publication date: Jul. 19, 2019

Ontario study: Women undergoing minimally invasive procedures for early-stage cervical cancer had double the rates of death, recurrence

By Matthew Bin Han Ong

Women who underwent minimally invasive radical hysterectomies had twofold the rate of death and cervical cancer recurrence, compared to women who received open radical hysterectomies, according to a large retrospective study conducted by researchers at the University of Toronto.

The population-based study, which included 958 cervical cancer patients who underwent minimally invasive between 2006 and 2017 in Ontario was designed to determine whether minimally invasive surgery is associated with adverse oncologic outcomes in cervical cancer patients. The study controlled for confounding factors, primarily the surgeons’ experience with minimally invasive procedures.

The manuscript has been accepted for publication by the American Journal of Obstetrics and Gynecology.

“Our study is one of the largest published on this topic,” said Maria C. Cusimano, a resident physician at the Department of Obstetrics & Gynecology at the University of Toronto and a PhD student in clinical epidemiology at the Institute of Health Policy, Management, and Evaluation. “In fact, it’s the second largest, after the National Cancer Database study that was published in The New England Journal in Medicine, alongside the LACC trial.

“We had sufficient power and follow-up to look at oncologic outcomes and account for confounding factors,” Cusimano said to The Cancer Letter. “And we looked at the level of an entire population in Ontario, Canada.”

The Laparoscopic Approach to Cervical Cancer trial by Ramirez et al. and another retrospective study by Melamed et al. were two groundbreaking studies published in NEJM October 2018—both found significantly reduced survival in women who were subjected to minimally invasive surgical approaches for early-stage cervical cancer (The Cancer Letter, Nov. 2, 2018).

“Regardless of what the numbers are, it’s clear that there is evidence of harm associated with MIS in all of these studies,” Cusimano said.

Cusimano et al. found that, over the past decade, Ontario women with early-stage cervical cancer were similarly subjected to an inferior standard of care.

“After hearing the preliminary results of the LACC trial, Maria and I set out to look at this in our population in Ontario, Canada, to see if we would find similar results,” said Sarah E. Ferguson, an associate professor of gynecologic oncology at the Department of Obstetrics and Gynecology at the University of Toronto and director of the Research Division of Gynecology at the Princess Margaret Cancer Center.

“The initial study by Ramirez et al. showing a survival difference between minimally invasive and open surgery was surprising and unexpected,” Ferguson said to The Cancer Letter. “Many surgeons asked whether this was really happening, or really true in their environment, in their patients, in the real world.

“So, we did a retrospective, population-based cohort study over a 10-year time period. We did not randomize patients, but looked at the outcomes of women who had already received one approach or the other. It’s real-world data. We looked at recurrence as well as survival, and we controlled for confounding factors, such as for surgical experience with the procedure. This was unique, compared to previous work.”

A conversation with Ferguson and Cusimano appears here.

The primary outcome of the study was all-cause death, with cervical cancer-specific death and recurrence as secondary outcomes. Of the 475 patients in the minimally invasive radical hysterectomy cohort, 89.6% received laparoscopic surgery, and 10.4% underwent robotic surgery.

The Ontario study comes on the heels of an FDA advisory indicating that device manufacturers looking to market surgical tools for use in the prevention or treatment of cancer may now be required to study long-term oncologic endpoints in surgical trials “for time periods much longer than 30 days.”

“There is limited, preliminary evidence that the use of robotically-assisted surgical devices for treatment or prevention of cancers that primarily (breast) or exclusively (cervical) affect women may be associated with diminished long-term survival,” FDA states in the Feb. 28 safety communication (The Cancer Letter, March 1).

The University of Toronto team’s findings are significant: the study found increased rates of death and recurrence at the population level in patients with stage IB cervical cancer who underwent laparoscopic and robotic radical hysterectomy—a standard of care surgical approach for early-stage cervical cancer before November 2018.

The team also found that the harms associated with this approach may be independent of the surgeon’s experience.

“The immediate response to the LACC trial was, ‘Well, perhaps there were surgeons who weren’t experienced in minimally invasive surgery in the trial.’ We know that’s not true—the LACC trial had very experienced centers,” Ferguson said, noting that UHN was a recruiting center for the LACC trial.

“Our study looks at this in another way. We showed that the association between MIS and poorer cervical cancer outcomes remains even after controlling for surgeon volume.”

As was the case at many academic institutions in the United States, UHN imposed a moratorium on minimally invasive radical hysterectomy procedures after the results of the LACC trial were published in October 2018.

“Our study did find a statistically significant association between MIS and poorer oncologic outcomes in patients with stage IB disease, but not patients with stage IA disease. However, it’s important to note that our study was likely underpowered in the IA subgroup—so those findings are really hypothesis-generating in this area,” Cusimano said.

“There are reasons why each study has slightly different estimates, but the key takeaway is that they all show poorer cervical cancer outcomes with minimally invasive radical hysterectomy.”

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