Navigating Fertility-Sparing Surgery for Early-Stage Cervical Cancer

Podcast Transcript

Dale Shepard, MD, PhD: Cancer Advances. A Cleveland Clinic podcast for medical professionals exploring the latest innovative research and clinical advances in the field of oncology. Thank you for joining us for another episode of Cancer Advances. I'm your host, Dr. Dale Shephard, a medical oncologist here at Cleveland Clinic directing the Taussig Early Cancer Therapeutics program and co-directing the Cleveland Clinic Sarcoma program. Today, I am very happy to be joined by Dr. Michelle Kuznicki, a gynecologic oncologist here at Cleveland Clinic. She's here today to talk about fertility-sparing surgery for early-stage cervical cancer, so welcome.

Michelle Kuznicki, MD: Thanks, Dale. Happy to be here.

Dale Shepard, MD, PhD: Excellent, so just give us a broad overview. What do you do here at Cleveland Clinic?

Michelle Kuznicki, MD: Sure. I'm a GYN oncologist, so I treat patients with gynecologic cancers. I perform surgery for these patients, I help with administration of chemotherapy for these patients, and then I also follow them in the survivorship mode of their recovery.

Dale Shepard, MD, PhD: Excellent, so we're going to talk about early-stage cervical cancer. We're going to talk about surgery and fertility preservation, fertility sparing. A lot of different kinds of people listening in, different backgrounds. Let's start, we're talking about fertility sparing. Give us an overview. What does that mean?

Michelle Kuznicki, MD: So, I think it's important to review this, and thank you for that question. When we talk about fertility sparing, it really depends on the goals of the patient. Now, with current science, we have many ways of patients being able to start their own family so fertility sparing can be broken into different groups, whether we're discussing uterine preservation or ovarian preservation, and then whether we're discussing the preservation of eggs or the preservation of ovaries for hormonal purposes, and all of those methods are possible when we're treating patients with early-stage cervical cancer.

Dale Shepard, MD, PhD: Talking about cervical cancer, we're talking specifically early-stage. What would be considered early-stage cervical cancer?

Michelle Kuznicki, MD: For our patients that are best candidates for fertility sparing surgery, and early-stage, it's really what we consider our low-risk, early-stage patients, so these are patients who are typical histologic types of cervical cancer. Either squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma, and it's confined to the cervix so there's no evidence of parametrial spread, lymph node involvement, distant metastasis, and it's a relatively small tumor, so the best candidates with the lowest risk of recurrence after these fertility-sparing surgeries are those who have relatively small tumors, less than two centimeters.

Dale Shepard, MD, PhD: And when we think about sort of impact in numbers, how many people on average are diagnosed with an early-stage cervical cancer?

Michelle Kuznicki, MD: So, we say probably about a third of patients are diagnosed with an early stage, and in general, of all of our patients who are diagnosed with cervical cancer, a little over a third of them are of reproductive age, so this can end up affecting a large portion of our patients.

Dale Shepard, MD, PhD: Again, just more from a public service standpoint, thoughts on screening? Importance of screening to pick up early-stage cancers?

Michelle Kuznicki, MD: Oh, absolutely, and unfortunately, despite all of our resources, even in the US, we have a very large proportion of patients who go unscreened or underscreened, so we follow ASCCP guidelines for screening recommendations. No matter what specialty you're in, it's always great to make sure that patients are up-to-date on their screening, and encourage them to either follow up with their primary care doctor or their OBGYN to get up to date on their pap smear screening. That is the biggest risk of a patient that I see in my office who has a diagnosis of cervical cancer, is that almost all of them, universally, have missed some kind of screening in the past. Then with that, I also want to stress that the FDA approval for the HPV vaccine was recently extended to age 45, so this is approved for men and women from the ages of 9 to 45. It reduces the risk of multiple different cancers, as we know. Again, almost all the patients in my office who are diagnosed with cervical cancer, they have not had a history of this vaccine.

Dale Shepard, MD, PhD: So, vaccine screening. The easiest patients to treat are the ones that don't get cancer in the first place.

Michelle Kuznicki, MD: Of course. Totally agree.

Dale Shepard, MD, PhD: All right, so patient comes in, they need surgery. Historically, sort of independent of thinking about fertility sparing. What has been the approach to surgery?

Michelle Kuznicki, MD: Patients who are surgical candidates, again, are those who we think have a cervical confined disease, so at the outset, most patients will come to our office, they have a pathologic diagnosis with a cervical biopsy. Our first step is to do some imaging to determine the extent of disease, so if we have done a PET scan and ruled out distant metastasis or nodal mets, we have done an MRI and a very good clinical exam and ruled out any concern for perimetrial involvement, the tumor appears relatively small, and then we start talking about surgical options with patients.

Historically, that option was really limited to a radical hysterectomy, so that involves removal of the uterus, the cervix, the upper vagina, and the perimetrial tissue that surrounds the cervix. This is a very, very effective oncologic treatment for cervical cancer, but the problem comes in with the fact that they do do well and they have long survivorship after this cancer diagnosis. There are very high rates of bladder dysfunction, bowel dysfunction, sexual dysfunction after these radical surgeries, as well as the very real intraoperative and perioperative risks for these patients as far as fistulas, infections, bleeding, so this led us to start investigating lesser invasive types of management, and then as you can imagine, doing a full hysterectomy precludes that patient from being able to carry a pregnancy in the future so we've added this uterine preservation model to these less invasive possibilities.

Dale Shepard, MD, PhD: Excellent. So, what has been the biggest breakthrough from a surgical standpoint? Kind of a way to think through surgeries to minimize that morbidity to the surgery and enable fertility sparing?

Michelle Kuznicki, MD: Yeah. There have been a couple of big trials that have been presented and published recently. One was the SHAPE trial and one was the CONSERVE trial, so both of these investigate less radical surgery. One of them involves a simple hysterectomy. The other involves a simple hysterectomy or a cone biopsy, depending on the reproductive goals of the patient. Again, these really focus on this low risk cohort who seems to be a very good population to research these less invasive surgical options, so it appears that even with a simple hysterectomy, so that includes the uterus and the cervix, but not the upper vagina, not the perimetrial tissue, so we're avoiding all of that nerve damage and potential bleeding complications, surgical fistula risks. We're avoiding all of that by staying close to the cervix when we do our hysterectomy. It seems really that, for patients who are good candidates, the oncologic outcomes are very similar for those patients.

Dale Shepard, MD, PhD: People sometimes hear about terms and, of course, people are more familiar with hysterectomies, but a couple of things people might have heard about, just so we can kind of define what these things are? Trachelectomy or colonization.

Michelle Kuznicki, MD: These terms are when we have the same low-risk patient, and they have the goal of preserving their uterus for future fertility. We have the option of essentially removing the cervix. In the case of a radical trachelectomy, removing a small area of the upper vagina, and then performing a reunification, where the uterus is basically reattached to the residual portion of the vagina, so that would be a radical Trachelectomy. In that sense, we remove the cervix, the perimetrium, a small portion of the vagina, and we preserve the uterus, preserve the distal vagina. In the less invasive fertility sparing option would be a cone biopsy, which takes much less tissue, and essentially performs what we consider to be just a very large biopsy of the ectocervix and the lower part of the endocervix, and that preserves, ideally, a good part of the cervix so that if a patient becomes pregnant in the future, they have a much higher success rate of a live birth.

Dale Shepard, MD, PhD: Now, you were a co-author on a study that looked at sort of the use of these various procedures. Tell us a little bit about what that study was about.

Michelle Kuznicki, MD: Sure, so I performed a systematic review with a number of my partners, and we looked in the literature basically for all of the studies that presented on fertility sparing surgical procedures that included recurrence rates, and most of them also reported on pregnancy outcomes as well, so this included all of the approaches of a radical trachelectomy because, surgically, they can be done either by vaginal approach, minimally invasive laparoscopic approach, or open abdominal approach, and then it also included cone biopsies. Then lastly, which is not really something I think that is in standard practice right now, but probably is in the forefront of the future of research, would be patients who do have locally advanced or do have tumors that are larger than we would typically recommend for a fertility sparing procedure, and then giving them some neoadjuvant chemotherapy to shrink that tumor and make them a fertility sparing candidate. So, we looked at all of these studies and made a conglomerate of all of the outcomes to try to summarize what the oncologic outcomes were, recurrence rates, as well as the pregnancy rates and live birth rates.

Essentially, all of the options, either radical trachelectomy by various approaches or cone biopsy, they have very good oncologic outcomes for good candidates. However, the pregnancy outcomes are much, much better with the less radical procedure, so either a cone biopsy or a simple trachelectomy. We're only removing the cervix, we're not removing all of that perimetrial tissue. Again, we had published this before the CONSERVE trial came out, but this is really the thought. That if we take these low-risk candidates, we have this really wonderful ability to do great imaging on these patients and really hone in on the patients who are low-risk. If they can do well with a less radical procedure, they can preserve their fertility, their quality of life, then this is really the direction we should be moving for these patients.

Dale Shepard, MD, PhD: Does that seem to be the trend, that there's more uptake for less invasive surgeries?

Michelle Kuznicki, MD: Yeah, absolutely. Last year, I published with, again, a number of my colleagues on the trends of these fertility-sparing surgery options, and it's definitely having a lot of uptake, so transitioning from a cone biopsy rather than a radical trachelectomy or radical hysterectomy, that's definitely being picked up more. I think something that really helps is that the NCCN guidelines have also been adapted to keep up with all of this, so cone biopsy, simple hysterectomy is listed on NCCN guidelines now for patients who desire less invasive options.

Dale Shepard, MD, PhD: It's great that NCCN sort of embraced that and recommended that, but as I recall in the study you did, it was still relatively little uptake. I mean, in terms of percentage of people that ended up with the least invasive surgeries. Do you think there was a reason for that? Was it sort of an appropriate based on risks for the patients, or is it something where either patients or providers are less likely to want to pursue that? What do you think is driving that?

Michelle Kuznicki, MD: Yeah, so to your point, in our systematic review at the time, there was a lot more robust data on the radical fertility sparing option, so radical trachelectomy. There was a lot of data dating back to the 1980s on that procedure, whereas a cone biopsy specifically for fertility sparing management, it was definitely a newer procedure that is being reported or has been reported in the past maybe five to 10 years as far as up taking that in general practice. I would say even since the time of my publication, a systematic review, the newer data with these prospective trials has really convinced a lot of people to change their practice.

Dale Shepard, MD, PhD: I mean, the reality is there's a lot of shared decision making, right? So, how much of this do you think is patient concern? "If I don't do more, it might be more likely to come back." How much of it is providers either being worried about that same outcome, or even technically not as used to doing the procedure? Who do you think drives more of those decisions?

Michelle Kuznicki, MD: I would say the patients, for sure, and it also may depend on the provider who is performing the counseling and providing the options, because sometimes patients aren't even aware that it is an option. So, it's really important for us as providers when we're having these discussions, especially with a reproductive age woman, to really investigate their obstetric history. What are their reproductive goals? Do they plan on having more children? What are their financial situations as far as for other reproductive assistance? Do they have the means to access that in the future, to really make a surgical plan that is in alignment with their goals? That's certainly something that is necessary in this timeframe when we're taking care of patients.

Dale Shepard, MD, PhD: I mean, I guess sort of going back, a little bit of a back step. From a risk standpoint, what are the primary things where if somebody comes to you and says, "I really want fertility-sparing surgery," what are the... Clearly, they would have to have localized disease, but what are the other sort of things where you'd say, "You know what? Bad idea. You really do need a more extensive surgery."

Michelle Kuznicki, MD: So, the things that we look for really are things that will come up naturally on our preoperative imaging, so you mentioned size. Different high-risk histologies are not considered very good candidates for this, so clear cell carcinoma, neuroendocrine cancers of the cervix. Those are more aggressive subtypes that we would consider. If we're treating them with surgery, they really should go down that traditional radical surgery route because we don't have good data that fertility-sparing, especially with a cone biopsy, or something less radical, would be safe for them.

Other things that we would consider is, the pathologist will always tell us whether there is lymph-vascular space invasion, so that will help us determine what kind of fertility-sparing surgery might be safe for those patients. So in the prospective data that we have, limited patients that had lymph-vascular space invasion because that portends a higher risk of parametrial involvement in lymph node metastasis for those patients. I didn't really mention this as we're discussing, but all of these procedures, despite the very, very low-risk patients that are the earliest stage with no LVSI, everybody else should have some element of lymph node sampling, whether that is in the form of sentinel lymph node biopsy or pelvic lymph node sampling that is done concomitantly with these procedures, even in the fertility-sparing setting.

Dale Shepard, MD, PhD: When you think about lymph nodes sampling, is there a clear advantage to more broad sampling compared to the lymph node? What's the impact on things like lymphedema and things like that?

Michelle Kuznicki, MD: Sure. I would say we have very good data from our endometrial cancer patients, and there is solid but limited data in the cervical cancer sense, so it is not universal that people are performing sentinel lymph node biopsies in cervical cancer, but in my review of the literature, it appears to be very safe. It appears to have a very good sensitivity to pick up lymph node metastasis for cervical cancer patients, so in reality, there probably is no oncologic benefit to performing a complete lymphadnectomy on these patients. Assuming that the oncologic risk is the same, then doing the sentinel lymph node biopsy will reduce those post-operative risks. As you mentioned, lymphedema, as well as intraoperative complications. Bleeding, surgical time, nerve injuries. At least in the endometrial cancer space, I think almost universally we have started to trend towards doing sentinel lymph node biopsies, especially in the low-risk cancer, so I think that cervical cancer is trending in that direction as well.

Dale Shepard, MD, PhD: I guess you mentioned surgical time. I guess the other thing I was curious was, what's the range between hysterectomies, the more localized conal biopsy approach? What does that look like for a patient in terms of procedure time, any hospitalization, that kind of thing?

Michelle Kuznicki, MD: Oh, yeah. Huge difference, for sure. I'm sure this depends on the technical experience of the surgeon as well, but performing a cone biopsy and a sentinel lymph node biopsy on a patient, that may take in total an hour and a half, whereas doing an open radical trachelectomy with pelvic lymph node sampling, or an open radical hysterectomy with pelvic lymph node sampling, that can take a number of hours, have much higher blood loss, et cetera, as I mentioned. So certainly from a surgical time, that's a big difference. Then from a recovery time, patients with a cone biopsy and sentinel nodes can go home the same day. Patients with any open radical procedure, whether it's trachelectomy or hysterectomy, those patients will typically stay in the hospital for a few days after surgery, and then there is a significant risk of post-operative urinary retention, so patients at times also have to go home with a Foley catheter, which can be a bit of a burden for patients until that can be removed.

Dale Shepard, MD, PhD: So, lots of variables there? It seems as though you're kind of moving into an area where, across the board, looking at a lot of different providers, either patients could be offered more aggressive surgeries that they may or may not need and lose an ability to preserve their fertility, maybe unnecessarily. You could run into a fact where people start doing these minimally-invasive surgeries that may have reasonable outcomes, but maybe higher risk, so there's certainly room for too much and too little. How do we teach people what's appropriate? What kind of educational efforts need to be out there?

Michelle Kuznicki, MD: Yeah, I think it's education on both sides. Education from a provider standpoint, and education for patients as well. From a provider standpoint, I really think that continuing to produce and publish literature that supports the safety of these will get more buy-in from providers. I know, especially more experienced GYN oncologists, they have seen certain practices adopted early, and then we go look back and we do other big randomized studies, and, "Oh, actually, it looks like that wasn't a safe thing to do after all from a cancer perspective," so then we end up going back. I think that's part of the delay in uptake, is that some providers are really waiting for the best data that we can possibly provide to show that something we're doing that has very good cancer outcomes, like a radical hysterectomy, that that can be substituted for something less radical, less invasive, and also maintain the good cancer outcomes.

So, I think from an "education standpoint", it's really just continuing to encourage people to publish these studies, publish their data. If you are performing these procedures at your institution, get that information out there. Like, is it safe? Is it not safe? What are the reproductive goals? What are the quality of life outcomes for the patients? That's a huge thing for this type of surgical intervention. Then from a patient standpoint, I think things like social media and internet access, that has really improved patients' education as far as what their options are.

Some of my patients will already come into the office saying, "This is what I have been told that I have. I'm 30 years old, I don't have any children. My goal is to be able to have children in the future," and this is one of the first things that they say to me, so I think that has really been a good... The internet is not always a good thing, but in that sense, it's really allowing patients to advocate for themselves and know that these options are available. Different educational resources for patients that offices can provide as far as brochures, or a list of reliable websites for patients to interact with to gain some education on their own. That is also a great option for patients.

Dale Shepard, MD, PhD: That's fantastic. A fascinating area, lots of good progress. Michelle, I appreciate you being with us.

Michelle Kuznicki, MD: Yeah, thanks so much. It's been great.

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