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Krukenberg tumors and mets to female reproductive organs: Drs. Xie & Sood

Doc Talks

In this panel DocTalk on Krukenberg tumors, PALTOWN Scientific Director Dr. Manju George mediates a conversation between Dr. Hao Xie, a medical oncologist from Mayo Clinic, Rochester and Dr. Divya Sood, a peritoneal surgeon from OHSU, Portland, Oregon. Recorded in May, 2023.

Table of contents:

0:00 Introduction to Dr. Sood and Dr. Xie
4:46 Molecular alterations in colorectal and ovarian cancer
10:43 How do we manage patients with ovarian metastases?
14:31 CT scan of a patient with colon cancer
20:03 Relationship between age and ovarian mets
25:17 What is the need for surgery for ovarian cancer?
34:10 Prophylactic oophorectomy and long-term survival
39:54 Surgery for secondary tumors in the ovary
44:07 What is the alternative to hormone replacement therapy (HRT)?
48:47 How long after initial diagnosis are ovarian metastasis data captured?
53:09 Deciding whether to surgically remove ovarian tumors

Manju George 0:00
Hello everyone. Welcome to Doc talks. I’m Dr. Manju George, the Scientific Director of Paltown Development Foundation, the nonprofit that supports Colontown. Today we have two expert clinicians to tell us about Krukenberg tumors and colorectal cancer mets to the female reproductive tract. I’m turning it over to Dr. Xie, could you please introduce yourself?

Dr. Hao Xie 0:23
Yes. Thank you for the invitation for the presentation. So my name is Hao Xie. I’m one of the GI medical oncologists at Mayo Clinic Rochester. So my specialty is about particularly focusing on colorectal cancer and also early drug development.

Manju George 0:42 
Okay, thank you. Dr. Sood. Could you please introduce yourself?

Dr. Divya Sood 0:47 
Hi, everyone. I’m Divya Sood. I’m a surgical oncologist at Oregon Health and Science University in Portland, Oregon. My focus is primarily in GI cancers but also in peritoneal surface malignancies, and oligo metastatic cancers, as well.

Manju George 1:09
Thank you for joining us, Dr. Xie, you can continue with your presentation. So, how we will do this, first Dr. She will speak and then there will be a gap for questions. And then we will hear from Dr. Sood. And then towards the end, both of them will take our questions. So as you hear the talk, when you have questions, please type them in chat. Thank you.

Dr. Hao Xie 1:33
Okay, sounds good. So I’ll get started. Since I’m a medical oncologist mainly I’m just gonna talk a little bit about what is Krukenberg tumor epidemiology, general treatment principles from medical oncology perspective. So first, people may ask what is the incidence of ovarian metastasis from colorectal cancer? Because there are a lot of different GI cancers such as colorectal cancer, gastric cancer, occasionally we see pancreas cancer can spread it to the ovaries or the other female organs. Occasionally we also see this from lung cancer and breast cancer, but the very important question is, how is this different from primary ovarian cancer?

Dr. Hao Xie 2:24
So first, the incidence of colorectal cancer ovarian metastasis is not common, but it’s about 4.6%. Different studies in the past and reported different incidences really depend on the patient selection. So from this so-called kind of summative metaanalysis basically demonstrated that the incidence is about 5%. Not a lot, but we see many in tertiary medical centers. So the next thing really is to talk about what are those histologic subtypes of colorectal cancer ovarian metastases, again, colorectal cancer is a type of cancer called adenocarcinoma, out of those you could have mucinous adenocarcinoma, could have signet ring type. But all those terms are really defined by how those cancer cells look like under the microscope, and there’s some, rarely you could see mixed adeno and the neuroendocrine tumor. So based on the different pathology, and most of the cancers are really the typical type, all we see is either adenocarcinoma, and it could either be well- differentiated, means that when you look at a cancer cell under the microscope, they look more like a normal colon mucosa or the lining of the colon, or it could look very differently from the colon mucosa. That’s why we say poorly differentiated. Also, nowadays, we talk about the management of colon cancer in terms, of the location, either there in the left side of the colon, rectum, or the right side of the colon, prognosis are very different. So in terms of the Krukenberg tumor from colorectal cancer, a lot of those are involved by the cancer from the left side of the colon, as you can see about 50% versus the other parts of the colon. And then nowadays, next-generation sequencing has become the standard of practice. For patients with stage four colorectal cancer. We usually do next-generation sequencing upfront, when when we see patients with newly diagnosed disease. This is a nice study from the Memorial Sloan Kettering Cancer Center where they look at their patients matched primary colon cancer, ovarian metastasis and metastatic disease from other sites. Then they sequence that tumor for different molecular alterations as shown here, those things represent different genes. As you can see, in general, primary colon cancer has a similar genetic alteration profile compared to metastatic colorectal cancer. However, in some cases, there are some small differences between the primary colorectal cancer and ovarian metastasis. Just to take a common gene into consideration we see tp 53 APC loss KRAS mutation SMAD4 Pathway alteration in colon cancer all the time. When you compare the patients with ovarian metastasis versus a patient without it, you can see there are some differences here in terms of more KRAS mutations in ovarian metastasis versus the less or fewer patients without ovarian metastasis, and also the SMAD4 alterations are more in patients with ovarian metastasis. Other things to consider would be gene amplification, that is one type of the molecular alterations typically people talk about mutations but also gene amplification specifically HER2 amplification is targetable nowadays, such as those that we see in gastric cancer, colon cancer and breast cancer. As you can see here, for Krukenberg tumor from the gastric cancer or stomach cancer. And certain gene amplifications are a little bit different between the primary cancer versus the ovarian metastasis versus in colon cancer, you do not see much difference between the primary cancer lymph node metastasis and ovarian metastasis. This is actually consistent with what we usually see in the literature that a molecular alterations are pretty much similar between the primary colon cancer and other metastatic sites.

Dr. Hao Xie 7:41
So next thing I want to talk about is really try to answer the question I mentioned earlier, the difference between primary ovarian cancer and Krukenberg tumor from other GI cancers. so typically a patient could present with a newly diagnosed cancer mainly ovarian metastasis, and we need to figure out is this a primary ovarian cancer which is treated very differently from if this could be an ovarian metastasis from the stomach cancer, colorectal cancer or other types of cancers. Again, the treatments are very different. So it’s important to figure out the difference, especially if there is a occult primary in GI and the patient only presented with an ovarian mass, it is very important again to figure out the difference. We, a couple of years ago, we did a small study tried to look at if we can identify any clinical pathologic or imaging parameters that can be used to predict or to distinguish the ovarian metastasis from the primary ovarian cancer. So basically, if you look at this table, the first row represents the report from the radiologist. So as you can see, the accuracy to distinguish these two entities is only 60% among the expert radiologist, at Mayo Clinic, then we try to use other clinical or biochemical factors, common things that we see, age, ca 125, which is a tumor marker for ovarian cancer and the CEA which is a common tumor marker for colorectal cancer and some other GI cancers. The accuracy to use these three factors as a model to predict what to actually distinguish ovarian metastasis from primary ovarian cancer, it’s about 88%. And since nowadays people talk about AI with deep learning algorithms. At that time, I used a neural network algorithm to try to predict the two entities based on the CT scan images. And unfortunately, we only see accuracy about 63%, which is not statistically different from our radiologists, but it’s a worse than just as simple three clinical parameters.

Dr. Hao Xie 10:33
Another important thing to consider is really the survival in a patient with newly diagnosed the colon cancer, ovarian metastasis. How do we manage patients? What are the survival difference? Again, this is only a univariate analysis, meaning we did not adjust for other clinical or pathologic factors. But as you can see, this is what we call a Kaplan Meier curve. The X axis represents how long a patient lives, meaning their survival. And the y axis represents the percentage or the proportion of the patients who have disease under control. That’s what we call the progression free survival versus overall survival, meaning the proportion of the patients who are alive at a certain time, if you look at the x axis, and the curve represents, if you go along with time you follow patients for a certain period of time, what is the proportion of the patients who still have the disease under control or, who is still alive? So see, you can see here if if the patient receives surgery, meaning surgical resection of the ovarian metastasis upfront, they seem to be longer compared to patients who only receive medical therapy, meaning chemotherapy, targeted therapy or immunotherapy that as a medical oncologist will, prescribe. If you look at the overall survival, it seems patients who receive upfront surgery also live longer. But again, the caveat is that we did not adjust the other patient factors, such as the patient who only present with ovarian metastases and war patients also have other metastatic disease, for example, in the other parts of their abdomen, liver while lung, so the survival obviously will be very different. The reason we didn’t adjust this was because we only had a 98-99 patients so it would it would overfit the model if we do that. But certainly, it does give us some suggestion that surgery was a very important role in the management of this disease. And Dr. Sood will talk more later. So again, there is also a interesting study a number of years ago, people looked at if we treat the patients with ovarian metastases with chemotherapy, what was the response to the chemotherapy. So as you can see here for patients with ovarian metastasis, and most of the patients, they either have new disease, disease progression, or only a minority of them had a stable disease versus metastatic disease outside of the ovaries, such as liver lung metastasis, you do see a number of patients, they could have responded to the therapy which was a consistent with what we know about how many patients who respond to FOLFOX, FOLFIRI or other type of chemotherapy, we usually use for patients with stage four colon cancer. So which means that the ovarian metastases are particularly resistant to traditional or standard-of-care chemotherapy agents, at least the way those things trend. Lastly, I will just kind of show you an example how people manage patients with colorectal cancer ovarian metastasis. As you can see on the picture on the left side on the top, this is the coronal view of a CT scan. So you can see this is the liver. This is the stomach you see normal liver look like this. You’ll see a little bit darker area. This is a tumor in the liver spread from the colon. And also you’ll see this big tumor here. That represents the ovarian metastasis. So basically a patient at that time was just started on standard-of-care chemotherapy called CAPOX plus another drug called Bevacizumab. another name is a Avastin. We also follow the tumor marker CEA as a marker for response. As you can see initially the patient responded to first line chemotherapy. However, after a few months, actually pretty soon, it develops the resistance, specifically the resistance from the ovarian metastasis. As you can see the image is showing and then bottom left, the tumor gets bigger compared to before the treatment, that’s when the patient had an elevated CEA. So at that time the patient was symptomatic from this ovarian tumor. So then the patient underwent a surgical resection with some improvement of the tumor marker. Keep in mind that when we remove the ovarian metastasis, we don’t typically remove other metastatic cancers, for example, in the liver. That’s why gradually that tumor marker will go up and to later time we have to start the second line chemotherapy such as FOLFIRI plus Bevacizumab, that’s where the other disease was actually was very sensitive to the second line chemotherapy and have disease control for quite a while. So that’s the kind of example of a patient with this condition as being seen in a clinic. So that’s all, thank you for your attention.

Manju George 16:53
Thank you very much, Dr. Xie. There are some questions in chat, maybe we can go through them. So the first question is, are there different results for those who are otherwise NED when they develop Krukenberg tumors?

Dr. Hao Xie 17:08
if they have different results, but also otherwise NED when they develop? I mean, so in the patients with colon cancer it is actually interesting for some of the metastatic sites for example, oligo metastatic disease in the liver, and or if the patient only has ovarian cancer, after surgical resection, they fully stay, while we call them at no radiographic evidence of disease for quite a long time. But a lot of this is really related to the disease biology. You know, if that cancer has a B RAF mutation has KRAS mutation, the duration of progression-free survival will be shorter compared to some other type of subtype of colon cancer.

Manju George 18:07
The next question is, is there any data about CtDNA and ovarian metastasis? And you see it typically raised with ovarian mets?

Dr. Hao Xie 18:17
To answer the first question that CT DNA– so there is no high quality randomized study to demonstrate the utility of using circulating tumor DNA in patients with stage four cancer. However, I do wonder, either the typical kind of commercially available CT DNA testing after surgical resection of the ovarian metastasis or the oligo metastatic disease in the liver, and if the CT DNA 2 have them in a row or negative, then the chance that the patient will be remission for a long time is much higher. So similar to you know, like early stage of colon cancer after resection, but based on at least our experience, we rarely so called cure patients with ovarian or oligo metastatic disease to the ovary. But again, it could be just because we don’t see that many patients compared to oligometastatic disease in the liver, which we do cure some of them. The CEA depends on if the tumor is producing the CEA. so a proportion of the colon cancer does not produce CEA to startwith so then those ovarian metathesis will now be able to produce CEA.

Manju George 19:51
Okay, okay, thank you very much. So, Amber has this comment saying that she’s very thankful that for her, during emergency surgery , the ovarian met was removed. So that’s great to hear. The next question is, is there any connection to age and ovarian mets?

Dr. Hao Xie 20:11
From our study, the small study again, if a patient presents with ovarian metastasis at a younger age, again, it tends to be a GI primary versus the primary ovarian cancer. But again, it’s there’s no large theory really, kind of demonstrate the relationship. But again, when we see patients at different age, again, we practice this, you know, we have to figure out is this ovarian metastasis? Is this primary ovarian cancer, regardless of patient’s age or other factors because it’s important to know which one is which.

Manju George 21:01
Okay. And related to that. So, are ovarian mets more commonly seen in colorectal cancer patients who are younger, do you see something like that?

Dr. Hao Xie 21:14
That’s a great question. That’s about our early-onset colorectal cancer. Again, based on the literature, my experience, is actually is now higher than patients who are older, we see both, actually the patients I have seen based on my experience are typically a little bit older. But again, a lot of factors contribute to it. for example, if the patient has a high disease burden, they tend to have ovarian metastases, the patient has a peritoneal disease, otherwise, they tend to have ovarian metastases, so it’s hard to definitively say.

Manju George 21:55
Okay. The next question, if, if someone has an ovarian met on one ovary, is it typically more likely that it will spread to the other ovary?

Dr. Hao Xie 22:06
So you could see patients with metastasis on only one ovary you could also see bilaterally, so this is not from the spreading from one ovary to the other, it is more the mechanism how people get peritoneal disease. It’s more like dropping to the ovaries.

Manju George 22:27
Okay. I think the next question that person asks is, so if a person has a met to one ovary, and they’re having the Krukenberg tumor removed, is it recommended that they remove both ovaries?

Dr. Hao Xie 22:38
That’d be a great question for Dr. Sood, I think.

Manju George 22:43
Okay, next question. For women with peritoneal mets, how often does an ovarian met happen?

Dr. Hao Xie 22:51
It’s a tough question, though. The way I guess the way to answer this is, if patient has peritoneal metastases, they of course, will have a higher risk of developing ovarian metastasis because the mechanism really is similar. So those without peritoneal metastasis they could also have it, it just not a higher risk, because the mechanism of spread is always not there. So I would say it’s a lot higher. Yes.

Manju George 23:26
Okay. Thank you very much. So then we will go with Dr. Sood’s presentation and at the end, if you have other questions, please post them in chat. And then we can look at them then. Thank you very much, Dr. Xie.

Dr. Divya Sood 23:42
Okay. All right. Well, thank you all for being here. And thank you Dr. Xie for that fantastic overview. I’m going to try to build on it a little bit. I don’t have any disclosures here. Briefly, what we’ll talk about are some sort of indications for surgery, why you might need surgery for a Krukenberg or a secondary tumor of the ovary. How we would go about doing surgery, what the options are for approaches to surgery. Some other considerations when thinking about having surgery for an ovarian tumor. And you know what to think about what to talk to your surgical team about. Generally, we touched a little bit on this, but we’ll talk briefly about some sort of prognosis and long term outcomes after having surgery. And then we’ll talk briefly also about the option of prophylactic surgery, which is sort of a newer concept that we’re thinking about. So for indications for surgery, there are honestly a number of different reasons that you might have surgery for an ovarian tumor or an ovarian In met, it may be something related to diagnosis. So in a patient who doesn’t currently have a diagnosis of colon cancer, or ovarian cancer or anything else, and they present for the first time with a large ovarian tumor, and as Dr. Xie had mentioned, you know, in the setting of an occult primary, meaning we don’t see evidence of a primary tumor anywhere else, and this is really all that we see, sometimes what’s needed is surgery to remove the ovary to get that tissue and get the diagnosis. So that certainly may be the case for some patients. For others, it may be related to symptoms or what we call palliative intent surgery. So they have a diagnosis, maybe they’re undergoing chemotherapy or other treatments. But they have as you can see, in this image, a rather large ovarian tumor that is causing fullness pain, abdominal cramping, bloating, it could be that they, you know, can’t eat as much because they eat a small amount, and then they get super full. And so it’s making it harder for them to go through the rest of their their chemotherapy or other treatments, that could be a reason to, to take out this mass so that they can otherwise continue with treatment. Similarly in the palliative intent, but not necessarily related to symptoms. But as kind of what Dr. She had mentioned that, you know, these tumors tend to be less responsive to chemotherapy. And so maybe they’re the patient is having a good response in the liver and to the rest of their peritoneal disease. But this just sits there the CEI remains CEA remains remains elevated. And so it’s not going to provide sort of the therapeutic or curative intent. But removing this allows them to kind of get rid of this almost clone of disease that isn’t responding to treatment. And then the next one would be more of a therapeutic or curative intent. This is for a pretty selective group of patients who, who fall under the category of saying, hey, if we take this out, and we can easily remove all of the other disease, they’ve demonstrated what we call good biology, meaning the tumor is behaving well responding to treatment in a stable kind of robust fashion, then maybe they’re a candidate for something like a cytoreduction, meaning removing all of the visible disease that we know is there. And sometimes augmenting that with intraperitoneal, chemotherapy or other adjuncts. And then, like I mentioned, prophylactic surgery is something prophylactic meaning, you know, don’t currently have metastases on the ovaries, but are at risk for it. And whether that’s something we should be kind of prophylactically removing the ovaries for this is something we’ll talk talk more about a little bit later. So potential approaches for surgery, there are a few to consider the most common is going to be an open surgery, meaning and a larger incision on the abdomen to remove the ovary, one or both sometimes with or without the uterus, and cervix. And that’s probably going to be the most common in this setting. Partly because of often they’re of a large size. And to get this out, you need a large incision. Partly it’s also related to the nature of the tumor that you know, if you have a benign tumor on the ovary or a cystic tumor, sometimes you can puncture it, suck out the fluid make it small enough to pull through smaller incision. When you’re dealing with colon cancer, rectal cancer or other kind of malignant tumors of the ovary, it’s usually not a good idea to do that. And so we caution against the idea of doing this minimally invasively with a laparoscopy approach or a robotic approach. Unless the tumor is already quite small that it’s going to be easy to pull it out through a small incision. Similarly, I kind of put a line through this one you may have heard of some, some people talking about the idea of NOTES or what we call natural orifice. transluminal endoscopic surgery, meaning not making any new incisions on the abdomen or or on the skin anywhere but kind of doing this through the vagina and pulling it out through a natural orifice in the body. And again, that’s something that’s really reserved for patients with benign disease. It doesn’t it’s not not something that I would I would strongly caution against that approach to do it just because of the risk of sort of spreading the cancer. So some of the other things to consider. So when having surgery on the reproductive organs, there’s a number of sort of short and long-term things to consider. And they’re things that really should be discussed with your surgical team and the rest of your oncology team. You know, often when undergoing an oophorectomy or removal of the ovary for a metastatic tumor. We touched on this briefly, but it’s often advised to remove both of them because of the risk of it being present in both. So often there’ll be kind of a dominant tumor on one of the ovaries. But we’ve found that more often than not, if we remove only one, in some amount of time, we can’t say exactly when, but the disease will show up in the other ovary. And, like Dr. Xie mentioned, that’s not that it spread from one to the other, it’s just the nature of how this cancer, how it got to the first ovary in the first place, it’s going to get to the second one, in the same way. And similarly, when we remove them, both of them, one of them often has a dominant tumor, or the other one, often we find on pathology, that there is some evidence of cancer there already, and it just hasn’t grown into the full tumor. So often, we do advise removing both of them when you go in for one. And when that happens, if you haven’t, the patient hasn’t already gone through menopause, then they’re gone going through what we call surgical menopause. And the symptoms associated with surgical menopause are similar. And often the same symptoms that you experienced going through menopause naturally, but can often be more noticeable and more acute in nature. And so there are things that can be done to sort of mitigate those symptoms. And so it’s important to have that conversation with your surgical team beforehand, so that you know what to expect. In addition, you know, there are some cases in which it’s appropriate to preserve one ovary. Despite that risk, it’s kind of a discussion that you have with your surgeon about desire to preserve fertility, anticipated risks associated with going through menopause at a very young age, including bone density and heart disease and other things that are associated with it. And so, in, in certain circumstances, that’s something that can be considered and kind of weigh the risks and benefits of doing that. Excuse me, similarly, the uterus is a discussion whether or not to remove the uterus along with this. Most often, you know, if we don’t see disease or cancer on the uterus itself, then just removing the ovaries is safe, when you’re in is not going to necessarily change the outcome related to cancer. If there is disease on the uterus, and we’re otherwise going for sort of a, what we call a curative intent, meaning trying to remove all of the cancer that we can see, then it’s often advisable to remove the uterus as well. But along with that comes some additional considerations regarding pelvic floor health, sexual function, bladder function, all of these other things that relate to having a hysterectomy and the other procedures that go along with that. So that these decisions are something that again, you want to have kind of a close discussion with your team about it, what makes the most sense for each patient can be different and variable. Oftentimes, you know, if fertility preservation and family planning is important to that patient, then they’ll want to engage the reproductive endocrinology team to have that discussion.

You can engage even pelvic floor physical therapy before and after surgery to to try to prepare for that. As well as sort of a urogynecology team to discuss options related to bladder function before and after surgery. So then, when it comes to sort of prognosis and survival, I think Dr. Xie, did a good job of of going over this. And I just wanted to provide kind of one additional aspect related to patients with this condition and what what things look like after surgery, you know, we used to have a fairly nihilistic view of metastatic colorectal cancer that, you know, particularly in patients with peritoneal disease and ovarian metastases, that there was a lot of kind of nihilism around it. And I think that’s really starting to change quite a bit. In patients who have ovarian metastases and peritoneal disease, if they are able to undergo a complete cytoreduction meaning remove all of that disease, the ovarian met as well as any other peritoneal disease that may have, you know, the median survival that we’re seeing is is getting up there into 40 to 60 months is kind of the range. So we’re looking at several years there, which is a big improvement over what we’ve seen with, you know, chemotherapy alone or historically the numbers that we’ve seen. Similarly, we’re looking at, you know, even the option of long term survival in a cohort of patients and so with, with low burden of disease, so I put on here PCI, less than 10, PCI being at peritoneal carcinomatosis index, which is essentially a calculation of how much disease there is within the abdomen. How much peritoneal disease we see where it’s located. And when it’s low, less than 10, we see overall 10 year survival reaching up to 40%, which again, is a big improvement over what we’ve seen with with chemotherapy alone. And that applies that PCI of 10 applies similarly to patients who have ovarian only metastases, meaning they don’t also have liver metastases or other things like that, that puts it into another category. But just as we’re seeing really big improvements in patients with liver metastases, we’re seeing big improvements in patients with peritoneal and ovarian metastases as well. One of the challenges that we have is that it’s harder to study, you know, most of the data that we have is around patients who have liver metastases, and patients with peritoneal or ovarian disease tend to be kind of not in most of the big clinical trials, because it’s harder to track the disease on imaging and CT scans and things like that. So we don’t have as much data around it yet, but we’re getting there. And so kind of along with that, it’s just a kind of a reminder that those who get a complete cider reduction overall tend to have better outcomes. Chemotherapy, as we talked about, is generally less effective on these secondary tumors of the ovary or these Krukenberg tumors. And so patients should, you know, make sure to be asked to be referred to a surgeon early, so they can at least consider whether there are a candidate for that. Not everybody is but for those who are, it’s good to have that discussion as early as possible. And that long term survival really is an appropriate goal that we should be looking at for these patients.

I mentioned a couple of times that we were going to talk briefly about the idea of prophylactic surgery. And up until recently, there’s really no data necessarily to support the practice of a prophylactic oophorectomy in this setting. Most of the time where that’s used is in patients with high risk genetic mutations. So for example, a BRCA mutation that puts them a very high risk of having a primary ovarian cancer. But nothing of that nature has really been, you know, demonstrated to be effective or useful in colon cancer. There was recently a clinical trial that was published just within the last month or so, which doesn’t directly apply to the use of prophylactic oophorectomy. But it does include it and kind of opens the door to this practice. What this study is looking at is the use actually of prophylactic HIPEC or intraperitoneal chemotherapy for patients with locally advanced colon cancer. So they don’t currently have stage four or metastatic disease or peritoneal disease, but they have a locally advanced primary tumor and possibly lymph nodes associated with that as well. Everybody in the in the study underwent a cytoreductive surgery, which included a bilateral oophorectomy for patients who were postmenopausal. And in addition to removal of all of their disease at the time of surgery, and then they were randomized to either receive HIPEC with that the intraperitoneal chemotherapy, or to not and then everybody went on to get systemic chemotherapy after surgery. And it did demonstrate, you know, their primary outcome was looking at the benefit of the addition of HIPEC or the intraperitoneal chemotherapy. And that demonstrated as positive results, meaning that there was a benefit to the use of HIPEC. But it’s and so they weren’t looking at the difference between doing a prophylactic oophorectomy or not, but it sort of opens the door to say that perhaps that addition to our standard cyto reductions that we’re doing are worthwhile or beneficial, and it’s something that we should at least consider looking at in the future. Something to stay tuned for.

Just kind of final thoughts on this as that, as we talked about, there are several potential indications for surgery. For the secondary tumors of the ovary, the surgical approach typically is going to be an open operation, but it depends on the size of the tumor, the indication as well as the patient themselves. And so it’s important to talk to your surgical team about. These really should be comprehensive, multidisciplinary approaches. And so patients should ask to meet with reproductive, endocrine and infertility specialists sexual health, urogynecology, psycho oncology team should all be part of the decision about whether to have surgery and how to prepare for it before and after. Long term survival, like I mentioned, is a realistic goal. And, there’s still a lot of improvements to be made. But a lot of improvements have been made. Early referral for consideration of surgery definitely improves outcomes. And then there are some kind of exciting areas in the pipeline that are coming down the road. That’s all I have right now. So I’m happy to take questions.

Manju George 41:06
Okay, thank you very much. I think there are a lot of questions in chat. Yeah, so Amber asked, Can preventative removal of the other ovary be something that can be requested to the surgeon, can be justified to insurance?

Dr. Divya Sood 41:22
Yeah, that’s a good question. And it’s definitely something that should be requested, particularly if you know, going in for one, the other one is, is very commonly going to be removed at the same time. And insurance, I at least, have never had a problem with it. I’ve never had an insurance company deny approval for the bilateral operation meaning both sides.

Manju George 41:49
Okay. Thank you, Tina, is this ovarian mass clearly grow quickly and are very large. Do we know how often ovarian mets rupture? If so what are the implications of that?

Dr. Divya Sood 42:03
In my experience, I have not often seen ovarian metastases rupture, I’ve seen them get to the point that they are very, very large and often kind of compressing other things in the body, but can quite large. But rarely do I see them actually rupture? If they do either, you know, before surgery or at the time of surgery, the implications essentially are that, you know, it increases the potential spread of peritoneal disease, I would say that in most of these patients, when they have ovarian metastases, even if they do not have visible peritoneal disease elsewhere in the abdomen, they often do have kind of microscopic peritoneal disease that was likely to grow at some point, anyway, or at least has already been exposed to it. And so it’s tough to say exactly whether the rupture of the ovarian met was necessarily going to change significantly the outcome, but in general, we try to avoid it during surgery if we can.

Manju George 43:15
Okay, thank you very much. So, say for example, you know, there was this patient who has a large met, and then for whatever reason it ruptured. So would you think that at that point, if the patient is considering HIPEC, you know, CRS and HIPEC, maybe that would be a good time to get it done? If they didn’t have any other indications that they were having peritoneal Mets? Do you think?

Dr. Divya Sood 43:40
Yeah, and that kind of falls under this category of kind of prophylactic HIPEC to some degree if we don’t have gross or visible peritoneal disease, but we suspect them to be particularly high risk. And I certainly would recommend it if they were otherwise a candidate for it. If they didn’t have, you know, visceral or extra peritoneal metastases, then I think it likely would be indicated at that time.

Manju George 44:07
Thank you, Elsa, asks if HRT isn’t done, what is the alternative? Who should that conversation be with?

Dr. Divya Sood 44:16
That’s a good question. So typically, that’s going to be a conversation that you have, either with a gynecology team gynecology oncology, about, you know, the best way to manage the kind of menopause symptoms after undergoing bilateral oophorectomy and, you know, if hormone replacement therapy is not an option or is or is preferred, a lot of times there are really good complementary alternative medicine options that can help support patients through those symptoms.

Manju George 44:50
Okay. And then for for bone health and or cardiovascular health. There may be other things that could be done.

Dr. Divya Sood 44:57
Absolutely. Yeah, there are definitely other ways to support that.

Manju George 45:00
So Liz asks, what is the overall survival for people with high PCI who are not eligible for surgery?

Dr. Divya Sood 45:10
You know, everyone’s a little bit different. I’m not sure that I have the exact number of median, you know, overall survival right now off the top of my head. But typically, you know, if they’re not a candidate for surgery, it’s partly dependent upon otherwise, their response to systemic therapy and if they are responding, if not, then survival does tend to decrease significantly and you start to look at you know, less than a year potentially of survival. Oftentimes at that point, when the PCI gets too high, then the risk becomes bowel obstructions which limit the ability to get other treatments.

Manju George 45:48
Okay. Dr. Sood, would you estimate peritoneal disease is being about 12% of stage for CRC? This is the only figure she has found.

Dr. Divya Sood 46:01
In terms of the total number of patients with stage four colorectal cancer 12% of them having peritoneal disease? I think that’s a reasonable estimate. I might even venture to say that it’s higher than that and that it’s probably under-measured in the literature, just because we are not, I think we’re not studying it as much as we could or should. But yeah, so I’d venture to say it’s probably higher than 12%.

Manju George 46:31
Thank you. And the next question is, should mutational analysis be done on these tumors?

Dr. Divya Sood 46:40
On the ovarian tumor? Well, I think that speaks a little bit to what Dr. Xie was was talking about that, you know, looking at the mutational analysis and comparing that to the primary tumor as well as to the the other sites of metastases, so he might be better to speak to that and the utilization of the mutational analysis.

Manju George 47:01
Dr. Xie, do you want to take that?

Dr. Hao Xie 47:03
Yeah, yeah. So we went to the mutational analysis, at least, you know, one of the tumor, some tumor specimen doesn’t have to be ovary metastasis because in my talk, I showed that there are not that much difference between the primary tumor, other metastatic disease versus the ovarian metastasis.

Manju George 47:26
Okay, thank you. So the next question is, you know, what do you think is going on about why they’re so resistant to chemotherapy?

Dr. Hao Xie 47:34
Um, honestly, I don’t know. I mean, it could be part of that could be the anatomy, the blood supply. And also, you know, like how drug can diffuse the into the cancer cells, the same thing applies to the peritoneal disease in general, certainly has something to do with the genetic makeup and also expression of, for example, the drug effluxing transporter of the cancer cells. So those have been studied, those could contribute to the resistance to chemo.

Manju George 48:19
Okay. Dr. Sood, do you have anything to add to that?

Dr. Divya Sood 48:24
No, I think that’s I think that all makes sense that it’s a combination, probably like he was saying of the genetic makeup, but also just the inability is similar to other peritoneal disease, there’s sort of a barrier of systemic therapy to reach it is the other component?

Manju George 48:43
Yeah. And she says, Thank you for bringing up that. Those with peritoneal mets are not often part of clinical trials or that their results or the results are broken down in subanalysis? Yeah, for those who get ovarian Mets long after an initial diagnosis, is that data commonly captured? Or are we not tracking that type of data? So, Dr. Xie, maybe you can tell us about the registry that you were explaining before we started the call.

Dr. Hao Xie 49:17
Oh, yeah. I mean, I don’t quite understand this question, if I understand correctly, is we are now particular. I mean, in any single clinical trial, other large data like registry, we’re now particularly capturing the, you know, the ovarian metastasis. But if I remember correctly, there were two papers in Lancet oncology about 10 years ago actually, the author’s look into the ARCADE database which is a database of all the metastatic colon cancer clinical trials that they look into the incidence of peritoneal disease, they did include ovarian metastasis, but again, a lot of study are really focusing on the peritoneal metastatic disease in general. People don’t really think about the ovarian metastases at all in large clinical trials, or data registry?

Manju George 50:29
Okay? Okay, so it might be a value to actually have a registry, like, you know, you were able to publish it, because you had that at Mayo, right. So it’d be, yeah, like, so the reason I say this is that in colinton, we have, you know, patients who are seen at all kinds of oncology clinics. So we have people who go to tertiary cancer centers, we have those who go to NCI centers, and we also have people who go to community clinics, and, you know, we can see the whole spectrum of it. So with patients who go to community clinics, and you have this large tumor, which is not responding to chemo, then you know, there, by the time they’re offered a surgical resection of the Krukenberg tumor, you know, that doesn’t really commonly happen. And because of the disease burden outside of the ovaries, you know, many patients don’t get to that. But in some cases, you know, once the Krukenberg tumor is removed, then you know, their overall response becomes better, because that is the one that is showing the super high CEA levels, you know, so maybe having a registry and having more information would be useful, because then you know, the patients could take that information to their doctor and say, you know, here’s some data, maybe this is something that we should consider, you know, so thank you very much for this, for presenting all these giving us all this information, because I think that’s the most important value of these kinds of talks. Let’s see if there are other questions. Yeah. So I don’t think there are any questions. So I have one question. So could both of you, like go through a case of a patient who’s like, say, for example, let’s do a oligometastatic disease, right? So you have this patient with stage four colon cancer, who has like a solitary met to the liver, and that patient had, you know, liver resection and the primary tumor resection, and they had some post operative cleanup chemo, and then like six months later, they have this rapidly growing mass in the ovary. So how would you manage that? You know?

Dr. Hao Xie 52:32
Well, I think I would sorry, did you want to go ahead and Dr. Sood, I would let you talk first.

Dr. Divya Sood 52:37
I was just gonna say that, you know, part of it is certainly dependent upon the patient’s tumor biology. Certainly, you know, the fact that there was sort of a relatively short interval between the time that they completed their therapy and when new disease showed up, when you’re looking at kind of less than a year, what we call disease free interval, or the time between completing therapy when you’re considered no evidence of disease, and then the next thing shows up. That is less than a year is a little bit of a higher risk situation. And that kind of guides the decision making a little bit. I would say that in some patients, if they demonstrate otherwise good biology, the first time that that ovarian mat shows up and you’ve restaged them, and there’s truly no other evidence of disease, I would usually recommend a laparoscopy to take a look inside the abdomen, see if there is any peritoneal disease that we’re not accounting for on the imaging and then make a decision about whether they should have the ovarian met removed or start some chemotherapy. Again, another line, similar or different to what they were receiving before kind of in discussion with the medical oncology team.

Manju George 53:58
Okay, Dr. Xie. Do you have anything to add? 

Dr. Hao Xie 54:03
No, I call it great. Yeah.

Manju George 54:05
Thank you. So then, let’s consider another patient. You know, the patient has been diagnosed with a primary tumor in the colon and has lung mets and liver mets. And they they got first-line chemotherapy with a biologic and they had very good response. And then now you know, they’re getting maintenance chemo, just CAPOX with the biologic and then a year down the road, you know, they have this rapidly growing ovarian met. How would you manage that patient?

Dr. Hao Xie 54:32
I would take it in a similar approach, actually. So you’re saying that disease like a developed while patient is receiving the maintenance chemo? Certainly I would have stopped the maintenance chemo first. And then I will get a good restaging evaluation on the like the CT scan, path for example, to look at if there are any other metastatic sites other than the ovarian metastasis. So if there is no other metastatic sites, it’s really a decision, either you’ll go, certainly I will consult our surgery team first, and then make a decision based on the multidisciplinary discussion. So But ultimately, it’s either you do surgery first, followed by a potentially kind of quasi adjuvant chemotherapy based on for example, Ct DNA results, versus like give the patient four cycles of the new line of chemotherapy, for example, in this case FOLFIRI+ something and then re evaluate, and then discuss if surgery is indicated in that case.

Manju George 55:52
Dr, Sood, do you have anything to add?

Dr. Divya Sood 55:54
I think the only other you know, decision point or the thing that kind of factors into the decision-making is whether or not there are symptoms related to it. Certainly, if it’s symptomatic, that may push you in one way or the other. But if it’s not symptomatic, then it may be a good idea to kind of get some systemic therapy on board in order to prevent, you know, it’s in case it’s a sort of a sentinel finding, meaning that we see the ovarian tumor and then there’s something else growing, it’d be nice to kind of shut that down with some systemic therapy before putting a patient through surgery, which is a has its own risks associated with it in terms of creating kind of a pro-inflammatory state in the body that gives cancer a chance to grow. So I think that would be the other decision point is whether there are symptoms.

Manju George 56:43
Okay. Thank you very much.

Dr. Hao Xie 56:45
If I could say one more thing just popped in my mind. Another thing to think about is that, you know, for patients who have to go through surgery, they have to be off chemotherapy, for at least four weeks, at least here our Surgeon prefers that if patient is on bevacizumab, it has to be six weeks before and after the surgery. So if, let’s say that disease biology is poor, then I always tell my patient, yes, you can do the surgery. But what you know if the disease biology is poor, when you come back, we do the CT, we see new disease in other places, right? So then you you have the surgery, especially if they are now symptomatic, you have the surgery for nothing, right, typically. So the surgery, one is like Dr. Sood said, either to try to cure the disease, or try to help with the symptoms. So really have to seriously think about and really based on the disease biology, we do have, you know, tools that we can use to try to get an idea about it.

Manju George 57:50
Okay, thank you very much. I think Tina was asking this question, and maybe you can expand on it. If they don’t tend to respond to chemo, then why treat with a new line of therapy? And I think Dr. Sood had mentioned that that is just to make sure that if there’s underlying disease that you can’t yet see, to keep that in check while you’re recovering from surgery. Is that right?

Dr. Divya Sood 58:10
Exactly, yeah, even if you know, on imaging, all you can see is the ovarian tumor that doesn’t mean that there aren’t microscopic points of disease that we can’t see on imaging. And like Dr. Xie was saying, the last thing you want is for us to go do a big surgery take out the ovarian met. Meanwhile, you’re off chemotherapy, we’ve increased the inflammation in your body. And now that microscopic focus in your lung or your liver has a chance to grow. And if we can give the chemotherapy ahead of time to prevent those other sites from growing, then that gives us a better chance of having an effective surgery.

Manju George 58:44
So this talk was requested by members in colon town because you know, there is not so much information about you know, specifically Krukenberg tumors and especially mats to the, you know, fallopian tubes, etc. So, the it was it’s really nice that you’re able to do this.

Dr. Hao Xie 59:04
Yeah, no problem. Happy to.

Manju George 59:07
Yeah. And that your paper is also really good. Like I had not found, you know, anything to share. So, it was great that I found that paper.

Dr. Hao Xie 59:18
Oh, okay. I will also cite a couple papers in my slides. And those are, I think those are especially the Sloan Kettering series, very informative, good quality data on this type of cancer and the metastasis. So not a lot out there.

Manju George 59:44
How did you get interested in Krukenberg tumors?

Dr. Hao Xie 59:48
Oh, my specialty is colorectal cancer. And we see quite a lot of patients with ovarian metastasis. The paper I was working on, was when I was a fellow in training at Mayo Dr. Jolene Hubbard and also, before that it was Dr. Axel Grothey, actually initiated kind of a small study looking into our patients at Mayo with Krukenberg tumors. So of course things changed. And so I took over. And then basically, initially, we were looking for some molecular patterns. But then I kind of adapted that project a little bit to my own interest in using initially at that time was thinking about deep learning AI, you know, still a lot of people talking about it. So I just give it a try. Okay. I’m still seeing, you know, patients with Krukenberg tumors from colon cancer specifically, sometimes gastric cancer but since I see more patients with colon cancer. So I collaborate with our Surgeon at Mayo, you know, to help patients versus this type of condition. Okay, Thank You

Manju George 1:01:18
Okay. Thank you very much. It’s like one minute past the time. And this was very informative. Thank you for the great talks and the great discussion.

Dr. Hao Xie 1:01:27
Absolutely. Thank you so much for having us. Thank you.

Manju George 1:01:30
Thank you. Take care. Bye. Thank you all for joining. Thanks for all the great questions. So the plan is for the recording to be posted in Colontown University and then you know, people can watch it at their convenience. Okay, take care. Bye