Episode 7.7 Cord Prolapse, Radical Hysterectomy for Cervical Cancer

In this episode, Dr. Stuart Winkler returns to discuss new evidence about the risks and benefits of radical hysterectomy for cervical cancers. Also, for fun, we torture a Gyn-Onc with a four tips for managing cord prolapse. Also, we discuss a new commentary on activity restriction after gynecologic surgery.

00:00:02 Management of Cord Prolapse in Labor

00:11:01 History and Evolution of Radical Surgery

00:25:03 Recent Trials on Cervical Cancer Surgery

00:48:33 Activity Restrictions in Surgical Practice

Links Discussed

Retrospective cohort study of diagnosis-delivery interval with umbilical cord prolapse: the effect of team training

The evolution of mastectomy surgical technique: from mutilation to medicine

History of Radical and Reconstructive Surgery for Gynecologic Cancer

Radical hysterectomy and pelvic lymphadenectomy for the management of early invasive cancer of the cervix

125 years of the Wertheim operation. What next?

Radical hysterectomy and pelvic lymphadenectomy for the management of early invasive cancer of the cervix

Original film of the Okabayashi’s radical hysterectomy by Okabayashi himself in 1932, and two films of the precise anatomy necessary for nerve-sparing Okabayashi’s radical hysterectomy clarified by Shingo Fujii

Minimally Invasive Radical Hysterectomy for Cervical Cancer: When Adoption of a Novel Treatment Precedes Prospective, Randomized Evidence

Activity Restrictions After Gynecologic Surgery

Transcript

Howard 00:18

Antonia.

Antonia 00:19

Howard.

Howard 00:19

What are we thinking about on today’s episode?

Antonia 00:21

Well, today we have Stuart Winkler back to discuss some of the new data in the surgical management of early stage cervical cancer.

Stuart 00:30

Thanks for having me. I’m always glad to be here, guys.

Antonia 00:32

Always glad to have you. So he’s going to give us the history of radical hysterectomy and we are eventually also going to talk about the simple hysterectomy, but that’ll be for another day. But first we’re going to discuss four tips for the management of a prolapsed cord. So I don’t know, stuart, if you still take any OB call, or is this conversation going to be triggering for you in any way?

Stuart 00:57

Yeah, I feel like this is a little bit of a bait and switch. I thought I was here to talk about oncology, but I do actually take some OB call not as much as I used to, but I’m glad to review this and hopefully never have to use the stuff we’re about to talk about.

Antonia 01:14

All right. Well, let’s get into four tips and do we just jump in with anything that comes to mind. If you want to switch over and think about obstetrics for a few minutes and then promise we’ll actually get to your area, but our first tip is to not even have it in the first place. So prevent cord prolapse with safe amniotomy. Howard. Anything else to say about that?

Howard 01:34

Well, yeah, sure, for a lot of these things we discuss, it’s always going to be true that an ounce of prevention is worth a pound of cure, and I think one of the interesting things we do on this podcast is we sometimes reframe some myths and canards for our listeners. So in this case, some listeners might assume that the thing to do to prevent cord prolapse is to avoid artificial rupture of membranes for a patient who’s in labor to not have it to begin with, but in fact, spontaneous rupture of membranes, if anything carries a higher risk of cord prolapse than intentional rupture of membranes. As long as you’re being thoughtful about the way you perform the amniotomy.

Antonia 02:10

Yeah, I think it was often drilled into us in training that we shouldn’t break the water too soon, or especially if the fetus is too high in the pelvis, in order to avoid cord prolapse. And we constantly think about that as one of the possible outcomes of amniotomy. But of course it doesn’t mean that we should just never do it. If we need to augment or induce labor In general, we still have to take that risk of cord prolapse in some way, because we know the water will break sooner or later in some way, because we know the water will break sooner or later whether we do it or it happens on its own, because an on-call delivery with the membranes intact almost never happens. But if we use good technique when we’re doing an amniotomy, then we can give the patient the lowest possible risk of cord prolapse. So if she’s laboring on her own and the water breaks on its own, then the cord prolapse could happen and we’re not there to diagnose it or manage it right away and that would really be a much worse outcome.

03:16

And that’s not to say that cord prolapse is common with membrane rupture In general. If someone calls in and said their water broke, we don’t immediately think like come in right now so we can check if you had a cord prolapse or not. But it’s always in the back of our minds and we’ll tell them just come on in. We want to check you out at least and watch you in the hospital, even if we’re not going to intervene. So it’s always there. I’ve read a statistic and it probably varies by so many things, but the incidence is probably about one in 300 or so.

Howard 03:47

Yeah, and it might be higher in a patient who’s in induced labor or something like that anyway.

03:53

So obviously we do have to induce people for medical reasons, and those fetuses are often at a higher stage when the water breaks, either spontaneously or with artificial rupture.

04:02

So one thing, though, about when water breaks spontaneously it’s usually going to be during a contraction, and so therein lies the tip for this If the uterus is contracting, it’s pushing the fetus downward during that spontaneous rupture, which helps to prevent the cord from prolapsing. On the other hand, if you go in and break the water and not during a contraction and without any pressure, any fundal pressure and the fetus is at a high station, then the rush of water around the fetal head may push the fetus up higher, and then the cord may rush down with the evacuating water. Then the head slams the door, and now you’ve got a cord prolapse. So the key is to use some pressure from an assistant to hold the fetus and the fetal head engaged in the pelvis while you break the water, and you should be able to prevent most cord prolapses. You could even do it during a contraction too. I think we just don’t do that culturally because the woman’s uncomfortable, but if she has an epidural breaking water during a contraction is not a bad thing.

Stuart 04:57

Yeah, I think what you’re talking about. I do remember you, when I was a baby medical student, talking about this and mentioning something about the Bernoulli principle, if I remember right.

Howard 05:06

Well, ok, well, there’s a fun tidbit for our physicist listeners or any fluid dynamicists who are listening. But yeah, the point is that we can actually lower the risk of cord prolapse by having a controlled amniotomy. And just as important, or maybe more important is that we’re there at the bedside when it happens and we can identify it and act quickly if it should happen.

Antonia 05:26

Yeah, and another thing is if we’re rupturing because we want to monitor the baby internally with a fetal scalp electrode, then another thing I was taught is you can just use that tiny little needle poke to just make the tiniest rupture and have the tiniest flow at first, until you’re a little more confident that a cord isn’t coming at you.

Howard 05:44

It decreases that Bernoulli principle because the fluid escaping at one time is less. But still just hold a little bit of pressure if you’re worried about it being.

Antonia 05:52

Yeah, so you don’t have to waste an FSE if you weren’t going to use it anyway just to do it that way. Then the risk to the baby is going to be less if you do it in a thoughtful way. But it’s not zero. It’s never zero, and I think people feel bad when it does happen, especially if it happens immediately when they broke the water, rather than if it just had happened on its own.

Stuart 06:13

Yeah, yeah, for sure that happens. We don’t like to feel like we’re at fault, but sometimes we just have to take some risks to reduce risk overall.

Howard 06:23

Yeah Well, that’s analogous to augmenting vaginal births after cesareans by giving oxytocin. We do slightly increase the risk of uterine rupture when we do that, but on the whole we may decrease the risk of catastrophic uterine rupture, which is where the fetus or the mother are permanently injured, because by definition we’re giving them oxytocin in a hospital setting where the team is ready with a running IV, as opposed to having uterine rupture occur outside of the hospital or on the way to the hospital. So we do increase the risk of one thing, but we decrease the total risk of the really bad thing.

Antonia 06:55

All right. So that was the first tip is prevention. The next tip is routinely perform in situ simulations. So if you’ve ever had one of these happen, you might have been frustrated if it took a long time to get the cesarean performed, but this is the sort of thing that it occurs rarely enough. But if you have routine simulations in your unit that involve everyone that’s needed so that would include maybe anesthesia, lnd, nurses, the OR techs then that can significantly speed up the process and then make it feel like a familiar thing, like a well-oiled machine when it does happen in real life and all the people that are part of it will understand what’s going on. Sort of it’s like a code, a code situation.

Howard 07:38

Yeah, I’ll put a link to an article from 2009 where a group in the United Kingdom implemented an in situ simulation and education program and they cut the time for their emergent cesareans after a cord prolapse from 25 minutes to about 14 minutes in cases they had before and after their simulation drills. So, yes, your unit should think of this as a code and everyone should have an understood role to play and everyone should understand the very emergent nature of what’s going on.

Antonia 08:05

All right. Well, the third tip is maybe the most obvious one, but that is that someone should elevate the fetal head with their hand to relieve the cord compression.

Howard 08:14

Right, and it is obvious, but maybe not quite as obvious as it might seem. This is something that you need to teach your nurses or other providers or whoever might be doing this Maybe it’s your midwife, or even a student or resident but the hand should be completely inserted into the vagina, with the palm of the hand pushing the head up so that there is no pressure on the cord, or as little pressure as possible, and that person can often also give some feedback too, if they can feel the cord pulsating about what the fetal heart rate is, both for themselves to know if they’re doing a good, effective job of elevating the head to relieve cord compression, but also for the team, who may not be actively monitoring the fetus continuously while all this is going on and you’re running to the operating room.

Stuart 08:54

So do you guys mind if I tell a story?

Howard 08:57

Please yeah.

Stuart 08:58

So I think y’all are talking about all this stuff and, like my core, memories from residency are coming back to me. It’s been about 10 years, but I remember being a baby and seeing him on his hands and knees in her bed while we all pushed the patient back to the OR on a triage stretcher. This like four-second year hadn’t tied his scrubs on very well and obviously his hands were busy, so they ended up around his knees while we were pushing him through the hall and in the commotion he was just hanging out in the breeze but there was a kind nurse who took pity on him and threw a blanket over him to restore his decency again. So always be nice to your nurses, right? I guess he had developed a good rapport with them as an intern. So anyway, that was my introduction to obstetrics.

Howard 09:57

Tip 3A tie your scrubs tight.

Stuart 09:59

Yep.

Antonia 09:59

And look out for the bed riders, just check them, see if they need their underwear coming up or something. Okay, well, okay. So if that was to happen outside the hospital setting, then you can’t do that. You definitely can’t get to the OR quickly and have someone holding the baby up like that. So a lot of books will actually talk about putting a Foley catheter in the bladder and backfilling it, or maybe just at least putting the mother in a knee-to-chest position with her head below her hips, and I suppose that makes some sense. But that’s still not going to be as good as someone manually elevating the head. You’d have to put a lot of fluid in the bladder, probably more than it should hold, to significantly elevate the head, and that might not work well anyway if the uterus is contracting down in active labor. So manual elevation is key.

Stuart 10:53

Man, all this obstetrics talk is making me. It’s for the oncology part. So can we just get our last tip out of the way here.

Antonia 10:59

Okay, sure, Okay. Last tip is despite everything we just said, there are some situations where you may not need to do a cesarean. You should still deliver ASAP, but it might not have to be through the abdomen.

Howard 11:11

Yeah, so there’s really two situations.

11:13

So one is if the patient’s completely dilated and the head’s engaged, it may be an option to either reduce the cord and sometimes that’s easy when the cervix is dilated or just do an operative delivery if the head is sufficiently stationed.

11:26

I think in particular if she’s parous and the head’s engaged, then an operative delivery may be a good choice. But even if not, you can at least try to reduce the cord and let her push, assuming that you can successfully reduce it and she’s not going to need much time. Some of these may still need to be delivered abdominally because you can’t reduce the cord or the head’s just too high and you’re worried about either of those situations. Now the other opportunity is if we’re talking about a second twin that’s breech or even vertex sometimes, or transverse, and cord prolapse happens with ruptured membranes, maybe just after delivery of the first twin or something like that, and this is cured simply by breach extraction, perhaps even by internal podalic version of a cephalic second twin followed by breach extraction. If the second twin is in any position you can do that. But it should be unusual that in the case of a second twin that a cesarean is needed due to cord prolapse.

Stuart 12:19

So this is another situation, really, where simulation can be so helpful. Like you guys mentioned in tip number two, there are a lot of things that we can’t simulate, but these team-based approaches where we need to respond to emergency really can be simulated, and that’s really the perfect place for simulation in our training and our ongoing preparation for these patients.

Howard 12:42

Yeah, these things that happen once a year, and when they do happen, everybody needs to be ready.

Antonia 12:46

All right. Well, let’s move on to what you’re here for, Stuart the cervical cancer. So most of our audience probably is going to be involved in the prevention of cervical cancer through vaccination, screening and treatment of dysplasia, and they’ll leave the management to the gynecologic oncologists. I doubt we have a lot of those as our listeners, but I’ve been hearing buzz about less radical surgery now being an option potentially for some cervical cancers. So what do we need to know about this?

Stuart 13:19

Yeah, that’s a good question and I think we can have a really good relevant discussion about this that hopefully all of the listeners can benefit from. I think to really understand where we are with this, we’ve got to understand where we’ve been and why. So I think this might be a good time to take a little trip through history. What do you guys think?

Howard 13:37

Well, before you tell us more about radical surgeries, history, I’ll briefly talk about simple hysterectomy, and maybe we can do more about this later when we talk about simple hysterectomy, but the earliest hysterectomies were done mostly for prolapse, as you can imagine, or just some mass that came out down through the vagina. Maybe it was cervical, maybe a prolapse polyp, but something you could see easily, and these go back for a while. Most of these surgeries before 1500 led to the patient dying, but we have cases going back as early as 50 BC, and surgery, though, didn’t really come of age until 1500 and later, and the big difference starting around 1500 was that there was just better knowledge of anatomy that led to more careful surgeries, but we still didn’t have many of the things needed to do surgeries like a hysterectomy, even basic things like suture or certainly many of the instruments, but still folks would operate again either on a uterus that was exteriorized due to prolapse and usually because their anatomy or tools weren’t very good, they’d leave a bladder or ureter injury or some mass growing off the cervix, and the outcomes were usually very poor. Surgery really came of age in the way we think of it now in the 19th century, and the main interest for us here was related actually to cervical cancer. These often started out as attempts at just cervical amputations or trachelectomies, but eventually ended up being either unintentional and, eventually, later, intentional hysterectomies. So you start cutting at the mass and before you know it, you’ve taken the whole uterus out, not realizing it’s what you were trying to do. The first of these was done by an Italian named Palletta in 1812. Mortality was very high and, again, many of these patients had cervical cancer. Anyway. We know of only three survivors out of 30 authenticated cases that occurred before the year 1830.

15:21

There was also no anesthesia and, of course, there was no antibiotics and no sutures that you could leave inside the body. If you tied something, you had to remove it. Finally, though, on April 6, 1850 in Augusta, Georgia, a man named Paul Leib did the first intentional vaginal hysterectomy for malignancy in the United States, and of course that malignancy was cervical cancer. Now, none of these would be what we would call a radical procedure. Surgery really got better, though, after the development in the 1850s of anesthesia as well as, eventually, antiseptic and then aseptic techniques. We got a lot better instrumentation, and by the 1880s and 1890s we really did enter the modern age, even though we still had antibiotics and other things to go. But, stuart, you’re going to talk more about the radical technique and its history.

Stuart 16:04

Yeah, yeah. So gynecologists are really great innovators. I know we talk about that a lot on this podcast, but when it comes to the approach to radical surgery, we can’t take the credit or maybe the blame for that initial philosophy behind surgical radicality. Now I know we have an actual Latin scholar in our midst, but from what I remember from my brief and unsuccessful study of Latin in high school, the word radical comes from a Latin word for root, so radical surgery aims to get at the root of the tumor or the cancer. And at least some of the surgical philosophy comes from the history of surgical treatment of breast cancer.

16:44

So we’ve all heard of William Halstead from Johns Hopkins and while he wasn’t the first to perform a large end block or section of the breast, he was famous and influential and was obviously at a large institution and promoted the use of this radical surgery.

17:02

And he lived at a time when there was some emerging knowledge of antisepsis and anesthesia and it actually made these aggressive surgeries more feasible.

17:10

So in 1894, he published a case series of his radical mastectomies and he promoted these as operations to cure cancer.

17:19

In the Halstead Radical Mastectomy the surgeon removed the entire breast, the skin and the surrounding tissues in block, along with the underlying pectoralis major muscle, and this really became the standard for over seven decades and this was developed in this dogmatic environment. And in this same environment came the first radical hysterectomy, also done at Johns Hopkins. Just as an aside to you before we go on with the hysterectomy, also done at Johns Hopkins, just as an aside to you before we go on with the hysterectomy. Eventually there was a surgeon who’s a fascinating surgeon named Bernard Fisher and he questioned the radical mastectomy and this was in the 60s and 70s and he was under a ton of criticism for doing this, but he performed some of the earliest randomized clinical trials to answer the question of radical versus less radical breast surgery in select breast cancer patients, and that’s where we get the lumpectomy radiation approach that we use some nowadays. So that was the approach to breast surgery, but we can talk more about the gynecology approach next.

Antonia 18:18

Okay, so just to sum that up, you’re saying that the radical end block mastectomy showed no benefit over less radical surgery in terms of breast cancer outcomes.

Stuart 18:31

Yep, that’s true.

Antonia 18:32

Is this maybe a premonition to what you’re going to talk about here? You?

Stuart 18:36

got it.

Howard 18:37

Okay, great yeah it sounds like that’s going to be a recurring lesson. So yeah, let’s get back to gynecology. That’s going to be a recurring lesson. So yeah, let’s get back to gynecology. As you mentioned, in 1895, it was John Clark who performed the first radical abdominal hysterectomy as a resident under the direction of Howard Kelly at Johns Hopkins. Howard Kelly, stuart and I have a big interest in, but today he would be a gynecologic oncologist. That’s where his work really would have taken him At this time.

19:01

In the early years of residency training, gynecology residents also spent a lot of time in the pathology lab In the studying specimens from hysterectomies performed for cervical cancer. Clark figured out that the margins were often positive for disease, especially in the upper vagina and the parametria. So he devised and executed an abdominal approach that allowed the removal of the pericolpos and the parametria on block. And shortly thereafter in Europe, Ernst Wertheim developed a more radical approach and incorporated removal of enlarged pelvic lymph nodes. And in one of the great rivalries in the history of gynecology, especially at that time, Friedrich Schauta developed a vaginal approach to radical hysterectomy that was heavily criticized by Wertheam, or we can say, Wertheim, if we want to be Americans.

19:47

In the pre-antibiotic era the mortality rate for radical surgery was well over 10%. So Schauta tried to minimize this by avoiding an abdominal incision. So this meant that he did it vaginally, but he couldn’t easily assess the nodes or explore the rest of the abdomen or even see the peritoneum that well, or the peritoneum of the pelvis. There was a real debate in this era about whether abdominal or vaginal surgery was better in terms of avoiding infection Remember, no antibiotics and so it’s interesting to see how this played out between these two men. But it was an era of big personalities and a single surgeon’s experience, without controlled trials, were used to answer many of these important questions. Howard Kelly, of course, was very influential in the country at that time and pointed towards big abdominal incisions. That really shoved gynecology in America away from vaginal surgeries and was very much on the abdominal side of these abdomen versus vagina debates.

Antonia 20:41

And then radiation therapy came about and probably paused further refinement of radical surgery, at least for a few years. And we know radiation can be very effective for cervical cancer. But in the early years of its use it wasn’t always employed in the most optimal or scientifically rigorous manner. It was thought to be a cure-all and it was even used to treat fibroids and other benign conditions, which we obviously don’t do anymore. But around the time of the Second World War, with advances in anesthesia and antisepsis some of it came actually from like the battlefield there was a renewed interest in the surgical approach.

Stuart 21:27

Yeah, that’s right. So in the era after World War II, around 1955, Joe Meigs, who is famous for Meig syndrome, which is not a female eponym, unfortunately. I was looking for it but couldn’t find any for this episode. But he expanded the operation and occluded all pelvic lymph nodes and he published his experience with almost 500 cases. And remember, while the breast surgeons were conducting trials on less radical surgery in the 60s and 70s Hervey Averitt, felix Rutledge and some of the other founders of modern gynecologic oncology in the US who were really like the grandchildren of Howard Kelly from an education standpoint, but they were doubling down on radical surgery for local advanced disease. Around this time, piver, rutledge and Smith described their five types of hysterectomy that most of us probably remember learning as residents.

Howard 22:19

When, of course, the United States and Europe weren’t the only places that were developing techniques for radical hysterectomy. In Japan, okabayashi developed modifications of the Wertheim procedure that allowed for even more radicality by further developing the perimetria and the vesicle-uterine space to get even more lateral and larger vaginal margins than even Wertheim had described. Incredibly, some of his original surgical videos from 1932 have been discovered and we can put a link to those in the show notes. Now, a big problem with these wide, deep margins is the disruption of the autonomic nerve supply to the bladder. That includes the hypogastric nerve, the pelvic splanchnic nerves and the bladder branch from the inferior hypogastric plexus. To minimize this damage, kobayashi modified Okabayashi’s approach and developed a nerve-sparing radical hysterectomy, and this approach is less radical in that it preserves the deep and lateral parametrium where those autatomic nerves run.

Antonia 23:15

This brings me back to one of my oncology attendings in training who is so fond of these Japanese radical hysterectomy videos and she would describe them to me during our surgeries and show me the technique and explain how they were very slow in these videos and she was also very slow in her technique, almost like a meditative process, and I’m not sure how much that was her versus the Japanese surgeons. But I enjoyed it because it was just this really straight geeking out over surgical technique. That was just so much fun. Anyway, my fond memories of oncology.

23:55

So the other big change since inception of radical hysterectomy so far has been the rise and fall of the minimally invasive approach, at least for cervical cancer. So the minimally invasive approach was very popular for some decades, especially with the rise of the robot. But the LAC trial published in New England Journal about five years ago reported a higher cancer-related mortality in the minimally invasive group compared to the open group. And this kind of fell right after I was done rotating through oncology. So I had gotten to do well assist in all of these robotic hysterectomies for cervical cancer. But then really the MIS radical hysterectomy has now fallen out of favor for that indication but I hear there might be some more to it.

Stuart 24:44

Yeah. Yeah, we’re awaiting the outcomes of a trial that looks at more stringent inclusion criteria and uses just an exclusive robotic approach, so it’s called the ROC trial, and hopefully we’ll be able to talk about those results here in a few years, we’ll have you back on in about four or five years.

Howard 25:00

Sounds good. I’m always glad to be here.

Stuart 25:02

All right. So we’ve given the big picture story of radical hysterectomy. So, from John Clark at the PATH lab at Hopkins up to the current day, now we need to talk about what’s changed very recently, like in the last two or three years. What’s interesting is that the origins of these recent trials looking at less radical surgery actually they also started in the PATH lab. So retrospective data shows that the risk of vaginal and paramecial involvement is very low in patients with certain low-risk features. And so this kind of begged the question do we really need these radical procedures for these patients who have low preoperative risk of paramecial and vaginal involvement?

Antonia 25:43

That’s really great. Some early cervical cancers do have a low rate of positive parametria or vaginal margins on the histology, but, as we know, it isn’t good enough for change in practice to just be biologically plausible, so it would have to be tested right. So do you have some data?

Stuart 26:03

I do. I do so. There’s a couple of important trials that we’re going to talk about that support the use of less radical surgery for locally advanced cervical cancer, and I’ll give you the condensed version of each. So first we have the CONSERV trial, which came out of MD Anderson at Houston and this was published in 2021. And it was a prospective single-armed multicenter trial and it was to evaluate the feasibility of conservative surgery in women with early-stage, low-risk cervical cancer.

26:34

So these risk factors are really important and they were actually based on patients who had a conization of the cervix. So you had to have a cone to get a study, as favorable risk factors included squamous cell carcinoma or grade 1 and 2 adenocarcinomas. So in other words, you couldn’t have high-risk histologies like merendocrine or other high-risk types. The tumor had to be two centimeters or less no lymphovascular space invasion and then the depth of invasion had to be less than or equal to 10 millimeters. The margins on the cone needed to be negative and then also they added negative imaging for metastatic disease.

27:15

So for women who desired fertility, they had a pelvic left out dissection only and this was remember after the colonization. For those who didn’t want fertility, they had a simple hysterectomy and a pelvic rubber dissection. There were 100 patients enrolled in this trial. Out of all these 100 with these low-risk criteria, 5% had positive lymph nodes and 1 of the 40 patients, or 2.5%, had residual disease in the hysterectomy specimen after a cone with negative margins. The two-year recurrence rate was 3.5 percent and none of these were in the cold knife cone group with the plain, simple hysterectomy and methamphetamine.

Antonia 27:56

Okay, I did actually peek at this study and it’s quite fascinating. And in case any of our readers look at it, I just want to address a couple unexpected findings that caught my eye, even though they might really just be red herrings here or just random bad luck. Firstly, a patient died after a lymphadenectomy from a post-op DVT, so that made the death rate in the study higher than what it really is. They obviously didn’t focus on that. That’s just something that can happen, probably bad luck. And then there was a second patient who had severe hemorrhage after a cone. That required transfusion and return to the OR.

28:31

The other anomaly was that there was a group that they called the inadvertent simple hysterectomies. So that meant that there was a group of patients who hadn’t initially met the cancer diagnosis criteria before they got their hysterectomy. So they got an indicated simple hysterectomy but then on that pathology they had an unexpected diagnosis and were then enrolled after the fact for subsequent pelvic lymphadenectomy. So that group had 16 patients and two of the cancer recurrences were in that group. And then the third cancer recurrence was in the fertility sparing group following a cone with no hysterectomy. So what do you make of that, of those recurrences?

Stuart 29:14

suspected, or at least based on the pre-op diagnosis. The authors did decal both cases. So one had AIS with negative margins on a cone, which was perfectly appropriate for a generalist gynecologist to take on, but her hysterectomy showed a grade 2 adenocarcinoma, again with negative margins and negative nodes. Nonetheless, she had a metastatic recurrence within a year and despite chemotherapy she unfortunately died of this cancer about six years later.

Howard 29:49

So her starting pathology was adenocarcinoma in situ right.

Antonia 29:53

Yeah, with negative margins on a cone.

Howard 29:55

But you’re saying, despite all that and obviously we sometimes do interventions for things because we see something, react to it and we want to prevent everything but we don’t have control over everything but you’re saying, despite all that, it’s still appropriate for her generalist to do a hysterectomy for AIS. I know that’s what the learners are asking here, or your learners are asking in residency and in training, and what our reactionary listeners want to hear. Ais is okay for the generalist.

Stuart 30:21

Yeah, I guess I don’t have to get your email so I can say what I want here. So, yeah, this is just a quick review for the residents. But about 2% of patients with AIS and negative margins on a cone will be diagnosed with invasive cancer. We remember that AIS and adenocarcinoma can be associated with skip lesions, and that’s just thinking about the spacing between the glands. But the other 98% will not be diagnosed with invasive cancer. So some of this depends on your local practice patterns in your community, but it’s not necessary to send every AIS patient to Gyn-Oncs for their hysterectomy when there’s negative margins, again, 98% of these will be benign.

31:04

So the patient in this study unfortunately was one of the unlucky 2% and there’s unfortunately a risk of malignancy with everything you do. There’s a missed diagnosis risk too with an endometrial biopsy. So these things do happen sometimes. It’s also notable that her recurrence didn’t involve a parametria, so it’s unclear whether a radical hysterectomy by an oncologist would have changed her outcome. Nonetheless, in this study they actually stopped enrolling these patients who had inadvertent cancer diagnoses after the hysterectomy because of the unexpected high rate of recurrence for them. So for now they concluded that more research is needed to see if someone with maybe just a precancer in their cone and then a real cancer on hysterectomy might benefit from either a different approach or going back and doing post-hysterectomy paramotrectomy, which is not a fine case, by the way.

Howard 31:55

She still came back and got lymphadenectomy after that discovery, which would be what your resident should do when they find that.

Stuart 32:08

Yeah, and lymphadenectomy I think is reasonable. We’ll talk about this too with the next paper. But the risk of lymphedema involvement is actually higher in a lot of these cases than parametrial involvement, but particularly certain histologies are more prone. So that’s a good point to make.

Antonia 32:21

Well, it was so good to see that this single-arm study showed some promise for a conservative approach to managing early-stage cervical cancer. Did they also talk about pregnancy outcomes?

Stuart 32:33

Yeah, they did. So they didn’t really have a clear denominator on how many women in the fertility sparing group attempted pregnancy, so we don’t really know that piece. But 11 of the 40 women had a cheat pregnancy and 90% of those delivered at a term.

Antonia 32:48

That’s really good for having had a cone. So what about level one data?

Stuart 32:54

Right. So the conserved data suggests that a cold knife cone with nodes or simple hysterectomy with nodes may have favorable outcomes, but the standard of care is still a radical hysterectomy for local against cervical cancer. But what about radical hysterectomy versus simple hysterectomy? So this is where we need to talk a little bit about the SHAPE trial. This was just published by Mary Plante in the February 2024 New England Journal of Medicine. It was a randomized, controlled non-inferiority trial, so it had to have England Journal of Medicine. It was a randomized, controlled non-inferiority trial, so I had to have a lot of patience.

Howard 33:29

Yeah, let me speak for a minute about non-inferiority trials, because we see a lot of those today published and I’m not sure everyone understands what they are or why they’re done sometimes instead of just a randomized controlled trial or particularly a placebo controlled trial. But a non-inferiority trial is a type of clinical trial designed to determine whether a new treatment is not worse than an established treatment by some pre-specified clinically acceptable margin. Now it’s important here. You’re not necessarily expecting it to be better, it’s just not inferior. That’s an important part of this. So it aims to show that the new treatment is not inferior to the existing standard of care by more than some predetermined amount.

34:09

These trials are typically conducted in situations where it might be unethical or impractical to conduct a placebo-controlled RCT.

34:16

They’re often used in scenarios where the new treatment is expected to have benefits though, such as reduced side effects, improved convenience, maybe lower costs, something like that compared to the standard treatment, but it’s not expected to be significantly more effective, just not worse, with maybe some upsides. So these trials are often done because an RCT again would be unethical, because it might mean withholding standard therapy from a patient, or when it’s just impractical or infeasible to randomize patients. Patients aren’t going to be expected to consent to randomization, particularly if they know there is a placebo group or some new therapy that they’re not comfortable with or just expense. So this particular study was a randomized trial, but there was no placebo arm, of course, and you can think of it like an RCT in this case. But statistically it’s not designed to show superiority of the new intervention, just that the new intervention is not inferior in terms of some important outcome and maybe it’s better in terms of cost, side effects, surgical complications, whatever you might have. But equally efficacious is the expectation.

Stuart 35:25

Yeah, thanks for that explanation. I think it was really helpful for our listeners. So I’ll talk about the SHAPE trial now. So it was 700 patients, so again a large study. 700 patients were randomized to a simple hysterectomy plus a lymph node assessment, versus radical hysterectomy plus a lymph node assessment. So just to emphasize, don’t forget the node piece here. So this isn’t just a simple versus a radical hist, which is how we talk about this trial shorthand, but both arms gathered lymph node assessment as well. The inclusion criteria were pretty similar to CONSERV, but they did allow levovaspo, space invasion and grade 3 adenocarcinoma. So it was a slightly higher risk rate in these patients, just a little bit.

36:08

The tumor still had to be less than 2 centimeters, and this is an important piece. A surgical manual is included in their protocol, but basically a radical hysterectomy was defined as a Rutledge type 2 or a Quailer-Morrow class B. There’s some nuances here, but for all intents and purposes these are basically the same thing. The surgeons removed the uterus, the cervix, the medial third of the parametria, two centimeters of the uterus, sacral ligaments in the upper one to two centimeters of the vagina, lymph nodes could either be a full lymphadenectomy or sentinel lymph nodes. The surgical approach could be open or conventional, laparoscopic or robotic-assisted. So, of note, these patients were accrued from 2012 to 2019. So a couple of things. First of all, we were using the old phyto-staging for cervix, which is different than the 2018 version, and then, second, the LAC trial hadn’t been published. We mentioned that was published in 2018. So in the LAC trial we know about half of those patients had tumors larger than two centimeters, so that was a higher risk group. But we’ll talk about how to maybe dovetail that piece into this here.

Antonia 37:17

Okay, well, show us the data.

Stuart 37:19

Okay. So for the primary outcome of three-year pelvic recurrence, the study did meet. Non-inferiority Recurrence was seen in 2.17% of patients in the radical hysterectomy group and 2.52% of patients in the simple hysterectomy group. So the three-year pelvic recurrence rate was really low in both groups. The three-year pelvic recurrence rate was really low in both groups. Now, interestingly, the authors actually changed the primary outcome from pelvic recurrence-free survival to just pelvic recurrence after the sample size was calculated, because the number of events was so low it was lower than they expected. This was before the data was unblinded, so this is a hiccup in the study analysis, but sometimes this happens when you’re studying low event rates.

Antonia 38:08

So is this trial practice changing yet?

Stuart 38:11

Yeah, I think it’s a really interesting trial and I think it probably will be practice changing Maybe not quite yet. I think there’s still some questions. It’ll be nice to see some follow-up data on overall survival in these patients. Even though these trials aren’t powered for this and you can run into issues with patients who are lost to follow-up, it can give you a better longitudinal picture of their benefits and harms.

38:36

We’ve learned that lesson, unfortunately, where we’ve changed practice too soon without waiting for the overall survival data. There’s a lot, lot of examples, but most recently within the last year, we had some changes in FDA approval for use of PARP inhibitors in the treatment of ovarian cancer. We no longer use it for treatment, even though we use it for maintenance. That was based on some updated overall survival data. So this is tough. We want to try to provide the most cutting edge thing for our patients, but I think we have to be careful not to harm our patients in the meantime while the data is still on the shore. So again, short-term data is promising, but I think the overall survival follow-up for this will be important.

Howard 39:18

Yeah, we make mistakes a lot. We discuss that a lot on here about using surrogate endpoints or outcomes. The endpoint we care most about is in this case is who’s alive and doing well, by some definition, at a given time point in the future. But that might be five, 10 years from now and that takes time. And for some diseases, overall survival is influenced by so many different factors or things that cross over that it’s hard to trace it back to a particular treatment. It takes a lot of patients over a lot of years to figure that out. So we’ll often use surrogate endpoints, like in the case of the study you mentioned. But unfortunately there’s a lot of data that surrogate endpoints don’t always correlate with overall survival, both in general medicine and in the things we’re talking about here. So we have to be really thoughtful about which surrogate endpoints we use in studies like this and, when reading studies, make sure that we apply it to our patient-specific factors.

Stuart 40:12

I think the other big question from this trial we alluded to this, but it’s what to do about the minimally invasive part. So about 70% of the radical hysterectomies and 85% of the simple hysterectomies were done laparoscopically. But it’s hard to justify an MIS approach now that we have the level one data from a LAC trial and I think it’s really convincingly demonstrated harm.

Antonia 40:37

Yeah. So it seems like we don’t really know everything that we need to know here yet. It seems like we don’t really know everything that we need to know here yet and I think, at least just as a mere generalist, I’d want to see the Marie Plante trial redone or continued, maybe post-LAC trial, so that we could see more numbers in the open hysterectomy comparisons the simple with nodes versus radical with nodes for cervical cancer. So maybe that’ll be something we see in the upcoming years, but nonetheless this is still. Maybe this can help us one day counsel our patients before we send them to the oncologist. I would always anything I would say, I would still say still defer to whatever the onc tells you whether it overrides me or not, Obviously they’re the final say.

Howard 41:26

Yeah, I think the question here would just be whether or not an open radical hysterectomy with nodes would be better than what will turn out to be a minimally invasive, simple hysterectomy with nodes, because that’s what we’re talking about in 2024. And if the listener doesn’t understand, the problem is that a significant portion of these cases in this new trial were minimally invasive radical hysterectomies and the reason why the LAC trial moved away from that is because there’s better outcomes. So now, if we’re talking about better outcomes from the open abdominal radical hysterectomies, which are not all of the cases in that trial, maybe that is. Maybe that wouldn’t hold up a non-inferiority study if we were comparing those two cases together. But I guess we don’t have the answer to that really.

Stuart 42:11

Yeah, I think it’s a great question. I think cross-trial comparisons are always hard. These are hard too, I think In oncology. A lot of times the standard of care will change while a trial is in progress, and so we run into this from time to time. I don’t know any current planned trials addressing this question right now.

42:31

I was just at the Society for Gynecological Oncology annual meeting in San Diego a couple weeks ago and I was actually listening out for this, but I didn’t hear anything. But you brought up some great points. Just a little more detail on the MIS piece too. I don’t know if it’s going to clarify it or muddy it, but it’s something to point out again with the LAC trial. The LAC trial was actually split about 50-50 between tumors that were less than two centimeters and tumors that were two to four centimeters, or now what we would call stage 1B2s. It’s a different stage in that trial. So in the less than two centimeter half they experienced only six of the 40 observed recurrences. So put another way, 85% of recurrences in the LAC trial were in tumors greater than two centimeters, which were not even included in the SHAPE trial.

43:20

So there’s supposedly another paper that the plant data is going to be presented with. It’s going to be post hoc and it’s going to look at the MIS versus open group. They didn’t have that at this talk. I was hoping they were going to present that, but you know we have problems with post hoc data. Right, they’re hypothesis generating, but on subgroup analyses you have to be really careful, especially if you look at 20 different subgroups. Chances of you finding something are statistically pretty high. So I think you have to be careful with doing these post-op analyses.

43:54

The low event rate in the less than two centimeter group in the LAC trial means that another randomized trial would be required to precisely estimate this risk in women with small tumors, and that would be again a lot of patients. Like I mentioned before, there’s this other non-inferiority trial called the ROC trial that’s currently accruing, and because only 16% of radical hysterectomies in the MIS group in the LAC trial were done with the robot all the others were conventional laparoscopy there is some question about whether the platform might allow the surgeon to be more precise or lead to better oncologic outcomes. We really don’t know this without a trial. So the ROC trial also includes tumors that were two to four centimeters. They tried to mirror their LAC trial inclusion criteria as much as they could, but we’ll have to await these results in a few years to still accrue patients on this trial.

Howard 44:45

All right. So for now, just to summarize real quick. I think most people will still continue to do radical hysterectomies in this context, although it wouldn’t be unreasonable for somebody to weigh the risks and benefits for a particular patient with a low-risk cancer and avoid a radical hysterectomy. Stuart, just real quick for the listeners. What’s the benefit to a patient of having a simple hysterectomy over a radical?

Stuart 45:09

hysterectomy. Yeah, so there’s actually a GOG trial that just presented and the primary endpoints on that trial were really patient-reported outcomes. So we know that with radical hysterectomy there’s more bladder dysfunction. It could be up to 20% at one year. So avoiding dysfunction issues with bladder. Length of stay is longer, risk of ureter injury is higher. So there’s short-term injury but then there’s long-term damage to the bladder and surrounding structures that can really cause some issues and these are in young women. That’s part of the big thing about cervical cancer. With our agita treatment, when we give radiation to these patients, we usually cause radiation-induced menopause and can cause a lot of scarring in the vagina in a woman in her 30s right. And when we have surgical complications, same sort of thing. These are women who are hopefully going to live long lives and sometimes the treatment can be in some ways really damaging. So that’s where we want to try to avoid radical hysterectomy, where we’re not providing the benefit. So it’s really about tailoring that tool to the right patient.

Howard 46:18

All right. Well, we probably have time for one more slightly different subject, but one that Stuart will have some interest in. So we’ve talked before on here about activity restriction after hysterectomy, and these are benign hysterectomies for us, and the results of a couple of randomized trials we’ve discussed show that activity restrictions that have been commonly recommended after surgery really lack a scientific basis. But in the March Green Journal there’s a new narrative review of activity restrictions after gynecologic surgery that I thought was quite interesting.

Stuart 46:49

Yeah, so that narrative review showed that the results of some surveys indicate that most gynecologic surgeons still tell patients not to lift more than 10 pounds for eight weeks after a minimally invasive hysterectomy. So just by comparison, as far as weights and lifting and that sort of thing, a gallon of milk weighs about 8.6 pounds and many common items like women’s bags and purses and things can weigh nearly 10 pounds. So these restrictions really do limit women and potentially guilt-sanction them if they have a complication postoperatively. Many women may not even get necessary surgeries because they don’t know how to deal with the six weeks of activity restrictions, and I can imagine how this would affect women in lower socioeconomic status situations more so than some of those with resources. But yeah, howard, I’m interested. How do you tell your patients? What do you counsel them? As far as when you do vaginal hysterectomy? What do you counsel?

47:48

them about lifting restrictions.

Howard 47:49

Well, we’ve talked about that a couple of times before and a lot of the surgeries I do are for pelvic organ prolapse and they’ll have concomitant repairs and some of these studies are specifically in that population or those types of surgeries. But yes, I tell them to do whatever they feel like doing without any specific restriction other than penetrative intercourse and most of my patients they go back to work in a week or two and I’ve had some patients come to me who’ve told me that they put off surgery that they needed because another OBGYN told them that they would have to have this long time off from work and these restrictions. That just weren’t compatible and, as you said, they didn’t have short-term disability insurance or just the financial ability to take so much time off or have help with rather onerous restriction.

Antonia 48:33

Yeah, we talked about that as a thing we do without evidence or for no reason in a much earlier episode, I think episode two of season six. So if anyone wants to go back and review that and we discussed several trials and other forms of evidence that indicate that most of the activity restrictions are unwarranted- yeah, it’s a really good article.

Stuart 48:55

I think everybody, like Everett said, should look at it. But another good point they make is related to causes of complications that we see. So we assume that patients develop cuff dehiscence or hernia or future prolapse or recurrent prolapse all these sort of things due to activities. But the truth is many of these complications might be due to other issues like impaired wound healing or infection or hematomas, or even patient-specific factors related to collagen or neuromuscular integrity.

Antonia 49:25

I do want to bring up a couple of my own anecdotes and see what you think and I’m sure both of you probably have some with as many surgeries as you do. But my feeling is that these restrictions were never just pulled quite out of thin air. They probably were pulled out of anecdotal experience related to extreme cases.

Howard 49:44

Which is still not good evidence, but we can listen. That’s true, though right, that’s. What we discussed earlier is, people have some outcome and they have a reaction to it. Somebody bleeds after a dose of Toradol and then they decide that Toradol should never be given again, or whatever.

Stuart 50:00

And then they teach their resident that yeah Right. So we have to be careful that yeah Right.

Howard 50:03

Yeah, so we have to be careful with these sort of reactionary responses. We want to prevent things and when bad things happen we try to do. Even if we do a detailed root cause analysis, a lot of times we don’t know that what we come up with will actually make a difference in preventing it. But we want to hear your anecdotes.

Antonia 50:21

Well, and I was just thinking, in case there’s a listener who has some anecdote of their own in their head and they’re already thinking well, I’m not, I can’t listen to this. I have to tell my patients no lifting more than a gallon of milk. Maybe. Maybe they also feel like they’re the most junior person on their team and everyone senior to them really adheres to telling patients these restrictions. So what’s the point? So if you’re a trainee out there and your whole team is saying no heavy lifting for 12 weeks to every single patient, then we see you. This is one of the many things that are, I think, ingrained in the culture of medical practice, or at least surgical practice, and those things just don’t change easily. But but there are always ways to recuse yourself from giving advice or doing things that you know to be incorrect or contradictory to the evidence, even if you’re at the very bottom of the totem pole. So just own what you do. Start now, even if you’re just a med student, just a med student.

Howard 51:19

Well, that’s all very nice. That’s why you’re on this podcast, I think. Right but are we going to hear your antidotes? Okay?

Antonia 51:26

So I thought immediately of two cases of severe vaginal bleeding after a procedure that related in some way to activity or intra-abdominal pressure. One of them was within two weeks after a hysterectomy. She was an older lady, had multiple comorbidities, I think she was a smoker and diabetic and a bunch of other stuff, but she had a chronic cough and then she missed her initial post-op visit because she got COVID which I think added to her coughing. And then one day she just started acutely bleeding and it ended up being just from the lateral edge of her cough repair. She bled probably at least 500 milliliters that we estimated just after her arrival in the ER and then it just took a few stitches to repair and then we gave her some cough medicine. We just made the assumption that maybe it was the cough that started this.

52:16

And then my second anecdote was a younger, healthy patient who had had just a colposcopy in the office with a biopsy, and she was her husband was deployed in the military. So she her reported history was that she had been carrying a ton of groceries up the stairs by herself and then suddenly just started bleeding through her clothes. And then the ER doc was panicked and it did look like a lot of blood. I don’t know if it was quite 500. It was probably a little bit less, but it all just came from her one biopsy site that we cauterized in the ER, didn’t even have to stitch it. But then for her we said maybe you shouldn’t carry heavy loads for the next couple of weeks.

Stuart 52:56

Yeah, what do you think about that? No, those are good stories. Thanks for sharing no-transcript. That actually probably increases your abdominal pressure more than a lot of the specific restrictions that we give patients. So I don’t know if we always know, like the cause and effect in the individual patients. Although I will say just, I agree with your antidote about the cough. I feel like somebody who is coughing, coughing, coughing. That probably is extra pressure, but I don’t think I have specific evidence for that.

Howard 53:51

And of course, there’s not going to be a randomized controlled trial of prevention of coughing, or something like that.