Women with early-stage cervical cancer treated with minimally invasive radical hysterectomy had a 71% increased risk of recurrence and a 56% increased risk of death compared with those treated with open radical hysterectomy, according to a systematic review and meta-analysis of 15 studies involving 9,499 patients. The study was published in JAMA Oncology.1
Women with early-stage cervical cancer are usually cured with radical hysterectomy, “with 5-year disease-free survival rates exceeding 90% in some studies,” the authors noted. An open abdominal approach has been used for more than a century, but since 1992, there has been greater acceptance of the minimally invasive approach, associated with smaller incisions, less pain, and fewer complications compared with open radical hysterectomy.
Two previous meta-analyses had shown no difference in overall and disease-free survival between these two surgical approaches. However, the results of the Laparoscopic Approach to Cervical Cancer (LACC) trial, published in TheNew England Journal of Medicine in 2018, found that women with early-stage cervical cancer randomly assigned to minimally invasive radical hysterectomy had four times the risk of recurrence and six times the risk of death compared with those assigned to open abdominal radical hysterectomy.2
The current review and meta-analysis investigated whether the LACC findings would be consistent with more recent and methodologically rigorous observational studies from real-world settings. The researchers concluded that the results “provide evidence to support the survival benefit associated with open radical hysterectomy.”
All Things Not Equal
“As a doctor who takes care of patients with cancer and does everything I can to try to cure them, it doesn’t make any sense to me to risk the recurrence of a potentially curable cancer just because of the benefits associated with minimally invasive surgery,” such as fewer complications and reduced pain, Alexander Melamed, MD, MPH, gynecologic oncologist and corresponding author of the recent review, said in an interview with The ASCO Post. Dr. Melamed is Assistant Professor of Obstetrics and Gynecology at NewYork-Presbyterian/Columbia University Vagelos College of Physicians and Surgeons.
“It doesn’t make any sense to me to risk the recurrence of a potentially curable cancer just because of the benefits associated with minimally invasive surgery.”— Alexander Melamed, MD, MPH
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“Obviously, if all things are equal, my preference would be to do minimally invasive surgery, but in this situation, there is overwhelming evidence at this point that all things are not equal and that minimally invasive surgery is associated with a statistically significant and clinically important increase in the risk of recurrence and death.”
Very Large Numbers
The randomized trial included hundreds of patients (319 assigned to minimally invasive surgery and 312 to open surgery), and the observational studies had thousands of patients (4,684 who had minimally invasive surgery and 4,815 who had open surgery), Dr. Melamed noted. “You do need very large numbers of patients, particularly for a cancer that in general has a good prognosis, to be able to precisely measure the effects of the intervention,” Dr. Melamed observed. The observational studies required a median of 2 years’ follow-up to be included in the meta-analysis, and the LACC study was published just 2 years ago, so all the observational studies “are based on data collected prior to the publication of LACC,” Dr. Melamed noted.
“Observational studies were abstracted that used survival analyses to compare outcomes after minimally invasive (laparoscopic or robot-assisted) and open radical hysterectomy in patients with early-stage (International Federation of Gynecology and Obstetrics 2009 stage IA1–IIA) cervical cancer,” the researchers reported. “There were 530 recurrences and 451 deaths reported. The pooled hazard of recurrence or death was 71% higher among patients who underwent minimally invasive radical hysterectomy compared with those who underwent open surgery (hazard ratio [HR] = 1.71; 95% confidence interval [CI] = 1.36–2.15; P < .001), and the hazard of death was 56% higher (HR = 1.56; 95% CI = 1.16–2.11; P = .004).”
Among patients who received minimally invasive surgery, 57% (2, 675) had robot-assisted laparoscopy, but that did not alter the magnitude of the association between minimally invasive surgery and the risk of disease recurrence or death.
Unexpected Results
Dr. Melamed and his coauthors noted the LACC trial findings of the higher risk of recurrence and death among patients receiving minimally invasive surgery were unexpected. That was partially due to the “long-standing consensus that minimally invasive and open surgery are both acceptable approaches to radical hysterectomy for cervical cancer,” they said.
In addition, “the LACC trial was designed as a noninferiority study. So, the hypothesis was that this was going to be just as good as the open surgery,” Dr. Melamed explained. “The theoretical framework was that if you do it once with an open incision or you do it with a few smaller incisions, in the end it is going to be the same operation; it should have the same outcome. At the time the LACC trial was recruiting, there were a number of randomized trials in other cancers showing that minimally invasive surgery seemed to produce similar outcomes to open surgery,” he added.
“All of those things together fit into a narrative where people thought we were good with minimally invasive surgery. In fact, the European guidelines previous to the LACC trial had even gone so far as to say that minimally invasive surgery was the preferred surgery for cervical cancer. People thought the problem was surgeons were not switching over fast enough, we were doing unnecessary open laparotomies on people, causing people to stay in the hospital, and causing unnecessary blood loss. People thought that was the issue, not the other way around.”
Shifting Trends
Following the publication of the LACC trial, the Society of Gynecologic Oncology issued a statement encouraging surgeons to discuss the data with patients, and the National Comprehensive Cancer Network® revised cervical cancer guidelines to define the open abdominal approach as the “standard and recommended approach to radical hysterectomy.”
Dr. Melamed senses the trend has now shifted back in favor of open surgery. “From my personal experience working at two major academic cancer centers since the LACC trial, at Massachusetts General Hospital and currently at Columbia University, I can say neither of those places routinely do minimally invasive surgery for cervical cancer. In talking with my colleagues across the nation, it is my sense that the vast majority have stopped routinely offering this procedure, with the exception of some outliers.”
Those Other Studies
“Two prior meta-analyses found no difference in overall and disease-free survival between minimally invasive and open radical hysterectomy. However, these meta-analyses do not include several recently published studies and include the results of studies that are unquestionably biased because of their failure to control for any confounders,” the JAMA Oncology authors wrote.
“Our meta-analysis differs methodologically from the older meta-analyses. We required that included studies demonstrate an effort to address confounding at a minimum by demographic factors and tumor size or stage. Studies that fail to control for confounding are likely to be biased in favor of minimally invasive surgery, because factors associated with a good prognosis in cervical cancer—including small tumor size, earlier stage, private insurance, and nonblack race—are more prevalent among women who undergo minimally invasive radical hysterectomy,” they noted.
“It is important to note that the 15 studies included in our meta-analysis are heterogeneous with respect to their conclusions. Some studies concluded that minimally invasive surgery was associated with an increased risk of death or recurrence compared with open surgery, whereas other studies concluded that there is no association,” the authors added.
“But overall, if you put it all together, the average data certainly support the conclusion of the LACC study,” Dr. Melamed said.
Residual Confounding
The authors acknowledged that their review and meta-analysis “include the possibility of bias because of residual confounding in the included studies. However, we believe this bias is likely to result in an underestimation of the harms associated with minimally invasive radical hysterectomy.”
Use of historical controls may bias studies in favor of minimally invasive radical hysterectomy because of treatment advances that have occurred during the time minimally invasive surgery was being adopted. “There has been better imaging, which has changed who goes to surgery. There has been more standardization of radiation therapy delivery. There has been progress made in adjuvant chemotherapy. All of this progress makes it more likely that patients who had minimally invasive surgery are going to do better, just by virtue of the use of historical controls,” Dr. Melamed said. “In some of these studies, these historical periods are a decade apart.”
Risk-Limiting Strategies
An editorial accompanying the JAMA Oncology article stated the “unusually high number of intra-abdominal recurrences after [minimally invasive surgery] in the LACC trial raises the possibility that cervical cancer cells might disseminate from the vagina to the pelvis and abdomen because of extensive cervical manipulation during minimally invasive surgery.”3 The authors, Amer Karam, MD, and Oliver Dorigo, MD, PhD, of the Division of Gynecologic Oncology at Stanford University, California, point out that surgical strategies “proposed to limit this potential risk, including the avoidance of uterine manipulators and anatomical isolation of the cervix by surgical closure of the vagina prior to laparoscopy” have shown promising results in case series, “but they have not been verified prospectively.”
Amer Karam, MD
Oliver Dorigo, MD, PhD
“These approaches need to be tested rigorously,” Dr. Melamed said. “I think the standard of care should be open surgery. People who are interested in advancing a minimally invasive agenda that is safe need to go through the process of developing these techniques and put patients who are willing on an experimental protocol.”
He continued: “It is totally reasonable that results for disease recurrence and mortality associated with minimally invasive surgery for early-stage cervical cancer can be lowered.” As noted in the editorial, however, factors that could provide an explanation for the reported differences in oncologic outcomes between minimally invasive and open radical hysterectomy have yet to be identified. “The particular expertise of the surgeon has been theorized as a risk factor for poor outcomes given that minimally invasive radical hysterectomies are especially technically challenging procedures that require appropriate training and experience,” the editorial writers pointed out.
“It is very hard to move forward with minimally invasive surgery at this point, not knowing what it is about it that is more often leading to disease recurrence.”— Alexander Melamed, MD, MPH
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Another possible explanation put forth is that the use of uterine manipulators could disseminate tumor cells during minimally invasive surgery. “Without empirical evidence supporting any of these kinds of hypotheses, it is very hard to move forward with minimally invasive surgery at this point, not knowing what it is about it that is more often leading to disease recurrence,” Dr. Melamed said.
“It is a big world, and people have lots of opinions, so I am sure there are people who don’t believe this evidence and are continuing to do these procedures. There is a randomized trial launched in Sweden to test robotic surgery against open surgery,” Dr. Melamed said. The editorial also mentions a randomized controlled study in China with an anticipated enrollment of 1,448 patients. “It will give us more information, which is always good,” Dr. Melamed said.
A Cautionary Tale
“The cervical cancer story is a cautionary tale about what can happen when we make decisions about establishing the standard of care based on weak evidence,” Dr. Melamed said. “With the benefit of hindsight, you can say the adoption of minimally invasive surgery was based on some pretty weak evidence and learn from that experience. This is a mistake that lots of fields are at risk for making if they don’t do the hard work of randomizing and getting high-quality evidence before adoption. Research has taught me that we have to be very careful with minimally invasive surgery.”
In the United States, cervical cancer rates continue to decrease “and hopefully in the course of a couple of generations, cervical cancer isn’t even going to exist, because there is a vaccine,” Dr. Melamed noted. “My hope is this will happen globally, also in the next 20 or 30 years, and the idea of whether people need an open incision or small incisions is going to be moot.”
DISCLOSURE: Dr. Melamed reported no conflicts of interest. For full disclosures of the other study and editorial authors, visit jamanetwork.com.
REFERENCES
1. Nitecki R, Ramirez PT, Frumovitz M, et al: Survival after minimally invasive vs open radical hysterectomy for early-stage cervical cancer: A systematic review and meta-analysis. JAMA Oncol. June 11, 2020 (early release online).
2. Ramirez PT, Frumovitz M,Pareja R, et al: Minimally invasive versus abdominal radical hysterectomy for cervical cancer. N Engl J Med 379:1895-1904, 2018.
3. Karam A, Dorigo O: Minimally invasive surgery for gynecologic cancers—A cautionary tale. JAMA Oncol. June 11, 2020 (early release online).
