Minimally invasive cervical cancer surgery may promote disease recurrence; professionals urge patience

Minimally invasive surgeries have emerged as often-preferable alternatives to open surgeries for a variety of malignancies, due to the lower risk for complications and faster time to recovery.

However, recent data show that women with early-stage cervical cancer who underwent minimally invasive radical hysterectomy had increased risk for recurrence and poorer survival outcomes than women who had open surgery.

This result — demonstrated in two studies published in October in The New England Journal of Medicine — surprised the gynecologic oncology community and could result in a fundamental shift in how the disease is treated.

“We were very surprised when we got the results, and even more surprising was the fact that we got very similar findings in both studies,” J. Alejandro Rauh-Hain, MD, MPH, assistant professor in the department of gynecologic oncology and reproductive medicine and assistant professor in the department of health services research at The University of Texas MD Anderson Cancer Center, told HemOnc Today. “We were pretty sure we were going to find that [minimally invasive surgery] was as safe as open surgery and that there wasn’t going to be any difference in the long-term outcomes.”

Based on these findings, MD Anderson stopped offering the minimally invasive surgery option to women with early-stage cervical cancer and now only offers open surgery.

However, acceptance of the study conclusions has not been universal, and the controversy surrounding the findings prompted a debate at the annual congress of the AAGL — an association promoting minimally invasive gynecologic surgery worldwide — with some experts arguing the data are inconclusive and that more study is needed before the practice is abandoned.

“To say that [these studies] should be used to completely ban laparoscopic hysterectomy ... I think that’s a stretch, do these results apply to all patients with cervical cancer, even those with minimal residual disease after a cold knife cone?” R.Wendel Naumann, MD, professor and director of minimally invasive surgery in gynecologic oncology, at Levine Cancer Institute at Atrium Health, told HemOnc Today.

Other experts say there are unanswered questions as to why minimally invasive surgery is riskier for women with this disease, especially considering studies on minimally invasive surgery for other forms of cancer have shown similar long-term results as open surgery, but often with fewer complications.

HemOnc Today spoke with gynecologic oncologists and surgeons about the results of these two studies, whether the data should have an immediate impact on clinical practice, what questions are left unanswered, and how surgeons should treat their patients before further conclusions are drawn.

Shorter OS

About 13,000 women are diagnosed with cervical cancer each year in the U.S. Radical hysterectomy with pelvic lymphadenectomy remains the standard recommendation for women with early-stage disease.

Because minimally invasive procedures were adopted as alternatives to laparotomy before sufficient evidence regarding their impact on survival was known, Melamed and colleagues sought to determine the effect of minimally invasive surgery on mortality among women with early-stage cervical cancer.

“Cervical cancer is a little less common than some of the other tumor types that have been studied, so it’s taken longer to study women who undergo this procedure,” Jason D. Wright, MD, associate professor of obstetrics and gynecology at Columbia University Vagelos College of Physicians and Surgeons, chief of gynecologic oncology at NewYork-Presbyterian/Columbia University Irving Medical Center, and a study co-author, told HemOnc Today.

The retrospective cohort study included data on 2,461 women who underwent radical hysterectomy in the U.S. for stage IA2 or IB1 cervical cancer between 2010 and 2013. About half of the women (n = 1,225; 49.8%) had minimally invasive surgery.

Median follow-up was 45 months.

Propensity score-weighted analyses showed the risk for death within 4 years was 9.1% among women who had minimally invasive surgery and 5.3% among those who underwent open surgery (HR = 1.65; 95% CI, 1.22-2.22).

Researchers also conducted an interrupted time-series analysis that included all patients in the SEER database with locoregionally confined cervical carcinoma who underwent radical hysterectomy and lymphadenectomy from 2000 to 2010.

Results showed that between 2000 and 2006 — prior to the adoption of minimally invasive radical hysterectomy — the 4-year relative survival rate for women who underwent radical hysterectomy for cervical cancer remained stable, with an annual percentage change of 0.3% (95% CI, –0.1 to 0.6).

However, the adoption of minimally invasive surgery coincided with a decline in the 4-year survival rate of 0.8% (95% CI, 0.3-1.4) per year after 2006.

Melamed and colleagues did not investigate why minimally invasive hysterectomy might be associated with shorter OS. However, researchers theorized that uterine manipulators — used to retract and visualize the pelvic area during the procedure — may spread microscopic tumor cells.

They also theorized that surgeons who performed the minimally invasive hysterectomies may have been more experienced with open surgery. If that’s the case, minimally invasive surgery may not be inherently inferior to open surgery and survival differences could diminish over time.

“I think it’s going to be hard to pin down exactly why we are seeing this phenomenon. It may be that when we introduce the uterine manipulator, it spreads microscopic cancer cells. Alternatively, we may not be resecting as much of the surrounding tissue when we are doing the minimally invasive procedure, or surgeon experience could play a role,” Wright said. “But, this is something that’s going to be very difficult to parse out, and I’m not sure that’s an answer we are ever going to be able to wrap our heads around and fully understand.”

Failure to show noninferiority for DFS

In the second study, Pedro Ramirez, MD, professor of gynecologic oncology and reproductive medicine at The University of Texas MD Anderson Cancer Center, and colleagues sought to determine whether minimally invasive radical hysterectomy was equivalent to the open approach in terms of DFS.

The multicenter phase 3 trial included 631 women (mean age, 46 years) with early-stage cervical cancer (stage IB1, 91.9%) treated at 33 centers around the world.

Researchers randomly assigned 319 of the women to minimally invasive surgery (84.4% laparoscopy; 15.6% robot-assisted). The other 312 women underwent open surgery.

Adjuvant chemotherapy or radiotherapy rates appeared similar among women in the two groups (minimally invasive, n = 92; open surgery, n = 86). Women also were comparable in terms of histologic subtypes, rate of lymphovascular invasion, tumor size and grade, and rates of parametrial and lymph node involvement.

At the time of the analysis, 27 women in the minimally invasive surgery group experienced recurrence compared with seven patients in the open surgery group.

Minimally invasive surgery appeared associated with poorer DFS than open surgery at 3 years (91.2% vs. 97.1%; HR = 3.74; 95% CI, 1.63-8.58) and at 4.5 years (86% vs. 96.5%; difference, –10.6%; 95% CI, –16.4 to –4.7). This result failed to suggest noninferiority because the lower boundary of the CI of the between-group difference at 4.5 years exceeded –7.2 percentage points.

Per-protocol analysis further supported the findings of poorer DFS rates with minimally invasive surgery after 4.5 years (87.1% vs. 97.6%; difference, –10.5%; 95% CI, –16 to –5; P = 0.88 for noninferiority).

Results for the minimally invasive group were consistent regardless of whether the procedure was performed with robotic assistance. The trends also persisted after adjustment for age, BMI, disease stage, lymph node involvement and lymphovascular invasion.

Recurrence occurred among women treated at 14 of 33 centers, and researchers did not observe a pattern in failure rates across the sites.

Most recurrences occurred in the vaginal vault or the pelvis (minimally invasive, 41%; open surgery, 43%). All nonvaginal vault pelvic recurrences occurred in the minimally invasive group.

The distribution of the tumor size in women who experienced recurrence was similar in both groups.

A total of 22 women died during the trial, including 19 among those in the minimally invasive group and three in the open surgery group.

Women who underwent minimally invasive surgery were less likely to achieve 3-year OS (93.8% vs. 99%; HR = 6; 95% CI, 1.77-20.3).

Researchers stopped the study in 2017 due to this noted safety signal. Thus, they acknowledged the fact that the study did not reach its final intended enrollment as a limitation.

“Our study reinforces the need for more randomized clinical trials in the field of surgery,” Ramirez said in a press release. “Too often, success of a new intervention in surgery is measured by retrospective data. We always need to test and measure our procedures to determine what is best for our patients.”

Ramirez also emphasized the need for more research to evaluate the effects of minimally invasive surgery in other scenarios where the approach is commonly used.

Impact on practice

Shortly after the results of these studies were released, MD Anderson announced that it would no longer offer minimally invasive surgery to women who have early-stage cervical cancer.

MD Anderson is the first institution to abandon the practice.

“It’s a big change in practice for us,” Rauh-Hain, who was a co-author on the Melamed study, said. “For many years in oncology, we always thought that minimally invasive surgery had the same long-term outcome as open surgery. So, this is a significant change in culture and I think people are still processing it.”

Other experts with whom HemOnc Today spoke, however, expressed uncertainty as to whether this will lead to a rash of institutions following suit.

Joshua P. Kesterson, MD, MBA, associate professor in the department of obstetrics and gynecology and chief of gynecologic oncology at Penn State Health, told HemOnc Today that oncologists first got word of these studies at the Society of Gynecologic Oncology Annual Meeting on Women’s Cancer in 2018.

He cautioned that although one of the studies was a randomized trial, researchers did not control for certain variables — including the use of a uterine manipulator and central pathology review — and follow-up therapy was not standardized.

On top of that, researchers are left with lingering questions about why minimally invasive surgeries put patients with cervical cancer at a higher risk for disease recurrence and death.

“I suspect there will be a multi-institutional review comparing outcomes for a laparoscopic and/or robotic approach vs. an open approach so that we can have more diversity of experience as far as initial and follow-up treatment goes,” Kesterson told HemOnc Today. “I’d also hope there are more post-hoc analyses of the initial MD Anderson data to look at variables that weren’t taken into account, such as the addition of adjuvant chemotherapy or radiation for these patients in the immediate postoperative setting, as well as the use of a uterine manipulator.

“The uterine manipulator is often used in minimally invasive cases, but not in an open case,” he added. “That is one of the concerns as to why the patients had a worse outlook.”

Further, researchers and outside experts believe the findings from these studies are limited to early-stage cervical cancer, because previous studies on minimally invasive surgeries for other types of cancer have shown long-term efficacy similar to that of open approaches in terms of RFS and OS.

For gynecologic cancers specifically, there are reliable data from randomized prospective trials regarding a minimally invasive approach in endometrial cancer, as well as historical data for the disease that show equivalency in oncologic outcomes with an improvement in interoperative and postoperative morbidity, Kesterson said.

Surgeons also offer a minimally invasive approach to some women with ovarian cancer. Those cases, however, are usually more advanced stages of disease, so surgeons are not necessarily worried about spreading the disease because in many cases it already has spread, Kesterson said.

Other researchers and medical professionals agreed that the study results probably will not immediately lead to widespread abandonment of minimally invasive radical hysterectomy.

The AAGL — one of the leading associations promoting minimally invasive gynecologic surgery among surgeons worldwide, founded in 1971 as the American Association of Gynecologic Laparoscopists — has taken a strong stance since the release of the studies, particularly against the noninferiority trial.

Medical professionals from the association argue the study by Ramirez and colleagues is inconclusive because of its noninferiority design and that the 95% CI generated crossed the noninferiority boundary.

“This trial did not meet the predetermined limits to state that minimally invasive surgery was inferior, and the open arm performed better than expected based on all previously published datasets,” Jubilee Brown, MD, professor and associate director of gynecologic oncology at Levine Cancer Institute at Atrium Health, as well as vice president of the AAGL, told HemOnc Today. “Before we abandon a minimally invasive approach to early-stage cervical cancer entirely, we should consider a confirmatory trial — perhaps in the U.S. alone, as our patient population may be different — and we should consider refining the indications for a minimally invasive approach.”

AAGL experts also argue that part of that trial was conducted in “low-resource” countries that may not have the technology to properly treat patients with this specific procedure. In short, the results could be because of a problem with the medical centers themselves, not the procedure.

“This was a multi-international trial. Many of the centers were in relatively low-resource countries, and my concern is whether this is applicable to practice patterns in the United States,” Naumann said. “We don’t know if the radiation or chemotherapy the patients received as adjuvant therapy was appropriate.”

Amanda N. Fader, MD, a member of the board of directors for the AAGL, wrote in an accompanying editorial that it was “curious” to see all the cancer recurrences occur at 14 of the 33 centers, but added that the results of both studies were powerful.

“Do these studies signal a death knell for minimally invasive radical hysterectomy in cervical cancer treatment? Not necessarily, but this approach has been dealt a great blow,” Fader wrote. “Although the data are alarming, select patient subgroups may still benefit from a less invasive approach.”

Compounding these concerns, a separate retrospective study conducted by Matanes and colleagues had the opposite finding — minimally invasive surgery did not lead to a higher relapse rate than open surgery.

In this study — published last year in Journal of Obstetrics and Gynaecology Canada — Matanes and colleagues compared 98 consecutive women with early-stage cervical cancer treated since 2003 at Jewish General Hospital in Montreal.

Of the 98 patients, 74 underwent robotic radical hysterectomy and 24 underwent open radical hysterectomy.

Median follow-up for patients who received the minimally invasive surgery was 46 months.

Over that time, 7% of the patients who had robotic surgery had disease recurrence, whereas 17% of patients who had open surgery experienced disease recurrence.

A regression analysis showed no statistically significant effect of surgical approach on OS (HR = 1.5) or PFS (HR = 0.29).

“In view of the recent controversy concerning the use of minimally invasive radical hysterectomy as primary treatment for early-stage cervical cancer, this study compared the survival and perioperative outcomes in a cohort of patients who underwent [minimally invasive or open surgery],” Matanes and colleagues wrote. “Based on the data on a limited number of patients in a Canadian context, robotic radical hysterectomy did not lead to worse oncologic outcomes. ... One might consider the evaluation of more personalized surgical decision-making.”

Difference in risks

Another factor patients and their physicians should consider before deciding on a minimally invasive or open surgery is the potential complications associated with each procedure.

A study conducted by Uppal and colleagues — published in January in Gynecologic Oncology — showed significantly fewer perioperative complications with minimally invasive procedures.

Researchers analyzed 7,180 radical hysterectomy cases between 2012 and 2015 from the National Inpatient Sample data set. They found a 44% decrease overall in the number of radical hysterectomy cases from 2012 (n = 2,220) to 2015 (n = 1,255). Of the minimally invasive surgeries, 41.4% were conducted with robotic assistance.

Results showed that at least one complication occurred among 24.8% of women who underwent open surgery compared with 10% who underwent minimally invasive surgery (P < .001).

On multivariate analysis, open surgery had higher odds of any one complication (OR = 2.9; 95% CI, 2.12-4), medical complications (OR = 3.25; 95% CI, 2.15-4.19) and infectious complications (OR = 3.76; 95% CI, 2.1-6.1). There was not a higher chance for surgical complications (OR = 1.7; 95% CI, 0.5-5.6).

Open surgery also resulted in longer hospital stays (4.3 vs. 1.9 days; P < .001).

“We all know the minimally invasive surgery is easier to get over. Someone can feel better and get back to work faster, and there are long-term risks like hernias or bowel obstructions that you must consider,” Naumann told HemOnc Today. “Consider a single-vessel coronary disease. Nobody really does open heart surgery on those patients but, if they do, the patient does really well. If you give them a stent, they have a 5% catastrophic conclusion rate in the first year. But that’s the risk you take instead of having thoracotomy. If the risk of minimally invasive surgery is really higher, then I think this is a similar situation.”

Source: Roswell Park Comprehensive Cancer Center.

Still, the ultimate goal of each procedure should be prolonged OS, Peter Frederick, MD, associate professor of oncology in the department of gynecologic oncology at Roswell Park Comprehensive Cancer Center, told HemOnc Today.

“The risks and benefits of a minimally invasive surgery vs. a laparotomy are important factors we discuss with all of our patients before deciding on the surgical approach,” he said. “Overall survival is ultimately the most important outcome, however, and I think a majority of surgeons and patients would be willing to accept a higher surgical complication rate and longer recovery if it resulted in better survival rates.

“It is likely that, as a consequence of these publications, more women with early-stage cervical cancer will be offered open radical hysterectomy or even chemoradiation if they are poor candidates for laparotomy,” he added.

In her editorial, Fader agreed that there are risks on both sides, but that minimally invasive surgeries could still be the better option for some patients.

“Patients with a tumor size less than 2 cm did not have worse outcomes with minimally invasive surgery than with open surgery in either study,” Fader wrote. “Until further details are known, however, surgeons should proceed cautiously, counsel their patients regarding these collective study results, and assess each woman’s individual risks and benefits with respect to minimally invasive as compared with open radical hysterectomy.”

Next steps

Medical professionals agree that, even in light of the studies by Melamed and colleagues and Ramirez and colleagues, there is no need for extra follow-up or treatment for women who underwent the minimally invasive surgery.

Instead, patients should continue to receive their routine treatment and consistently monitor their progress with their physicians.

“At this point, there are not any additional treatment or surgical procedures patients need to undergo following minimally invasive surgery,” Wright said. “I think patients need to be made aware that they are at a higher risk for recurrence and they need to have careful surveillance with their doctors. This is something that women would want to know about and we need to be mindful of this as we monitor these women going forward.”

Brown agreed.

“Clearly, we have to be upfront and share this with our patients so we can come to a shared decision, but I think the story is not over,” she said.

Rauh-Hain said MD Anderson will be offering more frequent imaging for patients the first 3 years following minimally invasive surgery.

Additionally, the prognosis for women with early-stage cervical cancer — whether they had open or minimally invasive procedures — is still very good.

“Patients with early-stage cervical cancer have an excellent prognosis. Most of these patients should survive,” Rauh-Hain said. “But, at this point, I would say when you have a good prognosis, why not do the standard [open surgery] approach?”

However, many experts still agree that more follow-up is needed before any drastic changes are made to standard care for patients with early-stage cervical cancer.

Rauh-Hain said MD Anderson does not have the funds right now to conduct a follow-up study. The AAGL will be intensely lobbying for follow-up studies, and Brown is confident they will be conducted.

“We need to be very careful that we don’t use a single inconclusive trial to change care patterns. Instead we may need to look further. We are going to be compelled to look at who is best served by minimally invasive surgery and who is best served by an open procedure,” Brown said. “We’re not speaking against the data that were published. It’s important to recognize the red flags these data suggest because we have to provide the best care for our patients. But, it may not be minimally invasive surgery, so we need to be mindful of how to recommend therapy to our patients.” – by John DeRosier

Click here to read the , “Would more aggressive adjuvant therapy following minimally invasive surgery help close the survival gap with open surgery?”

References:

Fader AN, et al. N Engl J Med. 2018;doi:10.1056/NEJMe1814034.

Melamed A, et al. N Engl J Med. 2018;doi:10.1056/NEJMoa1804923.

Ramirez PT, et al. N Engl J Med. 2018;doi:10.1056/NEJMoa1806395.

Matanes E, et al. J Obstet Gynaecol Can. 2018;doi:10.1016/j.jogc.2018.09.013.

Uppal S, et al. Gynecol Oncol. 2019;doi:10.1016/j.ygyno.2018.09.027.

For more information:

Jubilee Brown, MD, can be reached at Levine Cancer Institute at Atrium Health, 1021 Morehead Medical Drive, Charlotte, NC 28204; email: jubilee.brown@atriumhealth.org.

Peter Frederick, MD, can be reached at Roswell Park Comprehensive Cancer Center, 665 Elm St., Buffalo, NY 14263; email: peter.frederick@roswellpark.org.

Joshua P. Kesterson, MD, MBA, can be reached at Penn State University Milton S. Hershey Medical Center, 500 University Drive, Hershey, PA 17033; email: jkesterson@pennstatehealth.psu.edu.

R. Wendel Naumann, MD, can be reached at Levine Cancer Institute at Atrium Health, 1021 Morehead Medical Drive, Charlotte, NC 28204; email: wendel.naumann@atriumhealth.org.

J. Alejandro Rauh-Hain, MD, MPH, can be reached at The University of Texas MD Anderson Cancer Center, Suite 2500, 7900 Fannin St., Houston, TX 77054; email: jarauh@mdanderson.org.

Jason D. Wright, MD, can be reached at Columbia University Department of Obstetrics and Gynecology, 161 Fort Washington Ave., 4th Floor, New York, NY 10032; email: jw2459@cumc.columbia.edu.

Disclosures: Wright reports personal fees from Clovis Oncology and Tesaro. Brown, Frederick, Kesterson, Naumann and Rauh-Hain report no relevant financial disclosures.