Gynecologic oncologists need to reduce oncologic risk, but it’s not going to happen without knowing why minimally invasive radical hysterectomies decrease survival of patients with cervical cancer, said Joshua Kesterson, chief of the Division of Gynecologic Oncology at Penn State Cancer Institute.
“We have to kind of balance the risk of a laparotomy with that of a laparoscopy in the short and long-term … I think that’s where we need to have more studies,” Kesterson said.
“I think minimally invasive surgery still has a role. I do. I don’t know that majority of places are going to take the same approach on putting a moratorium on minimally invasive approach for cervical cancer. I don’t think that’s going to be the case.
“Hopefully, they’ve got some data looking at the use or non-use of the uterine manipulator and can look at that kind of an ad hoc or retrospective manner of this prospectively selected data. And so, that will be interesting if [MD Anderson’s Pedro] Ramirez has any plans on doing that going forward.”
Kesterson spoke with Matthew Ong, a reporter with The Cancer Letter.
Matthew Ong: What are your overall impressions of the two studies on minimally invasive radical hysterectomy that were published in the New England Journal of Medicine?
Joshua Kesterson: I think [the Ramirez study] is a much-needed trial, where they evaluated the equivalency of two different approaches for early-stage cervical cancer. Something that had been done previously was for endometrial cancer, and now done for cervical cancer.
I think it’s a nice jumping-off-point in conversations piece; I think in a lot of ways, my thoughts are still generating, but there are a lot of nuances within that study, based on the heterogeneity of results that leave a lot still unknown, truth be told.
Right, Dr. Pedro Ramirez and I briefly discussed high-risk vs. low-risk groups and whether that merits further investigation, but minimally invasive radical hysterectomy is the standard of care for cervical cancer, right, as we know it?
JK: Right. If you look at cervical cancer, if you have early-stage disease, we’ve shown previously with randomized controlled trials—probably the most prominent one being a study by a guy named Landoni out of Italy—looking at the equivalency of radical hysterectomy and radiation therapy in early-stage cervical cancer.
So, 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.
Obviously, there’s a couple subheadings within that minimally invasive approach being the laparoscopic approach, and then using the robot as the tool to facilitate that laparoscopic approach.
How long has minimally invasive radical hysterectomy been the standard of care for patients with cervical cancer? When did we move away en masse from open abdominal radical hysterectomies for cervical cancer?
JK: That’s a good question. I don’t know that I could give you a year, per se, in that it’s kind of a continuum. What you have is laparoscopy being accepted as an approach with some initial data coming out showing improved surgical outcomes as far as return to baseline activity, estimated blood loss, days in hospital, postoperative complications, all those things.
Looking at surgery as radical hysterectomy as the goal, how you facilitated that surgery wasn’t as important initially, but then, when we started seeing that you could have decreased intraoperative and postoperative complications, I think it kind of transitioned.
Within that, there’s also this ability or need to train surgeons on the newer modalities, and some people are more comfortable doing the open approach, some people more comfortable doing the laparoscopic and now, more so maybe even the robotic approach of that minimally invasive surgery.
I think the second study set the cut-off point at 2006.
JK: Yes. I think that’s an early adoption of it. Now, within that, I think that’s when that learning curve was probably at its steepest and just starting off, but that’s when it started to get some more traction.
What its penetration is in the market as a whole, I’m not so sure in that different people are going to adopt that technology a little bit more rapidly than other surgeons.
But I don’t think it’d be unfair to say what has evolved at the same time are the laparoscopic instruments, the robotic instruments, so within that “laparoscopy” or “robotics,” there’s an enhancement of a technology over that period of time as well as improvement in patients’ proficiency within those operations.
With studies like these, is it kind of a shift in thinking—you mentioned a learning curve—but are we at a point where the specialty is moving away from “Oh, patients are in the hospital for fewer days and experiencing less postoperative complications,” to “Ok, wait a minute, since there’s a risk of dissemination of malignant tissue, let’s look at long-term cancer outcomes”?
JK: That’s a great question, Matt. Anytime we talk about the surgery for cancer, first and foremost, we don’t ever want to compromise oncologic outcome.
And so, whether that means doing whatever it takes to facilitate removal of the entire tumor or enabling gross negative margins, in order to kind of improve these patients’ longevity, we never let the modality compromise the care.
We would only look at the modality, whether laparoscopic or robotic to enhance the quality of care for these patients. I don’t think anybody ever wanted to do any intervention, despite possibly a decrease in intraoperative or postoperative complications.
That would ultimately impact negatively the oncologic outcomes, especially with cervix cancer, where your best chance at cure is your first chance.
I think, as a whole, as gynecologic surgeons, we have an appreciation for the need for that quality upfront surgery and I think, previously, we had believed in the equivalency of those.
Here, the studies have shed some new light on that question, with some additional questions being asked as a byproduct of this study.
It sounds like the standard of care so far had been based on retrospective data saying precisely that—minimally invasive procedures in this indication aren’t inferior and the outcomes are equivalent. Was that data robust?
JK: I think there’s some variety of data that was supportive of that. The previous data may have, in some cases, compared the laparoscopic or robotic outcomes with historical controls.
So, you look at a period in time where it was treated with a laparotomy and a radical hysterectomy, and then now compare it with your cohort from a later era, where you’re treating with a laparoscopy or a robotic radical hysterectomy approach. That was some of the data.
And then, also, some of the data, truth be told, would be looking at surgical outcomes of a surgery, and that’s probably the historical data. You can see with this most recent trial, what we’re trying to do is go from a surgical intervention and then now evaluate clinical outcomes i.e. progression-free survival, overall survival, which is difficult to do, and is nicely attempted in this prospective randomized trial.
But you’ve got to realize that the prior studies were comparing surgical outcomes of a surgery and maybe more of a focus on that early postoperative period, and then what you do when you have cohorts you compare, you lose the follow-up of these patients, you lose the standardization of the adjuvant care of these patients.
Some of the limitations are being addressed in this most recent trial out of MD Anderson in that you’re going from a surgical intervention and then evaluating a clinical patient outcome.
Within that, there’s going to be a lot of variables that are unaccounted for, whether it’d be like a simple pathology review, whether the standardization of that adjuvant care after the hysterectomy like radiation or chemotherapy—that are going to impact the outcome.
Do we know whether these minimally invasive procedures—laparoscopic or robotic—are largely being performed by gynecologists, or gynecologic oncologists?
JK: That’s one of the benefits of the study, honestly. What they tried to do up front is have a quality control measure where they had surgeons send unedited surgical films of their selected radical hysterectomy cases.
And so, they tried to do a quality control, so they had, for the most part, I believe, gynecologic oncologists doing this surgery, and gynecologic oncologists that are comfortable doing this surgery, so that one of the faults couldn’t be poor surgery or poor surgeon.
But do we know whether, in the overall community, this is mostly being done by regular GYNs or trained gyn-oncs?
JK: In the overall community, in a large part, radical hysterectomy will be done by a fellowship-trained gynecologic oncologist.
And obviously, what we’re taking out here, Matt, are those patients that don’t see a gyn-oncologist or don’t qualify for surgery and therefore are radiated. So, this is a surgical-candidate population.
What do we know about the incidence of cervical cancer in the U.S. and worldwide? The rates in the U.S. are apparently really low compared to elsewhere, right?
JK: We’re looking at 11,000 cases of cervical cancer each year in the U.S. and a significant proportion of those being early-stage disease.
If you look at cervical cancer in the U.S., it pales in comparison to that worldwide, where you’re look at about 500,000 cases each year in the world, and about 275,000 deaths annually in the world.
Goodness, that’s a 55 percent mortality rate?
JK: Yes, a majority of these cases worldwide are in other developed or developing nations. You’re probably looking at 90 percent plus in a low-resource environment.
As you can appreciate, the diagnosis and in the subsequent treatments are going to be limited by available knowledge, resources, personnel in those areas. Without widespread screening programs, without access to HPV vaccination, what you’re going to have is a population that is at risk for developing cervical cancer, and oftentimes, advanced-stage, when your mortality from the diseases increases.
What is SGO’s stance regarding the MD Anderson trial findings? Are we anticipating an advisory communication, or a new set of guidelines in the near future?
JK: I think this is a interesting trial in that it evaluates the equivalency of different approaches to radical hysterectomy. Within that, I think there are certain variables that are unaccounted for, that need to be addressed, hopefully in a trial or a study going forward.
That being said, 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. Therefore, it’s kind of hard to correct the underlying cause.
I think one of the things that we’re struggling with is this unknown and how to move forward to go from an unknown to a known so that we can positively impact patients, because we’re definitely going to impact them if everyone is getting open surgery or a laparotomy to facilitate that radical hysterectomy.
I don’t know that this is the death of minimally invasive surgery by any means. What I do think it means is, we need to have a conversation about this data with our patients going forward, and try to evaluate what may be the underlying causes for this discrepancy in outcomes between the two groups.
How much does the average minimally invasive procedure in this indication cost, compared to open abdominal radical hysterectomy?
JK: Cost is always a tricky thing…
Right, it changes based on where you are, who you’re seeing, how the reimbursement rates are different, but maybe we can try and understand which approach is more expensive.
JK: Exactly, there’s the insurance coverage, there’s the cost, and then the charges.
The reimbursement is somewhat similar, there’s no separate charge for a robotic hysterectomy over a laparoscopic hysterectomy—that is somewhat equivalent as far as your hospital or surgeon’s ability to bill for it.
It also gets tricky, Matt, if you have a robotic platform that you’ve already purchased for $1.5 million, that’s a sunk cost that you no longer, for the most part, incorporate into your cost of doing hysterectomy.
There’s the other thing that’s this absence of the cost that doesn’t get accounted for, and that’s days not in the hospital—the subsequent ability of patients to do more things with a minimally invasive approach.
For the radical hysterectomy, for the most part, you can be home the next day, if it’s robotic or laparoscopic vs. a laparotomy, you’re going to be in the hospital for a longer period of time.
Historically, the latter has more postoperative complications. Now, in this trial, that wasn’t really the case.
Yes, Dr. Ramirez did say that the immediate postoperative surgical outcomes are really quite equivalent.
JK: Yes. The short-term outcomes are equivalent, not the long-term complications.
I understand the results of the Ramirez trial came as a major surprise for many in this field, because of equivalency signals in retrospective data—were there truly no patient reports or warning signs, or any flapping red flags since 2006, even anecdotally, of increased upstaging of cervical cancer and worsened survival outcomes with minimally invasive approaches?
JK: That’s a good question. I think you’ve got to realize that the way a trial is structured is going to be different than how we’ve cared for patients clinically.
When you have a relatively rare disease, such as cervical cancer, and then you have an even smaller subset, still, of those that are candidates for radical hysterectomy, and then you have individual surgeons performing these surgeries, it’s hard to have a large dataset that you can look at across the nation.
We definitely appreciate that those patients who have had a radical hysterectomy, either open, laparoscopic, or robotic, have a risk of recurrence, based on different factors.
Based on the rarity of the disease, what we believe to be the standardization of the technique, as well as different risk factors for recurrence, it would be hard for any one person or any one surgeon practicing to really notice an uptick one way or another.
We can mitigate some of that risk with the addition of radiation therapy, chemotherapy in the postoperative setting, based on pathologic risk factors, but even those patients have a subsequent risk of recurrence—therefore, they get surveillance for an extended period of time.
So, in a surgeon’s mind, like I said, you think that your approach is such that your surgical technique, dissection plans and margins are equivalent laparoscopically, robotically, and open, or else you wouldn’t even do that surgery. And so, in your mind, you’re more considering a radical hysterectomy in a patient that had a cancer.
We have standardized recommendations for how we treat those postoperative patients or how we don’t treat them, based on what the pathologic risk factors are. And, even in those patients, we understand there’s a risk of recurrence that we’re going to continue to follow these patients.
Based on the rarity of the disease, what we believe to be the standardization of the technique, as well as different risk factors for recurrence, it would be hard for any one person or any one surgeon practicing to really notice an uptick one way or another.
I’m bringing this up because I’ve written extensively about a former standard of care in a related setting. The debate over power morcellation, for instance, didn’t land on the scene as a beautiful double-blind phase III prospective RCT in NEJM. It was a process where gynecologists first responded to patient reports, and realized after the fact that, “Shucks, we’ve got to look at our risk estimates and prevalence rates for occult or missed uterine malignancies.” Do you see any similarities or differences here, from a big picture perspective?
JK: I think with the uterine morcellation, what we’re dealing with, very similarly is a relatively rare phenomenon in a leiomyosarcoma.
Right, or any other kind of hidden uterine malignancy, be it endometrial sarcoma, cervical or otherwise.
JK: Exactly. So, I think when we went back and looked at the data, there was a concern about the quality of the care that was being provided to some patients.
When you look at the uterine morcellation data, there was a large subset of these patients which had an incidental finding of an endometrioid adenocarcinoma, meaning, one that could be found in the endometrium, which would’ve been known about if you had sampled the patient preoperatively.
What that was, was a marker for saying, “Hey, I don’t know these patients are properly taken care of preoperatively,” and therefore, what we’ve done is increased their risk of morcellating an occult malignancy.
I think, here, we can also appreciate that 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. 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…
Right, it wasn’t in the design of the trial.
JK: Exactly. And this doesn’t take away the risk that some people incurred, but the majority of patients did well in both arms.
And so, what you’re trying to find out is, why this subset, specifically in the minimally invasive arm, did worse. And the thing that we don’t know is the variables that would be different between the two surgeries.
If we say we have a randomized controlled trial, and you only switch one variable, and that is the approach to the surgery—that’s one thing—but that wasn’t the case in this trial, because in those that had the minimally invasive surgery may have had, and I’m sure had a uterine manipulator placed.
But that’s not something that you would’ve done in an open case. And so, we now have a variable that is uncontrolled for in a randomized controlled trial. That can one potential cause, that you’re seeding the pelvis and/or apex of the vagina by manipulating this uterus with a tumor—or the cervix with a tumor—intraoperatively.
There’s some thought about the potential effect of the gas during a laparoscopy or robotic surgery, however, when I looked I don’t think there was an increase in abdominal or peritoneal metastases.
The increase was predominantly in vaginal and pelvic metastases—a potential role for this uterine manipulator seeding the peritoneal cavity, or seeding the vagina intraoperative.
I might be hypothesizing here, but unlike malignancies of the body of the uterus, here, we have an epithelial cancer that likely presents an immediate risk of being exposed to other tissues intraoperatively. Has the gross presentation of the tumor been a concern here when using minimally invasive procedures?
JK: Maybe to give some historical perspective to this, going back to the endometrial cancer. What you had is historically, you worried about positive peritoneal cytology associated with endometrial cancer, possibly through efflux of this tumor tissue through the Fallopian tubes into the peritoneal cavity.
But what we have was a lot of patients getting a hysteroscopy in a dilation and curettage, preoperatively, to make the diagnosis. Or place the uterine manipulator preoperatively before laparoscopic or robotic approach, and what you saw was an ability to kind of iatrogenically create a positive peritoneal cytology, but without any impact on the patient’s outcome or her stage, such that even now, the most recent staging system for endometrial cancer, no longer takes into account positive peritoneal cytology. And so, that may be part of the process that was going on with practicing gyn-oncologists.
Another thing that was going on is that majority of your cervical cancers are going to be squamous cell, and so the route of spread of these tumors, preferentially, is by contiguous growth, and so you’re going from one structure to adjacent structures. Now that can be from the cervix to the vagina to the bladder to the rectum, but preferentially, it would rather spread locally. And so, that may be an impactful factor in people’s either concern or lack of concern about possibly using a uterine manipulator.
A distant second would be lymphatic. All those things may impact kind of people’s perception of the natural history of a squamous cell cancer, and the potential ability or inability to cause a seeding of this with a uterine manipulator.
But I think it’s definitely something, in retrospect—and I don’t know what Dr. Ramirez said—that they would’ve liked to have controlled for, I suspect.
With these findings, are there subsets of patients for which the minimally invasive approaches can still be used without increasing the risk of adverse oncologic outcomes? And if these subsets exist, and the results are efficacious, what kind of adequate protections need to be put in place to prevent seeding of malignant tissue?
JK: Honestly, one of the benefits of this study is, in America, we have over 10,000 women with cervical cancer, about 4,000 dying of cervical cancer each year—for the most part, entirely unnecessary.
Obviously, we’re not doing a good job of either talking about this or getting people access to care, and so, I think this is a way of hopefully bring this disease to the forefront of conversation, and if it happens this way, so be it, where we can talk about cervix cancer is and how we treat it, and then come up with a standardization so that we can ensure the greatest outcome for these patients.
But, I think in order to do that, we have to kind of balance the risk of a laparotomy with that of a laparoscopy in the short and long-term, as well as the oncologic risk, and find out how we can reduce that oncologic risk, but it’s not going to happen without knowing the cause—and I think that’s where we need to have more studies.
Hopefully, they’ve got some data looking at the use or non-use of the uterine manipulator and can look at that kind of an ad hoc or retrospective manner of this prospectively selected data. And so, that will be interesting if Ramirez has any plans on doing that going forward.
Also, I know MD Anderson and a number of other academic centers are ending this procedure for cervical cancer as we speak—based on both equivalent short-term outcomes and the disparity in long-term cancer outcomes, as I understand it. What is Penn State doing about this? And what do you think should the next steps for hospitals everywhere?
JK: I think minimally invasive surgery still has a role. I do. I don’t know that majority of places are going to take the same approach on putting a moratorium on minimally invasive approach for cervical cancer. I don’t think that’s going to be the case.
I think minimally invasive surgery still has a role. I do. I don’t know that majority of places are going to take the same approach on putting a moratorium on minimally invasive approach for cervical cancer.
For some of the same reasons that we talked, as well as, if you looked at the recurrence, you can see that a majority of them were in this IB1 stage. I didn’t really see a difference or that many had a IA1 or IA2, so I think we can hopefully safely still do a minimally invasive approach.
I think that there’s some still unanswered issues regarding all the recurrences that were limited to 14 of the 33 sites, which is a little bit odd, in that you would think that these would be dispersed a little bit greater, so I’d be interested in seeing when these sites enrolled patients and how many were done at each site. There are also other variables in that being the surgeon, the site, the uterine manipulator, and other things.
The other issue that comes up is that a majority of patients in the “minimally invasive approach” was via laparoscopic approach. I think a lot of surgeons have assumed a more robotic-based approach, which hopefully, you can mimic more readily the open approach, whereby you have two hands operating simultaneously and surgeon autonomy—that also is going to kind of temper people’s haste to totally abort a laparoscopic approach.
Did I miss anything?
JK: No, I think it’s incredibly intriguing. I think it’s the start of an ongoing conversation regarding how to secure best possible outcomes for patients with early-stage cervical cancer.
