The unexpected results of two new studies have “dealt a great blow” to the standard of care for patients who undergo surgery for early cervical cancer, according to an editorial in The New England Journal of Medicine.
Both studies were published in the same November 2018 issue and presented at a medical meeting earlier this year.
Study One Details
The first, a phase III trial involving more than 600 early-stage cervical cancer patients, compared minimally invasive (laparoscopic or robotic) radical hysterectomy to open radical hysterectomy (N Engl J Med 2018;379:1895-1904).
Both operations involve taking out the uterus and surrounding structures. Open surgery is the traditional method of surgery and requires a large incision in the lower abdomen, while minimally invasive surgery uses just a few small incisions. The laparoscopic approach has become more common over the last decade because patients tend to have shorter hospital stays afterward and suffer less pain.
“When we decided to embark on this project, there was increasing evidence the minimally invasive approach was safe in terms of cancer-related outcomes,” said lead author Pedro Ramirez, MD, Director of Minimally Invasive Surgical Research and Education in the Department of Gynecologic Oncology at MD Anderson Cancer Center, Houston.
The study patients, whose average age was 46, were randomly assigned to undergo either open or minimally invasive surgery. Before the results were all in, however, the trial was halted halfway through by the data and safety monitoring committee. Early findings revealed that patients treated with minimally invasive surgery had a lower rate of overall survival 4.5 years after diagnosis compared to those who'd undergone open radical hysterectomy.
“We were all very surprised and certainly this was unexpected. We wanted to be sure there was a very thorough and repeated analysis of the data. There were three statisticians working on this study and after repeated evaluations, the conclusions remained,” Ramirez said.
After 4.5 years, only 86 percent of patients in the minimally invasive group were cancer-free compared with 96.5 percent of the patients in the open surgery group.
“The recurrence rate and mortalities were much higher in the minimally invasive group than the other group,” he added.
Study Two Details
The second study—a two-part, NCI- and NIH-funded epidemiological study—also compared minimally invasive radical hysterectomy with open surgery in women with early-stage cervical cancer and found a similar trend (N Engl J Med 2018;379:1905-1914).
“In our study, we used two large national databases and what we found is, among patients who had minimally invasive surgery, those patients had lower survival than those who had open surgery,” said study author Jose Alejandro Rauh-Hain, MD, MPH, Gynecologic Oncologist in the Department of Gynecologic Oncology and Reproductive Medicine, Division of Surgery, at MD Anderson Cancer Center.
In the first analysis of 2,461 women—about half had laparoscopic and half had open operations—4 years after minimally invasive surgery, 9.1 percent of women had died compared to 5.3 percent of women in the open surgery group. The second analysis tracked survival rates after cervical cancer surgery and found that, in 2006, the time when minimally invasive surgery started being used for cervical cancer, survival dropped by 0.8 percent a year.
“We were expecting survival to be pretty similar between both groups. We were really surprised,” noted Rauh-Hain.
Immediate Change in Practice
The study findings prompted the MD Anderson experts and those at other medical centers who had heard the results at the medical meeting earlier this year, prior to publication, to re-evaluate their surgical approach to cervical cancer.
“At our institution, we at that point decided to stop doing minimally invasive surgery for early-stage cervical cancer,” Rauh-Hain stated.
Ramirez also explained, “Since the meeting there has been a movement toward a change of practice in most centers not only nationally but around the world. This is truly a practice-changing study.”
Ross Stuart Berkowitz, MD, Director of Gynecologic Oncology at Brigham and Women's Hospital in Boston, said the results came as a shock to him and his colleagues when they were presented at the meeting prior to the publication of the research.
“Much to everyone's surprise, or rather, shock and dismay, the results showed that the survival rate in the patients with traditional open surgery was about 10 percent better. Then, to put another nail into this, so to speak, was the SEER database study. It further supported evidence that the minimally invasive approach, although less morbid, did not accomplish the same thing. I think people at this point are still trying to digest the information,” said Berkowitz.
“Within 24 hours after our return [from the meeting], we met as a group and said we can't continue to do minimally invasive surgery for this disease anymore,” he explained, even if that means longer hospital stays and more pain after surgery.
The researchers don't yet understand why the surgery outcomes are different, but there are theories.
“It is just hypothetical at this point. We don't really understand the mechanism. That's one of the limitations of our study,” said Rauh-Hain.
NEJM editorial author Amanda Fader, MD, Director of the Kelly Gynecologic Oncology Service and Associate Professor of Gynecology and Obstetrics at Johns Hopkins School of Medicine, wrote that uterine or cervical manipulators or carbon dioxide gas used to inflate the abdomen during minimally invasive radical hysterectomies has been “postulated to encourage local tumor spread.” Other factors might also include surgical technique, degree of procedural radicality, and peritoneal immunity, she noted. But more research is required.
Ramirez said he's spoken with some surgeons who've been reluctant to accept the results. “Just the fact that they've been trained to do this and have been doing it many years and can't see stopping. But one needs to reflect on the implications of doing that and the recurrence. The results of these studies need to be discussed with patients,” he said.
Safety and cure come first, Berkowitz said. “Everything else is less important. Our main goal is to preserve a patient's life. That's what's driving our decisions most. I think what was so upsetting about the results was that the treatment that was less morbid was not as effective. But also, the thought that, potentially, we may have hurt people in our desire and attempt to maintain the same outcome in a less morbid way,” he concluded.
Mary Brophy Marcus is a contributing writer.
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