Advances in Pediatric Neuroblastoma Care

Podcast Transcript

Dale Shepard, MD, PhD: Cancer Advances, a Cleveland Clinic podcast for medical professionals. Exploring the latest innovative research in clinical advances in the field of oncology.

Thank you for joining us for another episode of Cancer Advances. I'm your host, Dr. Dale Shepard, a medical oncologist here at Cleveland Clinic, overseeing our Taussig phase 1 and sarcoma programs. Today I'm happy to be joined by Dr. Stacey Zahler, a pediatric hematologist oncologist at Cleveland Clinic Children's. She's here today to talk to us about advances in the care of patients with neuroblastoma. Welcome, Stacey.

Stacey Zahler, DO: Thank you, Dale. How are you?

Dale Shepard, MD, PhD: I'm doing great. Thanks for being with us. Maybe just start out, can you give us a little bit of an idea what's your role here at Cleveland Clinic?

Stacey Zahler, DO: Sure. So, I am a pediatric oncologist. My specialty, I take care of children and adolescents and young adults with solid tumors, pediatric solid tumors, and one of those pediatric solid tumors is neuroblastoma. I'm the person here who takes care of those children.

Dale Shepard, MD, PhD: Okay. Well, we have a wide range of people that might be listening in and they're scratching their heads like neuroblastoma. I think I know what that is, but I'm not sure. So, what is a neuroblastoma?

Stacey Zahler, DO: A neuroblastoma is a neuroendocrine type of tumor. It arises from the neural crest cells in development. It happens to be what I think is a fascinating wide spectrum of disease, because you can have a tumor that is completely non-malignant or non-cancerous, and you can have an intermediate type of tumor. And then you can also have an aggressive malignant form, which is called the neuroblastoma form. And even within the malignant neuroblastoma form, there are tumors that don't require any treatment at all, and they regress over time on their own. And there are tumors that can be widespread and very aggressive and very resistant to the therapies that we give. So, it's a truly fascinating tumor type and can be frustrating to treat sometimes too.

Dale Shepard, MD, PhD: How common are these tumors?

Stacey Zahler, DO: Neuroblastoma is the most common pediatric solid tumor that is extracranial solid tumor. And so, there are about 600 to 800 cases per year in the United States. So yeah, it's the most common, but still quite rare.

Dale Shepard, MD, PhD: Gotcha. It sounds like from a treatment standpoint, there's a wide range of treatments everywhere from watching them to much more aggressive therapy. So maybe just give us an overview on what some of the treatment options are currently.

Stacey Zahler, DO: Sure. So, we risk stratify neuroblastoma, low, intermediate, and high-risk disease. And each of those disease entities require different treatments. And so, a patient with low-risk disease may not require any systemic chemotherapy or other therapy. They only may require observation. Sometimes they require surgical resection. A lot of these tumors arise from neuroendocrine organs such as the adrenal glands or the sympathetic chain ganglia. So, there may be surgical resection anywhere along in those areas of the body. And the intermediate risk tumors will require some form of local control, usually surgical resection, but then also some systemic chemotherapy. And patients with intermediate risk disease, we do response-based chemotherapy. So, every two cycles we're re-imaging and reevaluating, and sometimes we can stop after two cycles, and we usually do up to about eight cycles of typically pretty tolerable outpatient type of chemotherapy. High-risk disease on the other hand, requires what I call the kitchen sink of solid tumor therapy in pediatrics.

We give intensive inpatient induction, five cycles of induction chemotherapy. In the middle of that, we send the patient for usually what's a big surgery to resect the bulky primary tumor site of disease. A lot of times that's a big abdominal surgery followed by tandem autologous stem cell transplant, which lands the patients in the hospital for months and puts them at risk for some toxicities that can be life threatening.

And then after that, they receive radiation to the primary tumor site as well as any metastatic sites of disease that were still positive right before transplant. And then they undergo six months of immunotherapy, which includes an anti GD2 monoclonal antibody, because GD2 sits on the outside of neuroblastoma cells. And GD2 also sits on the outside of our nerve cells. So that is a treatment that is quite painful and requires IV pain medication during its administration. So, they're in the hospital for that. And we also give isotretinoin, which is 13-cis-retinoic acid, which can help with the differentiation of the neuroblastoma cells. So that is nowadays the standard of care, high risk neuroblastoma therapy. And with all that, we're still not doing well enough. Only 50 to 60 percent of the patients don't relapse.

Dale Shepard, MD, PhD: And so, do most of these patients have a pretty good response initially, but then ultimately relapse?

Stacey Zahler, DO: Sometimes. But it's not like our patients with, for example, rhabdomyosarcoma, where they respond amazingly well initially to chemo. A lot of patients may just have a partial response to chemotherapy prior to transplant. So, we take that into account with the rest of their therapy.

Dale Shepard, MD, PhD: That must be frustrating to providers and patients and families.

Stacey Zahler, DO: Yes, and it's why we've, through the decades we've added on all these therapies.

Dale Shepard, MD, PhD: Tell me a little bit about the BEAT Childhood Cancer Consortium.

Stacey Zahler, DO: So, BEAT Childhood Cancer Consortium is used to be called the NMTRC, but they partnered with BEAT and BE, which is a parent founded organization to support efforts for neuroblastoma research and to support patients and families going through it. And so BE Childhood Cancer Consortium is the research consortium that exists that was developed by Giselle Schuller, who is now down at Living Children's in Charlotte, North Carolina. We are a consortium of what used to be a handful of sites, and I think they're up to about 60 sites now across the nation and in Canada. And so, there are many clinical trials geared towards neuroblastoma, but there are also clinical trials that have been developed for other types of tumors as well, for example, brain tumors and things of that sort.

Dale Shepard, MD, PhD: So, some of the things you mentioned, the need, despite for patients with high-risk disease, despite really aggressive therapy, still needing some more therapy. Tell me about DFMO and trials and with that compound and what looks promising?

Stacey Zahler, DO: So, DFMO or difluoromethylornithine is a pill, which is kind of nice. It is actually FDA approved for the treatment of African sleeping sickness. So, it's been used for a long time for that purpose. But back about maybe 15, 20 years ago, they started studying DFMO against cancer cells, and they realized that the neuroblastoma cells, in vitro, were quite responsive and the tumor growth significantly decreased with DFMO administration. So clinical trials developed. We are now in phase two trials. We've been running these DFMO trial, Dr. Schuler I should say, and her group have been running these DFMO trials for well over a decade now, I would say about 12 years. And we've seen some really promising results. So, the patients that have really benefited the most are the patients who go through all of that high-risk kitchen sink therapy and then receive DFMO as a maintenance therapy for two years.

So, they take this drug, which is really pretty well tolerated, has minimal side effects, and they take it every day, twice a day for two years. And the patients who were in a complete remission at the end of their conventional therapy, were seeing five-year event free survival rates of the mid 80 percent, which is really significantly improved from what we know exists now. So, patients with relapse and refractory disease also respond to this drug less percentage, but still a patient who relapses with neuroblastoma has a very dismal prognosis in general. And so, to have a drug where we actually see some response is very promising.

Dale Shepard, MD, PhD: And so, patients, you say like refractory disease for instance, would that be patients that had that initial chemotherapy and then you get a break point, you go, well, do I do a transplant or do I do something like this?

Stacey Zahler, DO: Well, that's a great question. So, I wouldn't jump to DFMO right away, because we have found that DFMO works best with minimal burden of disease. But yes, even in those patients where they still have some disease left at the end of high-risk therapy, it can have some effect.

Dale Shepard, MD, PhD: Very good. Tell me about MIBG.

Stacey Zahler, DO: MIBG, all these acronyms, right?

Dale Shepard, MD, PhD: I know. It's crazy.

Stacey Zahler, DO: So MIBG is metaiodobenzylguanidine. There are two radio labeled forms of MIBG that have been used for imaging neuroendocrine tumors for many decades. For example, thyroid, medullary, thyroid cancer, other neuroendocrine types of tumors like pheochromocytoma. And then also neuroblastoma. While they used to use 131 iodinated MIBG to image. And they were realizing that, this was back in the 70s and 80s, and they realized that the tumor cells were actually dying as a result. And there was actually a response on the scans and also was ablating their marrow. So, we actually use 131 iodinated MIBG now for the treatment of neuroblastoma. And the indication is really not super well understood yet, but we're learning more and more as the years go on. So, we do know from many clinical trials in the pediatric world through Germany and through the European consortiums, and also through the American consortiums, that MIBG therapy can be used in combination in some way with autologous stem cell transplant.

And we also know that not all patients respond to induction chemotherapy and we need to do better. And the survival rates of those patients that don't respond, we haven't improved in the last two major clinical trials here in the States. So, the currently open children's oncology group clinical trial is incorporating MIBG therapy upfront in the middle of induction chemotherapy and several weeks out from tandem autologous stem cell transplant. So, we here at Cleveland Clinic Children's are becoming an MIBG therapy center, and we've been working on this now for about the last year and a half. There are about 24 other institutions across the nation that have this therapy available and we’ll be the 25th. So, it requires very specialized, as you might imagine, care. Our radiation safety team is highly involved. Our nuclear medicine team is highly involved, and I'm excited that we'll be able to offer this therapy soon here at Cleveland Clinic Children's.

Dale Shepard, MD, PhD: Doubling back quickly for the DFMO, you said there have been trials going on for 10, 12 years and data's looking promising. Phase two setting. What's kind of path to approval? When might that be something that would be more broadly available?

Stacey Zahler, DO: Excellent question, and yes, I should mention that Dr. Schuler's hope was to apply for approval very soon this year or next year. So, the group has been in conversation with the FDA and tailoring the clinical trial needs to fit what the FDA is going to need for approval. And the Children's oncology group even has incorporated DFMO into their clinical trials as well. So, I think it'll happen in the next couple years.

Dale Shepard, MD, PhD: I mean, certainly it would meet unmet need criteria and things like that.

Stacey Zahler, DO: Absolutely.

Dale Shepard, MD, PhD: That's great. Yeah. Are there other compounds that you're excited about in this disease? It's a rare disease, so yeah, it's impressive to be so far along on a couple of therapies as is. But is there anything else that seems promising?

Stacey Zahler, DO: So, I talked a little bit about the anti GD two monoclonal antibody. There is one that's FDA approved; it was approved back in 2016. It's called dinutuximab and we use that now in upfront therapy. But there's also a different monoclonal antibody that is humanized form that was made out of Sloan Kettering that was just last year FDA approved. It's called naxitamab for relapse refractory neuroblastoma, and is starting to be used in clinical trials in the upfront setting as well. So excited about that. Sloan Kettering also has a vaccine trial that exists against neuroblastoma cells, and I think the criteria are they have to be in a complete remission in order to receive that vaccine, but has shown some efficacy as well. So, there are other things out there.

Dale Shepard, MD, PhD: Serious things out there. And I guess at the beginning you talked about this low intermediate high risk, a lot of these therapies are more for the high-risk patients, if you look at the breakdown, you said six, 800 patients, where do most of the patients fall? Do they mostly fall within that high-risk category?

Stacey Zahler, DO: No. So right, that's a great question. About 20 percent of patients are low risk, about 40 percent of patients are high risk, and then the other 40 are intermediate risk. Now, I will say that anecdotally, I have seen here several cases in the last few years of intermediate risk patients who relapse. And again, when a patient relapses, the prognosis is poor, even with intermediate risk disease initially, because they usually relapse in a metastatic fashion. And so that is something that I think needs to be studied better. We don't have a good grasp on why these patients with intermediate risk disease relapse and we don't have a good way to salvage them. So that is something that I personally would like to study in the future.

Dale Shepard, MD, PhD: Are there any other significant gaps that need to be answered in this disease?

Stacey Zahler, DO: I would say right now that's the big one, is the patients. Patients obviously who relapse, yes. But patients with intermediate risk disease where there should be an 87 percent survival rate. What's happening in those 13 percent?

Dale Shepard, MD, PhD: Seems like every disease is being studied in greater detail on a genomic basis and things like that. Are there any genomic studies that might either point to additional treatment options or ability to maybe more accurately define intermediate risk based on the way we categorize that, but maybe not so much intermediate?

Stacey Zahler, DO: Yes. So, I didn't mention when talking about neuroblastoma in general, the molecular features of the tumor itself. So, the main molecular feature that's very important prognostically, is MICEN the amplification of MICEN. And those patients that do have MICEN amplification in the tumor, fare much more poorly. And so, we haven't found yet, we've tried, but we haven't found yet a great way to target MICEN. There is other, in the last decade or so, we've had more and more segmental and whole chromosomal aberrations. So, when you do a targeted micro array analysis, you may find loss of heterozygosity of 1P or 11Q, 17Q gain. These are a few examples of a handful of molecular findings, and I don't know how you target that, but we do know that those are important.

Dale Shepard, MD, PhD: Well, it sounds like this is a rare disease, but an amazing amount of work that's been able to be accomplished, which is pretty impressive.

Stacey Zahler, DO: Yes.

Dale Shepard, MD, PhD: Oftentimes rare tumors, it's hard to get targets and trials and things. So great insights on neuroblastomas today. Thank you.

Stacey Zahler, DO: Thank you very much, Dale.

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