Beth Helmink, M.D., Ph.D. Hi, I'm Dr. Beth Helmink, and I'm an assistant professor of surgical oncology at MD Anderson Cancer Center. Today I'm joined by Dr. John Paul Shen, who is an assistant professor of GI Medical Oncology at MD Anderson Cancer Center. And this is the Cancerwise Podcast. Welcome, Dr. Shen. Thank you for being here with me today.  

John Paul Shen, M.D. Thanks so much for having me. 

Beth Helmink, M.D., Ph.D. Absolutely. Today we're going to discuss appendix cancer, the rates of appendix cancer and how they're going up in young people. And then talk a little bit about new research into new treatment options for these patients. Should we start with an overview of appendix cancer and why it can be so difficult to treat? 

John Paul Shen, M.D. You know, appendix cancer is known as a rare tumor, but it is becoming more common. And it's not rare at all at MD Anderson, we see, you know, between 300 to 400 new patients every year as a, as an institution. I personally see generally three new appendix cancer patients every week. And appendix cancer has been hard to treat for a lot of reasons. I think a big part of that is this, I think now, people recognize, outdated idea that appendix cancer is the same as colon cancer, and that the patients get the same chemotherapy as colon cancer, because we know that at least for some types of appendix cancer, this colon cancer chemotherapy doesn't work very well. 

Beth Helmink, M.D., Ph.D. And why do you think we're seeing it now more in young people? So, there was a recent study that came out saying that we are seeing increasing rates of appendix cancer being diagnosed, but specifically among younger people. Do you have any insight into to why that might be? 

John Paul Shen, M.D. Yeah. So, great question. Why questions are always difficult, but I think there's a lot of reasons to think that it could be related to potentially diet and to microbiome. You know, the, the scary part is, is that when the people who are in their 20s and 30s are now in their, you know, as they progress into their 50s and 60s, we expect that the rates are going to be even higher. And so, you know, it's really critical that we develop better treatments for appendix cancer because the, unfortunately, we may be looking at the tip of the iceberg in terms of the number of, of new patients. 

Beth Helmink, M.D., Ph.D. Yeah. What I think was great about this study is they actually looked at the rates in young people as compared to older people. It's not that appendix cancer is being diagnosed as a whole more. It is. But but also specifically among younger people. Right? Because you could argue, you know, because there was confusion, you know, a while back or, you know, years ago, that it could be just colon cancer, is the same as colon cancer, right? I think there is now a, a better diagnosis. And so, we are diagnosing it globally more frequently. But to see that increase specifically in younger people suggests that, you know, we could have a real problem going forward if this is to continue. We're seeing also in other colon cancer and other GI cancers, also increasing rates among younger people. We both see a lot of appendix cancer. It's obviously a difficult disease for us to treat because it's often presents late. Do you have any insight into why that is, or why it is so difficult for people to find and to diagnose? 

John Paul Shen, M.D. You know, it's unfortunate that the vast majority of patients with appendix cancer don't have any symptoms until the tumor is already spread throughout their abdomen, and that is partially because you can't feel your appendix. In some cases, the appendix tumor can cause an appendicitis. And then you would have pain and you'd go to the emergency room. In that case, when it is caught early, the outcomes are very good. We, our data, as you know, shows that the chance of being alive five years down the road, if you're caught at stage II or stage III, is better than 95%. So, the vast majority of those people are cured. The problem is, it's very silent in that if the tumor is not near the very tip of the appendix, you won't know that you have it until it's already spread throughout your abdomen, at which point it's already metastatic. 

Beth Helmink, M.D., Ph.D. I think the other thing that's unique from colon cancer is that, you know, people get colonoscopies and they come to me so frustrated that their colonoscopy didn't show anything. But what they don't realize is that, you know, a colonoscopy is never going to look inside the appendix or be able to, you know, the scope itself is bigger than the appendix. And so you can't actually look inside. So, there's, there's no way to screen for this. There's no way, and it doesn't cause symptoms. So, it unfortunately is discovered very late. I think the other thing is, you know, it is often misdiagnosed. So many of our female patients, for example, are misdiagnosed as ovarian cancer. And that's partially just because it similarly spreads in the same way. And it similarly has vague symptoms that, you know, and a lot of these tumors actually do form ovarian metastases too. So, sometimes these people do have ovarian masses. It's just coming from the appendix, not coming from the ovary. What do you think makes it so difficult to treat with regards, I know you alluded to the chemo options and how it is not colon cancer, but what are the struggles that you face with treating these patients from a medical oncology side? 

John Paul Shen, M.D. Yes, a great question. The, you know, the, because it's a relatively rare tumor, there has not been a lot of investment in prospective clinical trials, which is generally, you know, considered to be the gold standard of, you know, medical knowledge. And that is generally what, you know, informs you as an oncologist. These are the treatments that work. And the other thing that we've been doing a lot in our research is that we can recognize that while appendix cancer is a unique entity, it shares common features with other more common tumors. And we, we've identified that, you know, there are drugs that are being developed for other tumor types that are active in, in appendix cancer. And one one classic example that we've shown recently is that, you know, the old drug paclitaxel, which was not used in appendix cancer because it doesn't work in colon cancer, but it works in other GI tumors, in breast cancer. We found, you know, turns out to be quite active in appendix cancer. And so, we think that there's going to be many other opportunities to take drugs that work in other tumors and identify, you know, the subtypes or the subset of patients where they're working in appendix cancer. 

Beth Helmink, M.D., Ph.D. It sounds like, you know, while there aren't drugs approved specifically for appendix cancer, number one, there are treatment options that we can use that are used for other cancers. And thinking about the unique features of appendix cancer that are more like other cancers kind of helps you think about different types of treatments that may already exist and are used in other cancers. Is that, is that correct, or how do you approach a new appendix cancer patient? 

John Paul Shen, M.D. Yeah. So that's that's a great question. So, we don't have drugs specifically for appendix cancer, but that doesn't mean that we don't treat our appendix cancer patients. And so, we try to learn as much about the tumor as possible by doing molecular testing. We see what genes are mutated in that tumor. We now have specialized ways that we can look to see how the immune system and the non-tumor cells around the tumor are reacting to the tumor. And based on that, it helps us identify, you know, potential targeted treatments, the potential to use immune therapies, which have been very effective in other tumors and, and in some cases, effective in appendix cancer versus, you know, the kind of traditional colon cancer chemotherapy. 

Beth Helmink, M.D., Ph.D. I should add, you know, as a surgeon, like obviously surgery is, is a mainstay of appendix cancer treatment as well. And, you know, how do you think about getting patients to surgery or getting patients to see a surgeon? Like, how do you think about when you see a patient, when to engage surgery, when not to? 

John Paul Shen, M.D. You know, far and away, the best treatment for appendix cancer is to remove it all surgically. There is a very good chance that even though it's metastatic to the abdominal space, patients can still be cured, which, which is pretty incredible. You know, it is a challenging question that we're still working on who should have a surgery and who not. You know, part of that is related, as you know, to the amount of spread of the tumor, but part of it is also related to how aggressive the tumor is. And we're, we're trying to get better at predicting, you know, which tumors are very likely to come back after surgery versus which tumors are less likely to come back, and, you know, those are the patients that are really going to benefit from having the surgery.  

Beth Helmink, M.D., Ph.D. Yeah. And to your point about aggression, like, I guess we should talk too a little bit about the the grades of appendix cancer, because some, some appendix cancers are quite low grade, meaning not very aggressive, while others are very high grade. And and you know, for the low-grade patients anyway, surgery in fact is, is one of the best treatments. And in fact, we often don't treat those patients with chemotherapy. 

John Paul Shen, M.D. So, great, great point. And it really, I should have said this when you asked the question about, you know, what makes appendix cancer so hard to treat. A big part of it is that, you know, appendix cancer is relatively rare, but it's also very diverse. And so, because it's not that common, there's always been a tendency to lump together low-grade tumors, which, you know, grow very slowly. Don't respond very well to traditional chemotherapy and are best treated with surgery. You know, those get lumped together with high-grade tumors, which are, you know, on the spectrum more similar to colon cancer, you know, probably should get chemotherapy. And it's very unfortunate because we, you know, very commonly we'll see people, you know, coming to us with low-grade tumors that have been getting, you know, sick from chemotherapy that's not really helping that much. When in reality, they probably could have had a surgery. 

Beth Helmink, M.D., Ph.D. Yeah. I mean, I think one of my favorite studies that we've done here is your study on low-grade appendix cancer, where you guys literally took patients who had the same disease and either gave them chemo or not, and then switched it later on. So the patients that had not gotten chemo got chemo, and the ones that had gotten chemo went off of it and basically saw no difference at all in what that tumor did with chemotherapy. 

John Paul Shen, M.D. Yeah, absolutely. Yeah. So, yeah, specifically for low-grade mucinous appendix cancer, which is a significant fraction, maybe a third to 40% of all appendix cancer tumors, you know, don't really respond very well at all to 5-FU chemotherapy, which is the backbone of, of colon cancer chemotherapy and that, you know, that study which was, you know, started many years ago even before I got to MD Anderson, really is what, you know, solidified me that we need better treatments. We can't just keep, you know, using colon cancer chemotherapy and expecting it to work for appendix cancer because they're just very different. 

Beth Helmink, M.D., Ph.D. Yeah. And the surgery for those different patients are very different as well. You know, for low-grade patients we can be quite aggressive surgically and still have really good outcomes. I mean, these patients with low-grade tumors we anticipate will live for years, many years and for higher-grade patients, you know, we work with you really closely and try to think about when might be the best time to operate. You know, we obviously have to be technically able to resect everything, but we also kind of talk about whether it biologically makes sense. You know, if we think we can get them a long time of not having cancer or not requiring another treatment, than then it's probably worth it. 

John Paul Shen, M.D. So, I'll ask you a question. So, why do you why do you think it's important for a patient with appendix cancer to come to a place with surgical expertise? 

Beth Helmink, M.D., Ph.D. Yeah, I think it's absolutely the most important thing, honestly. I think, you know, you alluded to the fact that we see a lot of patients who, unfortunately, are treated a little bit differently than than we would. I hesitate to say incorrectly because it's not with malintent. It's just what, you know, because it's a rare tumor the, the practitioners just aren't familiar with it, aren't familiar with the latest research and the latest findings and the latest treatment guidelines. And so, as you mentioned, we see a number of patients who have been treated with chemo where it's not been helpful and it's only causing problems. We also talked about patients who are misdiagnosed and kind of mismanaged and being treated with ovarian cancer, for example. And we see them and clearly, this is coming from the appendix. And so, I think what we offer here is, you know, we have excellent pathologists who specialize in this disease and are able to kind of sort out low-grade and high-grade. We have radiologists who are very good at picking out small tumors, which this disease happens to form. The radiology is not straightforward. We have medical oncologists who think about this and are clearly thinking along the lines of, you know, this, this is a unique cancer. This is not colon cancer. We need to be thoughtful about this. And then from a surgery standpoint, you know, it's not just our surgeons who are specialized, but, you know, my job is rather unique because I treat only appendix cancer. No other surgeon in America other than the surgeons here really, really have that degree of specialization because they just wouldn't see enough patients. But we have enough patients here where that is actually the job of three full-time surgeons here. The number of surgeries we do here, too, it leads to specialization in our anesthesiologists, our nursing staff, our floor staff. Around the time of your surgery, you know, you're cared for by people who see these patients all the time, rather than going to a center who does maybe two or three of these a year. You know, we do over 70 of these a year. So, I think for all of those reasons. And then I think, you know, the other thing for us is, is our multidisciplinary conferences that we have every week, which, you know, we have every Tuesday morning, basically. And, you know, we combine a group of probably 15 to 20 physicians sometimes on the call, who are thinking about a given patient from all of these different perspectives, and all of these people on the call have specific expertise in appendix cancer. I think it makes complete sense. You and I are working on a phase I study together. And this is something I'm really excited about. But this, you know, is a result of the work that your group had done regarding the use of paclitaxel, which you alluded to earlier, a drug that, you know, kind of had not been used in appendix cancer previously. But can you talk about how you figured out how that it might be a good target in patients with appendix cancer? 

John Paul Shen, M.D. Yeah, absolutely. No, I, I share your excitement. Paclitaxel is a well known chemotherapy drug. It's been used to treat literally hundreds of thousands, if not millions of women with breast cancer. And it's active in esophagus cancer and gastric cancer. Really, colon cancer is kind of the exception where it doesn't work very well in colon cancer. But we thought that because of the mutation profile of appendix cancer being different than colon cancer, we thought, you know, paclitaxel in that class of drugs called taxanes would be active. So, as a way to test this, we, you know, made preclinical models which which took a lot of work so that we would have ways to kind of test our ideas before moving into patients. But it worked very well there. And then based on that success, we were able to open the clinical trial, which do you want to talk about how it's going? 

Beth Helmink, M.D., Ph.D. Yeah, I mean, I think it's going really well. You know, it uses paclitaxel. It's in patients that we are not able to operate on. So, so typically, patients with high-grade disease who don't really have a lot of other options. And so, you know, basically that trial requires a diagnostic laparoscopy or a surgery at the beginning to look at the disease, see where it is, what it looks like, and at the same time we place a port. So, just like a port that goes in your vein for IV chemotherapy, this one just goes into your abdomen. And we actually deliver the chemo right into the abdomen. This is not a new concept altogether. This, this has been used in patients with gastric cancer and ovarian cancer kind of over many years. And actually, there are phase III clinical trials or lots of patients that have been treated. And it's actually been shown to be beneficial in those cancers. And so, this is the only time that it has been used in appendix cancer, though, and I think that's what makes this unique. But we place the port. And then over the course of eight weeks, we deliver chemotherapy directly into the abdomen. Thus far, we've treated about 12 patients now. And you know, we had to lower the dose once, but that's it. And this dose has been very well tolerated. And in fact, we're actually seeing some pretty impressive results. You know as well as I do that it's kind of hard to determine the amount of cancer by a scan. So, we're using scans. We're using tumor markers. We're using that the diagnostic laparoscopy also to kind of see how the disease is responding. But I will say we've had multiple patients who've who've had really good results. 

John Paul Shen, M.D. Yeah, I, I share your excitement. This is, we think, going to be a launching pad for combinations. You know, pretty much every curative or highly effective regimen in cancer uses not just one drug but multiple drugs. I'm an impatient person by nature, but you know, the way that you have to go about is you have to do one drug first and show that that works. And essentially that is nearly done. And so, now we're really excited for and are already planning for combination studies, where will combine paclitaxel with drugs that activate the immune system to try to get a synergistic effect. 

Beth Helmink, M.D., Ph.D. Yeah. But but to have seen, you know, results with just the single drug, like you said, to me, is really impressive. And I would also add that these are patients who, you know, multiple lines of chemotherapy have not worked really well on. And so, you know, despite that, these patients are still seem to be having a response to this particular drug. So, you know, in addition to the combinations of different agents, gosh, it might be nice to move this earlier into their treatment regimen so that we could catch them at a little bit earlier stage when they have less disease. And it might be even more beneficial in those patients. 

John Paul Shen, M.D. Yeah, absolutely. We we may even be able to, you know, achieve shrinking the tumor enough to potentially get patients who weren't previously candidates for surgery to surgery if we can move it up into an earlier line of therapy, which, which is something that we were actively attempting to do. 

Beth Helmink, M.D., Ph.D. Yeah, I think it's it's great. And as you said, gosh, it's it's not the answer for sure, but it's at least a baby step towards getting there. And as you said, this is just a process. And if we don't start though somewhere we're we're not going to get anywhere is kind of how I look at it. Before we wrap up, we should maybe talk about some of the difficulties that patients experience while being treated with this. You know, whether they are being misdiagnosed or, you know, they don't feel like they're getting anywhere with their diagnosis or they have a diagnosis that's confusing to them, but they think they may have appendix cancer or patients with appendix cancer who feel like they've kind of reached the extent of what their local oncologist knows about appendix cancer. Like, how do you recommend that those patients, you know, advocate for themselves or advocate for their own family members who might be suffering from from this disease? 

John Paul Shen, M.D. Yeah. Great question. I think it's important, you know, as a patient, you do need to advocate for yourself. And if you don't, you know, feel like the plan that you're on is making sense. It's important to ask questions. And your oncologist should not feel threatened. If you ask, you want, you know, a second opinion, someone that has more experience. You know, we actually have a really good relationship with medical oncologists because people will come to us, we'll give chemotherapy recommendations, and they'll go back close to home and they'll, and they'll, you know, continue the therapy close to home. From a medical oncology standpoint, you know, rather than trying to figure out how to treat a rare disease on your own, they would rather you go and see a specialist, come up a the treatment plan, bring that back home, and then you can continue your infusions locally. 

Beth Helmink, M.D., Ph.D. And from a surgery standpoint, well, gosh, I say the same thing, right? I, as a surgeon, I would never be offended if one of my patients asked to get a second opinion. Right? And I think with these surgeries being such a big undertaking for the patient, I think it's totally appropriate that they, you know, even if a surgeon on the outside is saying they need this particular surgery, they need the the appendix cancer surgery, that they ask for a second opinion. And I also, you know, have a cohort of my own patients who are always very willing and able to talk to other patients you know, about to undergo the surgery or about, you know, or just have received this diagnosis. And gosh, I think it's so helpful for them to talk to other patients who have been through something similar again, just since it's such a rare disease. 

John Paul Shen, M.D. What are common questions that patients ask you about the cytoreductive surgery for appendix cancer? 

Beth Helmink, M.D., Ph.D. Yeah, I mean, I think the surgery itself is a pretty big surgery. And so, you know, we talked a little bit about appendix cancer, why it's so hard to treat. And part of the reason surgically why it's so hard to treat is it actually forms lots of tiny little tumors in lots of different places in the abdomen. When we do this surgery, it could mean anything from, you know, a colon resection to a small bowel resection to part of the stomach, the gallbladder, the spleen, the omentum, the ovaries, the uterus. You know, it can really be, you know, a kind of 15 different surgeries combined into one. And that, you know, it just is a very hard surgery to undergo because of all those, you know, all the little complications that can arise from any one of those surgeries just gets combined. The other thing that we do for this disease, to address all those tiny little things we may not be able to see and may not be able to get out. We do something called heated intraperitoneal chemotherapy or HIPEC. So, you know, what that is is basically pouring heated chemo into the abdominal cavity and circulating that through over the course of about an hour, hour and a half. Again, the goal of that is to address all those little things that we can't take out. But you know that chemo has effects and it has effects on healing. It has effects on the bowel and how the bowel recovers after a big surgery. And so all of this together, you know, it just means that this is a very long recovery for patients. And so, I mean, honestly, you know, I usually tell patients to expect to be in the hospital at least a week, probably closer to ten days. You know, they often have not been able to eat or drink regular food for about a week. Sometimes we even have to use IV nutrition. I usually tell patients that even when they go home, they're not going to be back to normal, and they may not get back to normal for about six or nine months, to be honest. Where they, you know, are having no pain or no problems with eating or have normal energy levels. Now, that doesn't mean that we don't get people through this routinely like we do a lot of these surgeries and many patients do quite well, but it certainly has the potential for a very long recovery. And so, I think patients kind of come in knowing a little bit about this and kind of having read a little bit about it. And so, their questions are usually along the lines of, you know, is it really this bad? And, you know, I think, as you said earlier, like coming to a place where we do this all the time and coming to a place where the surgeons are very experienced in this, and there are multiple surgeons here who do it, you know, gives them the best shot at having a really good outcome. But, you know, mostly I have to allay their fears that this is something we get people through every week here and every day here. And it's, it's definitely doable, but it is something that we do have to think long and hard about and be very thoughtful about when and who we operate on. But I think most times when patients come to me, they're, they're scared about the surgery. And I think my job is to educate. Well thank you, JP. This was, this was fantastic. This was a really great conversation, and I think really helpful discussion of appendix cancer. 

John Paul Shen, M.D. Yeah. Thank you so much for having me. This was a pleasure. 

Beth Helmink, M.D., Ph.D. And thank you for tuning in today. If you enjoyed this episode, be sure to follow or subscribe on Apple Podcasts, Spotify, YouTube, or wherever you get your podcasts. And don't forget to comment or review. For more information or to request an appointment at MD Anderson, call 1-877-632-6789 or visit MD Anderson.org. Thank you for listening to the Cancerwise Podcast from MD Anderson Cancer Center.