated with one of the still-blinded treatment arms. Martinez noted that the data for the primary outcome were about 40% complete at the time of the analysis, and that the data for overall survival were 37% complete.

The intention-to-treat analysis showed a 4.5-year DFS rate of 96.5% in the open-surgery arm and 86.0% in the MIS group, representing a 13% difference in the hazard ratio in favor of open surgery. A per-protocol analysis showed 4.5-year DFS rates of 97.6% and 87.1% -- a 12% HR advantage in favor of open surgery.

Martinez reported 27 recurrences in the MIS arm versus seven with open surgery. The difference translated into a DFS hazard ratio of 3.74 (95% CI 1.63 to 8.58, P=0.002). The MIS group had 19 locoregional recurrences -- a sixfold difference versus the three that occurred in the open-surgery group (95% CI 1.77 to 20.3, P=0.004). The hazard ratio for disease-specific survival was 6.74 for MIS versus open surgery (95% CI 1.48 to 29.0, P=0.013).

Retrospective Analysis

Rauh-Hain from an analysis of all-cause mortality with MIS versus open hysterectomy. He and his colleagues also evaluated whether adoption of MIS into clinical practice influenced trends in 4-year survival.

The analysis involved patient records included in the , which covers 70% of new cancer diagnoses in the United States. Eligible patients had surgery during 2010-2012 for stage IA2 or IB1 cervical cancer of any histology, and a procedure that included radical hysterectomy and pelvic lymph-node dissection. The investigators used propensity-score analysis to help ensure the similarity of the two treatment arms.

Rauh-Hain and colleagues also performed an interrupted time series analysis using data from the NCI Surveillance, Epidemiology, and End Results (SEER) registry program. The objective was to determine how adoption of MIS for radical hysterectomy affected survival, and the analysis showed a 1% decrease in 4-year survival for each year after 2006.

The team identified 2006 as the first year of MIS adoption, and 2000-2006 provided data to estimate pre-existing trends. The objective was to determine whether trends in 4-year relative survival differed significantly after 2006.

The analysis included 2,221 patients, 47.5% of whom underwent MIS procedures, which were robotic-assisted in 79% of cases.

The analysis produced a hazard ratio of 1.48 (95 CI 1.10 to 1.98) for MIS versus open surgery and an adjusted probability of death within 4 years of 8.4% with MIS and 5.8% with open surgery. An increased mortality risk persisted in sensitivity analyses of:

• Adjuvant therapy -- HR 1.44, 95% CI 1.07 to 1.93
• Robotic assistance -- HR 1.39, 95% CI 1.01 to 1.91
• Traditional laparoscopy -- HR 1.42, 95% CI 0.93 to 2.18
• Exclusion of hospitals without MIS -- HR 1.33, 95% CI 1.05 to 1.6

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