Women who were subjected to minimally invasive surgery for early-stage cervical cancer were four times more likely to die from that disease within three years, three times more likely to have a recurrence within three years, and had shorter overall survival, compared to women who underwent open surgery, according to two groundbreaking studies published in The New England Journal of Medicine Oct. 31.
Conducted by two teams of researchers, the studies chart the widespread adoption of minimally invasive radical hysterectomies over the past 10 to 12 years, to the detriment of women who received these procedures.
One of the studies is a prospective phase III randomized clinical trial of 631 women, conducted from 2008 to 2017. The other is a retrospective cohort analysis of 2,461 women who underwent radical hysterectomies between 2010 and 2013. The latter study also included an analysis of NCI registry data going back to 2000.
“This is a very unexpected finding,” Pedro Ramirez, lead author of the prospective study and director of minimally invasive surgical research and education at MD Anderson Cancer Center, said to The Cancer Letter. “In October 2017, the statistical team did a reanalysis of the data, and they said, ‘Well, not only is the safety signal persistent, but actually accentuated, and now, we’re definitely recommending for the study to stop accrual. We will unblind the results to the investigators, and what we found was that there is a higher risk of recurrences—in fact, four times higher risk of recurrence and a high risk of death from cervical cancer—in the minimally invasive arm.’”
A conversation with Ramirez appears here.
“These results highlight the hazards of assuming the oncologic equivalence of a new method of performing a cancer operation and adopting it widely in the absence of Level I evidence,” Stephen Rubin, chief of the Division of Gynecologic Oncology and the Paul Grotzinger and Wilbur Raab Chair in Surgical Oncology at Fox Chase Cancer Center, said to The Cancer Letter. “Taken together, these findings are practice-changing, and should prompt gynecologic oncologists to employ open surgical techniques for their patients with early cervical cancer who are candidates for radical surgery.”
Experts say the findings are reminiscent of the controversy over power morcellation, another minimally invasive procedure that had become a standard of care over 20 years, contributing to early deaths in a subset of women by disseminating occult or missed uterine malignancies via intentional fragmentation of tissue (How Medical Devices Do Harm, The Cancer Letter).
“We jump into these procedures before they are proven, and we need to remember that patient outcomes and survival come first,” Brian Slomovitz, director of the Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, at University of Miami Miller School of Medicine, said to The Cancer Letter. “I think this is another example that for us, as surgeons who care for patients that could have deadly diseases, ‘getting the tumor out’ is not simply the answer, but how we get the tumor out and in what fashion, and whether that affects the biology and aggressiveness of the disease.
“We learn that here, and we learned that in morcellation for sarcoma and other uterine cancers, that it does matter,” said Slomovitz, co-leader of the Gynecologic Cancers Site Disease Group at Sylvester Comprehensive Cancer Center.
‘Getting the tumor out’ is not simply the answer, but how we get the tumor out and in what fashion, and whether that affects the biology and aggressiveness of the disease—we learn that here, and we learned that in morcellation for sarcoma and other uterine cancers, that it does matter.
Brian Slomovitz
The parallels between the two controversial procedures are striking: both are used in gynecology, both are minimally invasive, both involve laparoscopic or robotic surgical instruments, and both are associated with worsened cancer-related outcomes.
Finally, both had become standard practice in gynecology without high-quality prospective data on recurrence rates, cancer-related mortality, and overall survival as primary endpoints.
But there is a difference:
Power morcellation was used in hysterectomies and myomectomies, with the assumption that the tissue being pulverized was benign. By contrast, minimally invasive radical hysterectomy—complex surgery indicated for the excision of cervical cancer—was designed to remove malignant epithelial tissue, both en bloc and with good margins, presumably according to basic Halstedian principles of surgical technique.
And, unlike malignances of the body of the uterus—sarcomas, for instance, are embedded within otherwise benign uterine tissue—cervical cancer presents as gross tumor, exposed on the surface of the cervix and adjacent tissue, which arguably places it at greater risk of dissemination.
How did an entire category of minimally invasive radical hysterectomy procedures, crafted by gynecologic oncologists specifically for an indication in cancer, become the standard of care without prospective data? Also, why did it take so long to determine that this procedure actually worsens outcomes for cancer patients who are, overall, supposed to benefit from this innovation?
Over the past 36 hours, gynecologic oncologists reported overwhelming shock and surprise at the findings.
“I guess my first thought was, I was shocked. It was unexpected,” said Noelle Cloven, a gynecologic oncologist at Texas Oncology-Fort Worth Cancer Center, and a member of the Society of Gyneologic Oncology Communications Committee. “I don’t think any of us really thought that there was going to be any effect on outcome, doing robotic surgery.
“We’ve all been so focused on decreasing the morbidity from surgery and improving patients’ quality of life, and we’ve had studies in other cancers including endometrial cancer that showed no impact on outcome in doing minimally invasive surgery,” Cloven said to The Cancer Letter. “I don’t even think Ramirez et al. were expecting it to be inferior in survival.”
The results are practice-changing—MD Anderson Cancer Center immediately imposed a moratorium on minimally invasive radical hysterectomy procedures, which are conducted with laparoscopic and robotic devices, including the popular da Vinci robots, sold by Intuitive Inc.
“In March of this year, we presented it at the Society of Gynecologic Oncology meeting,” Ramirez said. “Obviously, since that time, this sent a shockwave through the field of gynecologic oncology, because of the unexpected findings of the study.
“The shock was because when we looked at [earlier] retrospective data—granted, retrospective data is not as high quality as prospective randomized and not as good level of evidence—but that’s all we had, and the retrospective data has shown, at least in the studies that mention oncologic outcomes, there seem to be no difference.”
The studies published in NEJM were not designed to assess seeding of cervical cancer in benign hysterectomies: if women with known disease are being harmed by minimally invasive procedures designed to save them, what about women who don’t know that they have cervical cancer?
What is the risk of dissemination of occult or missed cervical cancer in minimally invasive surgery for benign indications i.e. non-radical hysterectomies?
In a study by Yale researchers published earlier this year in Obstetrics & Gynecology, the prevalence of cancers undetected at the initiation of hysterectomies was almost as high as one in 70. For women who underwent total laparoscopic or laparoscopic-assisted vaginal hysterectomies, the estimated prevalence rose to nearly one in 50 (The Cancer Letter, May 18).
Out of 24,076 patients who underwent benign hysterectomies, 0.6 percent—almost one in 170 women—had occult or missed cervical cancer.
Without adequate preoperative workup and screening, women with undetected malignancies face significant cancer mortality risk when undergoing minimally invasive techniques that may not be oncologically safe, or that involve fragmentation of potentially malignant tissue.
“That is something that we see from time to time in our practice,” Cloven said. “Even really thorough doctors that do a work-up before surgery, it’s possible that you can have an occult cervical cancer, and have a regular hysterectomy rather than a radical hysterectomy.
“At that point, they usually get sent to us, and we have to counsel them whether it’s better to go in there and remove lymph nodes, whether we need radiation, or how do you proceed. Even in best-case scenarios, it happens. I’ve seen it, even with cervical cancer.
“They say that the false-negative rate for a Pap test could be as high as 40 percent. So, it’s probably a little bit better than that, now that we’re doing HPV-typing with it. Some people think that the future is going to be that you test for HPV rather than doing a Pap smear, and that’s going to improve the sensitivity. That’s in flux right now, as far as whatever recommendations are for screening for cervical cancer.”
In May, Robert Redfield, the director of the Centers for Disease Control and Prevention, said the agency is reviewing the methods gynecologists use to identify women at risk of uterine cancers (The Cancer Letter, May 25).
Of an estimated 11,000 to 13,000 cases of cervical cancer reported every year in the U.S., about 1,500 to 1,700 women undergo radical hysterectomies. Up to 60 percent—over 1,000—of these women are subjected to minimally invasive surgery, especially for early-stage disease.
“I think surgical removal of those candidates with disease confined to the cervix is definitely standard of care, and per NCCN guidelines, there’s also a mention in there of minimally invasive approach,” said Joshua Kesterson, chief of the Division of Gynecologic Oncology at Penn State Health Milton S. Hershey Medical Center, and vice chair of the Society of Gynecologic Oncology Communications Committee.
“I think this data is impactful and it definitely needs to be transmitted to patients when you’re discussing with them the different approaches to a radical hysterectomy going forward. We don’t entirely know the reason for the increased rate of failure in the minimally invasive approach.”
A conversation with Kesterson appears here.
“I have already made a change in my practice,” Cloven said. “I’ve already started doing more open radical hysterectomies. I feel like I’m obligated to discuss this with the patient and say, ‘Hey, there’s some data now that shows that it might be better if we go ahead and open you up.’
“Really, what everybody wants in the end is to have a good cancer outcome. That’s where I stand.”
The NEJM papers are expected to have even broader impact outside the U.S. About 500,000 cases of cervical cancer are reported each year globally, and about 275,000 women die from the disease annually.
Of the 631 patients who were randomized to minimally invasive vs. open surgery, the prospective study led by Ramirez found that:
Minimally invasive surgery was associated with a higher rate of death from cervical cancer (3-year rate, 4.4% vs. 0.6%; hazard ratio, 6.56; 95% CI, 1.48 to 29.00);
Minimally invasive surgery was associated with a higher rate of locoregional recurrence (3-year rate of locoregional recurrence–free survival, 94.3% vs. 98.3%);
The rate of disease-free survival at 4.5 years was 86 percent with minimally invasive surgery vs. 96.5 percent with open surgery, a difference of −10.6 percentage points (95% confidence interval [CI], −16.4 to −4.7); this means that for approximately every nine women who undergo minimally invasive radical hysterectomies instead of an open procedure, one of these women would have a cancer recurrence that could’ve been avoided;
Minimally invasive surgery was associated with a lower rate of disease-free survival than open surgery (3-year rate, 91.2% vs. 97.1%; hazard ratio for disease recurrence or death from cervical cancer, 3.74; 95% CI, 1.63 to 8.58), a difference that remained after adjustment for age, body-mass index, stage of disease, lymphovascular invasion, and lymph-node involvement; and
Minimally invasive surgery was also associated with a lower rate of overall survival (3-year rate, 93.8% vs. 99.0%; hazard ratio for death from any cause, 6.00; 95% CI, 1.77 to 20.30).
In the retrospective study, researchers found that:
Over a median follow-up of 45 months, the 4-year mortality was 9.1% among women who underwent minimally invasive surgery and 5.3% among those who underwent open surgery (hazard ratio, 1.65; 95% confidence interval [CI], 1.22 to 2.22; P=0.002 by the log-rank test); and
Before the adoption of minimally invasive radical hysterectomy (i.e., in the 2000–2006 period), the 4-year relative survival rate among women who underwent radical hysterectomy for cervical cancer remained stable (annual percentage change, 0.3%; 95% CI, -0.1 to 0.6).
In a startling line graph that illustrates the retrospective analysis of data from NCI’s Surveillance, Epidemiology, and End Results database, four-year relative survival rates among women who underwent radical hysterectomy for cervical cancer started to tank in 2006 in association with the adoption of minimally invasive radical hysterectomies.
According to the time-series evaluation, by 2010, over 30 percent of women were undergoing these new procedures, and the significant change in trend had resulted in an up to 3.2 percent decline in four-year relative rates (annual percentage change, 0.8%; 95% CI, 0.3 to 1.4; P=0.01 for change of trend).
Gynecologic oncologists hypothesize that two intraoperative factors may contribute to the higher risk of dissemination of cervical cancer in minimally invasive approaches:
The use of a uterine manipulator, a device that is placed through the cervix into the uterus to move the uterus around during minimally invasive surgery, and
The use of carbon dioxide gas to inflate the abdomen, increasing the propensity for cervical cancer cells to implant along the surface of the lining of the abdomen and pelvis.
Unlike morcellation, where patients who do not undergo thorough preoperative work-up are at risk for dissemination of missed cancer, the reasons for upstaging of cervical cancer in minimally invasive radical hysterectomy are less clear, said SGO’s Kesterson.
“It rationally makes sense that, if you have a tumor within the muscle of the uterus or an occult endometrial tumor, that you now morcellate and spread these cells throughout the peritoneal cavity, that’s a rational cause and effect,” Kesterson said. “And I think we can all get behind that.
“The difference here is that we can postulate what some of the causes may be, but they’re not known or not controlled for,” Kesterson said.
In the prospective trial, most recurrences of cervical cancer occurred in the vaginal vault or pelvis (41% of the recurrences in the minimally invasive surgery group and 43% of those in the open-surgery group).
A higher proportion of vault recurrences occurred in the open-surgery group (43%, as compared with 15% in the minimally invasive surgery group), and all non–vaginal vault pelvic recurrences occurred in the minimally invasive surgery group.
Recurrences occurred in 14 of 33 recruiting centers, with no clear pattern of failure rates across sites. A total of 22 deaths were noted, 19 in the minimally invasive surgery group and 3 in the open-surgery group.
“The one thing that did cross my mind that I think is different when we do an open radical hysterectomy is, the first thing we do is we put two clamps right across the Fallopian tubes on either side at the top of the uterus,” Texas Oncology’s Cloven said. “The whole difference with an open radical hysterectomy vs. a robotic or minimally invasive is that, with an open surgery, we’re pulling up by those clamps. That’s how we’re manipulating it.”
In standard minimally invasive procedures, surgeons make no effort to prevent cervical tumors from being exposed to the pelvic cavity, MD Anderson’s Ramirez said. Before FDA severely restricted the use of power morcellators in 2014, gynecologists also routinely exposed potentially malignant tumor fragments to surrounding tissue in the abdominal cavity.
“I would think that there’s an element that directly leads us to the instrument itself like it was with the manipulator, but I think that it does ring a bell along with that same principle of cell implantation, and perhaps the gas being a potential etiologic factor in this setting,” Ramirez said.
Cloven said she does not perform laparoscopic surgery, only robotic procedures.
“I won’t say that I would never do another robotic radical hysterectomy, but I don’t do the laparoscopic, because there might be a case where it’s microscopic and it’s not a big tumor, and I think that the patient would be a good candidate, because they’re low-risk for recurrence,” Cloven said. “I stopped robotic radical hysterectomy on large tumors a long time ago, just because I felt like I couldn’t get adequate manipulation.
“It’s a lot different. Laparoscopy has been around forever, robotic surgery has only been around for about 10 years. The robotic instruments, rather than being completely stiff, the very tip bends and rotates, so you have more precision. The way I compare it is, laparoscopy is like picking at a piece of tissue with a pair of chopsticks; it’s a little awkward sometimes.”
Minimally invasive robotic procedures generally start with a vaginal exam and a cup over the cervix, Cloven said.
“Then, we change our gloves and gown, we go up and we make four small incisions and we do all the surgery through the smaller incisions, and then we remove it in one piece vaginally,” Cloven said. “Then, we remove the lymph nodes and we put those in bags. There’s no morcellation or fragmenting or anything like that.”
How did surgeons make a choice between minimally invasive or open surgery for patients with cervical cancer?
“Well, for many years now, most surgeons would choose minimally invasive surgery based on retrospective data,” Ramirez said. “Interestingly, we often would see patients who would tell us, ‘Look, I think it’s great that you’re doing this study, but I don’t want to be randomized to the open approach, because my doctor that referred me to you said that the minimally invasive surgery was better. I want the minimally invasive surgery.’
“Basically, it was a bias by patients, bias by physicians that was driving this movement towards a growing embracing of the minimally invasive approach, without actually having cancer-related outcome data.”
When a new experimental surgical technique is introduced, it should be subjected to a prospective randomized controlled trial to demonstrate safety, efficacy and superiority, said Hooman Noorchashm, the cardiac surgeon who launched an aggressive campaign against power morcellation in 2013. His wife, Amy Reed, an anesthesiologist, died from complications related to abdominal sarcomatosis in 2017 (The Cancer Letter, May 26, 2017).
“This is like putting the cart before the horse, and the only thing driving it are money and professional egos, not patient safety and good medicine,” Noorchashm said to The Cancer Letter. “It is absolutely unprecedented to be subjecting a high-volume, already established standard of care in surgical oncology to an RCT—remember, minimally invasive hysterectomies have already been performed on, literally, millions of women across the world for cervical cancer.
“Why didn’t the minimally invasive gynecologists perform this RCT back in 2006, when this practice was taking off? Just look at the survival difference between the open vs. minimally invasive procedures, the number of women harmed by this level of carelessness in gynecology is simply massive—and unforgivable.
“How could any reasonable physician not express moral indignation at these data? These are real women living on these iatrogenic death curves created by gynecologists! There’s something wrong with the thinking that is guiding this specialty’s leadership.
“The data on iatrogenic harm to women is unequivocal. The CDC has been exceptionally slow in moving to protect American women from harm. Where are the defenders of public health in government?”
Leaders in gynecologic oncology agree that the results of the NEJM papers must be presented to patients in surgical planning discussions.
“As clinicians, we are certainly obligated to discuss this new evidence when advising early stage cervical cancer patients, particularly those with cervical lesions that are 2.1 to 4 cm in diameter, on their surgical approach options for radical hysterectomy,” Ronald Alvarez, chair of the Department of Obstetrics and Gynecology and the Betty and Lonnie S. Burnett Professor of Obstetrics and Gynecology at Vanderbilt University Medical Center, said to The Cancer Letter.
Gynecologic oncologists need to focus on disease progression and overall survival as primary endpoints, beyond the management of postoperative short-term outcomes for patients with cancer, Sylvester’s Slomovitz said.
“The primary objective of these studies is survival or recurrence rates—we can’t overlook those objectives and those findings, even if robotic surgery can give you a shorter length of stay,” Slomovitz said. “We have to look at ourselves carefully as a specialty that treats women and make sure that we’re moving in the right direction.
“At Sylvester Comprehensive Cancer Center, we’re discussing the results with our patients, but the first choice is open surgery based on the results of the study.”
