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Sumanta Pal, MD: Hi, my name is Monty Pal, and I am a medical oncologist at the City of Hope Comprehensive Cancer Center. Welcome to Medscape's InDiscussion series on renal cell carcinoma. Today we're going to discuss renal medullary cancer (RMC). I have a very special guest, Dr Pavlos Msaouel, who is the lead on the RMC program at the MD Anderson Cancer Center. He's an assistant professor and a physician scientist focused on kidney cancer. His lab focuses on ways that we can prevent, diagnose, and treat renal cell carcinomas, and he has a special emphasis on variants like RMC. Pavlos, welcome to InDiscussion.
Pavlos Msaouel, MD, PhD: Thank you so much for the very kind introduction. I am very happy to talk about RMC today.
Pal: On this program, we usually don't spend a lot of time talking about pathophysiology. Most of the subtypes and topics that we have covered have been related to clear cell carcinoma. That biology has been really well established. Tell us what you know about the biology of RMC. What types of patients are impacted? What's underlying RMC as far as we know today?
Msaouel: RMC actually does have a very unique pathophysiology in the sense that in more than 90% of cases, it predominantly afflicts people who have sickle cell hemoglobinopathies. As long as you have a blood disorder that could cause red blood cell sickling, sickle cell disease, sickle cell trait, or any of these variants like hemoglobin SC disease (SC) or sickle cell beta thalassemia (S-beta), you are at increased risk for RMC.
Pal: Interesting. With that biology in mind, I'm thinking of the patient population it afflicts. Can you give us a sense of the demography of where we typically find RMC?
Msaouel: Absolutely. That is another very unique characteristic of RMC. For example, in the US, RMC predominately afflicts young individuals of African descent, African Americans in the United States. Essentially, in every area that has a high prevalence around the world with sickle cell trait, you will see individuals with RMC. There are 3 million individuals with sickle cell trait in the United States, but there are 300 million individuals with sickle cell trait around the world, mainly in Africa, but also in other areas like India and Greece. There are some areas with high incidence of sickle cell trait because of its protective effect from malaria. It's the areas that actually had high incidence of malaria where you see people with sickle cell trait. Now we know that those populations are at risk for RMC. In the past, we weren't sure. We thought maybe it's something in the water in the United States. As we raised awareness about RMC, we are now having people diagnosed in Greece, Africa, and everywhere around the world.
Pal: That's so interesting. I didn't realize that, prior to this call, we were actually seeing a surge and recognition of this in other parts of the world. Are there experts in those locations whom you're working with to help address these at-risk populations?
Msaouel: It's a fantastic question, and it is indeed so important to raise awareness about RMC. It's made such a huge difference. When I first started getting involved in the field around 2015 and 2016, we thought that RMC was much rarer than we realize now. We thought that RMC was rarer or as rare as collecting duct carcinoma. As awareness has been raised, now we know that RMC is probably 10 times more common than collecting duct carcinoma. That's definitely in our experience and how frequently we see it. As you said, what makes a big difference is patient awareness, patient advocacy, and creating a network of people from all over the world whom we collaborate to help patients with this disease.
Pal: That is fascinating. When are we catching RMC? Are we catching it early on in the disease course? Are we catching it late in most patients?
Msaouel: That is another challenge with RMC. RMC is one of the deadliest, if not the deadliest, renal cell carcinoma. If you do not treat it or if you treat it the wrong way, the average survival is anywhere between 3 and 4 months from diagnosis. That is why this disease is almost always diagnosed at a late stage. Even if you think that it is stage II or stage III, if you wait for a few weeks and you re-image, you will realize that it is in fact stage IV. There has been a lot of progress in diagnosing it accurately, but we still need to do more work in potentially screening and diagnosing it at an even earlier stage to increase the chances of curing these patients.
Pal: Interesting. You verged on a discussion of treatment there. What is your approach to the patient who presents with RMC independent of stage? Walk us through how you might treat a localized patient vs a metastatic patient. Are there common threads?
Msaouel: That is such an important question. The key message here is that RMC is managed very differently than most other kidney cancers. It does not respond to either the standard immune checkpoint therapies or the anti-vascular endothelial growth factor (VEGF) tyrosine kinase inhibitors (TKIs) that we give for clear cell renal cell carcinoma, for example. It can respond to platinum-based cytotoxic chemotherapy that does not work for most renal cell carcinomas and definitely not clear cell renal cell carcinoma. This is why it is so crucial to diagnose RMC accurately.
What do we do when we catch it early? That is another key difference compared with most other kidney cancers. We typically do not do upfront nephrectomy in the vast majority of patients with RMC, with very few exceptions. Instead, we typically give upfront, platinum-based cytotoxic chemotherapy to debulk the tumor and make sure that the tumor is responding. Then, after at least a few cycles and evidence of response, we do a nephrectomy with the hope of curing these patients.
Pal: I've seen some of these patients recently, and I almost always call you to pick your brain about these cases. I encourage all of our listeners to do that. Dr Msaouel is incredibly generous with his time and is very accessible. If you see an RMC patient, I know that Pavlos is going to be willing to help. When it comes to platinum-based chemotherapy, what particular type of chemotherapy should we be thinking of?
Msaouel: Great question. And, as you said, please get in touch with me. We are more than happy to help with these patients, whether we can see them in person or not. There are often logistical challenges with them coming to Houston, enrolling in clinical trials, etc. We will help and guide them to the best of our abilities. It's always a dialog as we do, Monty, whenever you give us a call to discuss a case.
With regard to platinum-based chemotherapy, we've tried a lot of different permutations, even old-school standard carboplatin/paclitaxel, carboplatin AUC 5 or 6. Typically, these patients are young, and they can tolerate higher doses. Paclitaxel 175 mg per square meter every 3 weeks can produce responses. We haven't really seen much difference between cisplatin and carboplatin. As we have discussed, we do want to do nephrectomy, if possible, and carboplatin may be a better choice in this regimen than cisplatin. Sometimes, when patients are particularly young, we may include triplet regimens with gemcitabine and other combinations. Depending on the context, we're more than happy to share our evolving experience with how to sequence or use these regimens.
Pal: I was so intrigued because on Twitter, I just came across this phenomenal case report of a complete response to triplet therapy. I wonder if you could share that with our audience.
Msaouel: Absolutely. That is another key message. It used to be that RMC was a death sentence, and it's still a very deadly cancer. But there is hope. Nowadays, I would say that 5%-10% of our patients with stage IV RMC can be rendered disease free. Now that's not enough. We definitely need to do better. This is progress, but we are working nonstop to get this to 100%. Nowadays we have first-line regimens like the platinum-based chemotherapy that I mentioned. We have second-line regimens, which can be, for example, gemcitabine plus Adriamycin plus minus other therapies. Even now, meaningful third-line regimens targeting the epidermal growth factor receptor (EGFR) pathway have shown to be effective. This, along with the ongoing research, is creating more options. The case report that you mentioned is a nice example of a patient who presented with stage IV RMC. This is a unique case in the sense that this patient had a germline neurofibromatosis type 2 (NF2) mutation. This is the first time we've ever seen this. Interestingly, this NF2 pathway is connected with our research. We had noticed that RMC may be related with the NF2 pathway, but we have never observed the connection with germline NF2 mutation. What this tells us is that we should keep an open mind. Sometimes, patients may end up having a rare diagnosis, including RMC, where we least expect it. That particular patient did not have any sickle hemoglobinopathies — just the NF2 germline mutation — and we were able to render her disease free with platinum-based cytotoxic regimens.
Pal: That's amazing. It's a huge win for the patient. It brings up this question that I'm sure many clinicians struggle with in a patient population like this. Should we be profiling everybody? Have you run into other anecdotes where the profiling has been helpful in terms of really directing targeted therapy approaches?
Msaouel: We should definitely keep an open mind, and RMC should be in the diagnosis whenever a pathologist encounters a high-grade adenocarcinoma morphologically, particularly if radiologically it appears to be more central arising from the medulla. We should always think about checking for a sickle cell trait because up to 40% of our patients with RMC did not know they have the sickle cell trait. We should always think about checking for sickle cell trait and think about RMC every time we see a young, athletic (that's another new thing we're noticing now) African American in the US — also, if the patient is male, because it happens twice more commonly in male individuals who present with a gross hematuria and a right-sided kidney lesion. Another unique feature of RMC is that in 75% of cases, it arises from the right kidney.
Pal: That's just brilliant. All of your talks are really fantastic, but you gave a fantastic presentation 2 years ago at the Kidney Cancer Research Summit (KCRS), and you were highlighting your detailed look at this biology and how exercise might be biologically linked to the evolution of RMC. We always tell our patients to exercise, but here's a case where high-intensity exercise may actually have a detrimental effect. I hope I'm not misinterpreting that, Pavlos.
Msaouel: Absolutely. This is an excellent point. This was something that we've worked on a lot to make sure that this evidence is indeed real. Through a lot of work in mouse models and clinical observations, we do have evidence that high-intensity but not moderate-intensity exercise is a modifiable risk factor for RMC among individuals who have sickle cell trait or other sickle hemoglobinopathies. The reason why this happens is that the extreme hypoxia and dehydration, which very high-intensity exercise can cause, can result in sickling of the red blood cells in the medulla, causing the kind of damage that can lead to RMC. We do have weaker evidence in our mouse models where we have noticed that due to the vasodilation that it causes, moderate-intensity exercise may actually reduce the risk of RMC. When I say moderate-intensity exercise, I mean exercise where you get up to 50%-70% of your maximum heart rate — legitimate exercise as opposed to high-intensity exercise that is constantly gaining more than 80% of your maximum heart rate. In fact, because of the connection of sickle cell trait with rhabdomyolysis and potentially sudden cardiac death in the setting of high-intensity exercise, the Centers for Disease Control and Prevention (CDC) has made specific recommendations on exercise programs so that the community can continue to be highly active, athletic, and even be professional athletes without increasing their risk of such complications, whether they have sickle cell trait or not.
Pal: That's just brilliant. The way that you were able to establish that continuum to me is fascinating. It makes me think that it's something we should be doing, for the more common histology is in renal cell carcinoma, and really tying together these links. We talked about the obesity paradox on this program before. There are so many nuances to how day-to-day living might either lead to evolution or propagation of some of these malignancies. I wanted to switch gears and talk about the clinical trials that you're running at MD Anderson in this space. We've talked about some of the big phase 3 clinical trials that are running. But I applaud you for taking on these rare histologies in the form of clinical trials. We always dismiss them at the cooperative group level. You've been successful in running some of these RMC studies. Tell us about them.
Msaouel: This is something that, as you said, took a lot of effort and championing, but it is feasible. In 2007, we opened the first clinical trials specifically dedicated to RMC. That is how we discovered that standard immune checkpoint therapy does not work in RMC and may actually even feed RMC. We wouldn't know this if we were just running a basket trial that just included a couple of cases of RMC. When you do a dedicated trial for a specific histology, you can see clear patterns. In 2018, we opened the second investigator-initiated trial testing cytotoxic chemotherapy, plus the proteasome inhibitor ixazomib based on our preclinical data in RMC. We hope to publish these results in 2023. We saw some very interesting clinical signals that will help the community. In September, we opened the third investigator-initiated clinical trial specifically for RMC testing nivolumab anti-PD-1 inhibition combined with high doses of relatlimab, because our previous research has now shown us that T-cell exhaustion, in part due to engagement of lymphocyte-activation gene 3 (Lag3), may be one of the reasons why we're not seeing responses with other immune checkpoint therapies. To test that hypothesis, we activated this trial in September, and we've already enrolled six patients as of March 2023 at a single center. I wish we could open it across the country and across the world. We're restricted to open it only in Houston due to funding constraints. Those trials are feasible. We open them, we complete them, we learn from them. We hope by early 2024 to open the fourth trial dedicated for RMC. Our goal and next step is for the next trials to be multicenter, to get the funding to open them everywhere around the country and potentially around the world.
Pal: You've definitely got a fan in me for that vision. I'm so proud of everything that you've done. That segues into the last bit here, which is that you are really a visionary in the field. You've done a lot at a very young age to advance these elements of kidney cancer therapy. What's your advice to the young folks getting into the field? How can they carve a niche, as you have in the domain of kidney cancer research?
Msaouel: Having good mentors and sponsors is key. I cannot praise Nizar Tannir enough. He is my mentor, sponsor, and essentially surrogate father for getting me both in the kidney cancer field and RMC, in particular. He is the one who infected me with his enthusiasm about RMC.
Academia is a marathon in the sense that you have to build your portfolio meticulously over a long time period. It is important to remember that junior faculty will have to balance two key principles. The first is that knowledge is more efficiently created when we constrain, in a way, our degrees of freedom. This is just a fancy way of saying that we should stay focused. At the same time, it can be risky to put all our eggs in one basket. We want to maintain some diversity in our academic portfolio. How can we achieve this balance? Well, there are at least two broad paths. The first is to become very focused and very deeply learn a method. The method can be anything from analyzing clinical outcomes or knowing single-cell sequencing bioinformatics or the microbiome. That's a field that is near and dear to your heart. Then we keep things diverse by applying this method across different cancers or contexts. The other path is what I did, which is to stay very focused in a specific disease like RMC and keep things diverse by exploring every aspect of this disease, from its epidemiology to its pathophysiology, clinical and molecular hallmarks, and therapeutic vulnerabilities.
Pal: I love that. I'm not sure that I'm going to remember the degrees of freedom concepts, but I will definitely recall this principle of focus. I think that's so critical, and I'm glad that you've highlighted it. Today, we've talked to Dr Pavlos Msaouel from the MD Anderson Cancer Center about this brilliant program that he's built in RMC. I personally think it's really revolutionized treatment paradigms for RMC. Thank you for your efforts there. Please take a moment to download the Medscape app to listen and subscribe to this podcast series on renal cell carcinoma. This is Dr Monty Pal for InDiscussion.
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Cite this: Renal Medullary Carcinoma: The Importance of Early and Accurate Screening, Diagnosis, and Treatment - Medscape - Jun 06, 2023.