Worse Survival With Minimal Invasive Surgery for Cervical Cancer

Roxanne Nelson, BSN, RN

November 01, 2018

New data show shorter survival times for patients with early cervical cancer who underwent hysterectomy with minimally invasive techniques as compared to patients who underwent open surgery. The findings are "unexpected and alarming," said the lead investigator of a randomized trial comparing the two surgical approaches.

The trial was stopped early after an imbalance between the two groups was found.

"At that time, 631 patients had been enrolled, and we had initially planned for 740 patients," said lead author Pedro T. Ramirez, MD, professor and director of minimally invasive surgical research and education in the Department of Gynecologic Oncology at the University of Texas MD Anderson Cancer Center, Houston.

The interim analysis showed that at 4.5 years, the disease-free survival rate was lower with minimally invasive surgery compared with open surgery (86.0% vs 96.5%; difference, −10.6 percentage points).

In addition, the 3-year rate of overall survival was lower (93.8% vs 99.0%; hazard ratio for death, 6.00).

These results come the phase 3 Laparoscopic Approach to Cervical Cancer (LACC) trial, which was published online October 31 in the New England Journal of Medicine.

Initial results were presented earlier this year at the annual meeting of the Society of Gynecologic Oncology.

"Since that time, there has been a significant amount of buzz because of this unexpected element," Ramirez told Medscape Medical News.

Ramirez emphasized that the higher death rate was attributed to cervical cancer recurrence and that the only difference between the two groups was the surgical approach.

"The groups were well matched as far as risk factors," he explained, "and all other factors, including surgical margins and skill of the surgeons, were equivalent."

"But the likelihood of recurrence in the minimal surgery group was four times higher, so this was rather alarming to medical community caring for these patients," he said.

"In most institutions, it is now the standard of care, but we have stopped doing it at MD Anderson, based on these results."

Similar Results From Second Trial

A second study published in the same issue of the New England Journal also found that survival was shorter for women who underwent minimally invasive surgery compared to patients who underwent open surgery.

In an accompanying editorial, Amanda N. Fader, MD, from the Johns Hopkins School of Medicine, Baltimore, Maryland, writes that although the results of both studies are "powerful, scientific scrutiny demands consideration of potential study-design or study-conduct issues that may affect outcomes unexpectedly."

Surgical trials, in particular, can be difficult to conduct and pose particular practical and methodologic challenges, she writes.

Do these studies "signal the death knell for minimally invasive radical hysterectomy in cervical-cancer treatment?" she asks.

This approach has been dealt a great blow. Dr Amanda N. Fader

"Not necessarily, but this approach has been dealt a great blow," she comments.

Select patient subgroups may derive a benefit from the less invasive approach, she suggests.

Women with tumors measuring less than 2 cm did not have worse outcomes with minimally invasive surgery than with open surgery in either study, she points out.

However, Ramirez told Medscape Medical News: "We don't know if there is a subset of patients where it is safe to undergo minimally invasive surgery, because our study was not designed to answer that question.

"The recurrence rate in low-risk patients is low, but we cannot make that assumption that this procedure is safe in that group of patients," he added.

Ramirez recommends that any patient who is scheduled to undergo this surgery have a long discussion with her surgeon about the risks. "Patients need to be aware that there is a higher likelihood of recurrence," he said.

In her editorial, Fader writes that until further details emerge, "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."

Data Until Now

In other cancer types, including early-stage uterine, colorectal, and gastric cancers, randomized clinical trials have found that survival is similar for patients who undergo minimally invasive surgery or open surgery.

Minimally invasive hysterectomy is beneficial to the patient in that it is associated with a lower risk of infection and faster recovery. The first laparoscopic radical hysterectomy for cervical cancer was reported in 1992. Since then, numerous trials have shown that the procedure is feasible and is associated with less blood loss, shorter postoperative hospital stays, and fewer complications compared to open surgery.

However, these have been primarily single-institution series or observational cohort studies. Long-term survival data evaluated in randomized trials or large, well-designed observational studies have been limited.

Despite limited data, current guidelines from the National Comprehensive Cancer Network and European Society of Gynecological Oncology indicate that either laparotomy or laparoscopy performed with either conventional or robotic techniques is an acceptable approach to radical hysterectomy for patients with early-stage cervical cancer.

"The rates of minimal invasive procedures began to rise in the United States in 2006 and accounted for more than half of all radical hysterectomies in cervical cancer in 2013," commented Jose Alejandro Rauh-Hain, MD, MPH, assistant professor, Department of Gynecologic Oncology and Reproductive Medicine, the University of Texas MD Anderson Cancer Center, Houston, who is lead author of the second study.

"But up until now, there was no strong data showing a survival difference, since studies were small and did not have enough power to find the survival differences," he said.

In the period from 2000 to 2006, prior to the adoption of minimally invasive radical hysterectomy, the 4-year relative survival rate for cervical cancer remained stable (annual percentage change, 0.3%; 95% confidence interval, −0.1 to 0.6). The advent of minimally invasive surgery coincided with a decline in the 4-year relative survival rate of 0.8% each year after 2006 (P = .01 for change of trend), he noted.

Higher All-Cause Mortality

The second study published in the New England Journal, from Rauh-Hain and colleagues, compared the two surgical approaches in a large cohort of women who underwent radical hysterectomy for stage IA2 or IB1 cervical cancer from 2010 to 2013.

The results were consistent with the randomized trial in that minimally invasive radical hysterectomy was associated with poorer overall survival.

Within this cohort of 2461 patients, 1225 (49.8%) underwent minimally invasive surgery, and 978 (79.8%) underwent robot-assisted laparoscopy. Conversion from minimally invasive surgery to open surgery occurred in 2.9% of cases.

At a median follow-up of 45 months, the 4-year mortality was 9.1% in the minimally invasive surgery cohort vs 5.3% in the open surgery group (hazard ratio, 1.65; P = .002 by the log-rank test).

Overall survival was shorter for women who underwent minimally invasive surgery compared to those who underwent open surgery. The difference corresponds to a 65% higher risk for death from any cause (hazard ratio, 1.65; P = .002 by the log-rank test).

Patient demographics differed between the two groups. Women who underwent minimally invasive surgery tended to be white, had private insurance, and resided in ZIP code regions characterized by higher socioeconomic status. In addition, these patients had smaller, lower-grade tumors and were more likely to have received a diagnosis later in the study period than women who underwent open surgery.

"Women who had minimal invasive had better prognostic factors," explained Rauh-Hain, "so they were actually a better group of patients and should have had better outcomes."

Because the data were drawn from a database, it is difficult to know how surgical decisions were made as to the selection of the specific approach. As of now, it is difficult to say why one group had worse survival.

"We just don't know," Rauh-Hain said. "More research is needed to figure this out."

The LACC study was supported by a departmental research fund in the Department of Gynecologic Oncology and Reproductive Medicine, University of Texas MD Anderson Cancer Center, and by a grant from Medtronic. The second study was funded by the National Cancer Institute, the National Institute of Child Health and Human Development, the American Association of Obstetricians and Gynecologists Foundation, the Foundation for Women's Cancer, the Jean Donovan Estate, and the Phebe Novakovic Fund. Dr Ramirez and Dr Rauh-Hain have disclosed no relevant financial relationships. Dr Fader has received personal fees from Ethicon outside the submitted work.

N Eng J Med. Published online October 31, 2018. LACC study, Full text; Second study, Full text; Editorial

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