Neuroblastoma: New Hope for Kids — In-Depth Doctor’s Interviews
John Maris, M.D., Chief of the Division of Oncology at the Children’s Hospital of Philadelphia, talks about a new type of immunotherapy for neuroblastoma that offers the first substantial cure rate of the cancer in more than 10 years.
What is neuroblastoma?
Dr. John Maris: Neuroblastoma is a childhood cancer. It is a disease that affects young children. The average age of diagnosis is about 18 months, so these are generally toddlers or very young children. In fact, it’s the most common cancer that afflicts children less than twelve months of age. It’s a cancer that is a subset of patients and up to half of patients have a benign form of the disease. It is very curable with the surgeon’s knife and/or moderate chemotherapy, but the problem is a little more than half of patients have a very aggressive form of the disease that is generally widely metastatic, spread from where the primary tumor starts to multiple sites in the body at the time the cancer is diagnosed.
What is the primary site of neuroblastoma?
Dr. Maris: Neuroblastoma is not a brain cancer. It is a disease of nerves in the peripheral nervous system in the body. It is actually a disease that arises in something called the sympathetic nervous system, which are the nerve cells that give us our fight or flight response. Therefore, one of the reasons why it often is difficult to diagnose is that the disease can occur in the neck, in the chest, in the abdomen, or in the pelvis. It’s a solid cancer that arises often near the spinal column, and can be deep within the body and can get pretty large before it’s detected.
What are the symptoms of neuroblastoma?
Dr. Maris: The signs and symptoms of neuroblastoma can be anything from a lump in an otherwise well child to a child who has been sick for weeks or months with basically the dwindles –just not feeling right and just getting a little more pale. Oftentimes, it’s thought to be a flu or a viral illness that just doesn’t go away. Ultimately, it’s pain. It’s a disease that spreads to bone, and nothing hurts more than pressure inside your bones, so many of the children, when they’re diagnosed, are in significant pain.
Because you’re talking about very young children that can’t verbalize what’s going on, can the symptoms last awhile before it’s diagnosed?
Dr. Maris: Anything that’s afflicting young children where they can’t verbalize things can be tricky, and certainly it can be insidious in its onset and slow in its onset in some cases, so the child just sort of gets used to not feeling well. That said, in this day and age, most children are diagnosed as soon as they come to medical attention. It’s very rare for this to be missed, and I think that children get into our hands at the appropriate time. It’s just that this high-risk side of the disease can be very aggressive and spread, even when picked up as soon as possible.
What have been the traditional treatments for neuroblastoma?
Dr. Maris: For most of our discussion, I’m going to focus on the children who have the high risk disease. I mean, that’s the huge problem that we’re facing. The therapy is really everything that’s in our armamentarium. Children receive surgery – usually more than one surgical procedure. Children receive chemotherapy, and at the typing and the doses and the intensity that far surpasses the equivalent doses in most adult patients, so it’s very aggressive chemotherapy. All patients receive radiation therapy, and this can often be very extensive, and finally, neuroblastoma is one of the few diseases where very high doses of chemotherapy are given enough so to oblate, or wipe out the body’s own bone marrow system, and then a rescue is given that was collected before. This is one of the few diseases where this has proven to be effective, so all children receive a transplant. It’s a very aggressive treatment. It’s a treatment that lasts about a year, and it has to occur with children in the hospital.
What is the treatment that you’ve been studying?
Dr. Maris: There has been a long interest in the field of immunology related to cancer, and the fact that cancer could be a failure of our own immune system to fight off the disease, to recognize a cancer cell as foreign like a virus, and try to get rid of it, and there has been enormous interest in trying to fix that problem or to harness the body’s own immune system to combat the disease. What you need, in order to make this work, is something specific about the cancer cells that’s different from the rest of the body. There is something called GD2, which is a chemical that’s on neuroblastoma cells – essentially, all neuroblastoma cells have this chemical on the surface of the cells – and some very smart investigators in the 1980’s actually figured out how to make an antibody against this molecule, GD2. This study that we’re talking about now is the culmination of multiple investigators working together over the years to first figure out whether this is safe to do, whether it has hints of effectiveness, whether it should be given by itself or with combinations of medicines, and to get to the point where we have what we thought was an effective total therapy that was tested in a clinical trial.
What did you test?
Dr. Maris: All of the work that was done up until now showed that if you had just this antibody, that by itself was not strong enough to get the body’s own immune system to work to eradicate the neuroblastoma cells, that if you combine that with hormones that the body naturally makes – in this case, we use something called GMCSF and IL2. These normal hormones that are used when you get the flu or whatever, to help rev up your own immune system, if they are given in combination with the antibody, at least all of our test tube studies and prior studies have shown that it seemed to work better. Finally, there was another drug used for believe it or not, acne. Accutane, which had been proven in the past to make some cancer cells and neuroblastoma, in particular, not die, but to differentiate, to turn into a normal nerve cell. That had been used standardly for children with neuroblastoma for the last four or five years. It’s really four drugs altogether that we tested, and very importantly, it was done at the end of therapy, where we traditionally would’ve stopped therapy where children were apparently in a remission, cannot detect the disease anymore. The problem in the past was that the majority of children that we got into a remission – can’t see it, scans are all negative, everyone is patting each other on the back – at least two-thirds of the time the disease would come back, a relapse, so this was really a therapy designed to get any of these rare cancer cells that are hiding in the body quiescent, just hiding there, to get those cells and eradicate them so that they could not contribute to a relapse.
What did you discover when you started the trial?
Dr. Maris: The clinical trial, first of all, was a randomized clinical trial. I think it’s very important to know that for all the children that enrolled in the trial, there was a 50/50 chance that they would either get the new experimental treatment or the standard, which was just this Accutane medicine alone. What we learned early on is that this stuff is toxic. I said earlier that you need to have this GD2 on the tumor cells, but there is some of it on normal nerve cells because this is a disease that comes from nerves. This stuff hurts. Almost all patients get pain while the drugs are going in. It goes away when you turn it off, but pain is almost universal. What we knew is that we were basically giving these children the flu, I mean, we’re giving them the same chemicals that give you flu-like symptoms – aches and pains and fever and that sort of thing. We predicted, before we started the trial, and knew from our prior studies, that this would be a toxic therapy, and indeed, it was, but what we learned at the end of the day when we had treated over 200 children on this trial is that it works. It prevents relapse and that the children who were randomized to receive this immunotherapy had a 20 percent better chance of not suffering a relapse, which in the world of cancer clinical trials is a pretty remarkable result to improve a cure rate by 20 percent.
What would be a normal rate?
Dr. Maris: The overall cure rate for children with neuroblastoma, high risk neuroblastoma, prior to this trial, is probably in the 40-45 percent range, so we predict this trial will boost it up significantly. The results of this trial were so significant that we were able to close it early. I think every randomized clinical trial is really asking the families and the patients to trust us. This trial was monitored very closely, and as soon as we were 100 percent sure of the difference that we began to see a few years ago, it got to a point that it was not possible to be a statistical fluke, not just a chance that it appeared patients were doing better, we closed the trial early. The trial was originally designed to accrue over 400 patients, and we closed it when there were 226 patients enrolled.
How long do the patients have to be on the mix of medications in order to prevent a relapse?
Dr. Maris: The study was designed for the children to receive five cycles of immunotherapy, which lasts about five or six months.
What is the next step then?
Dr. Maris: There are a couple of important points about where we’re heading next. First of all, we have an effective therapy, and it’s our duty and our obligation to get that to all children who could stand to benefit, so the immediate action was to close the control arm of the clinical trial, leave the clinical trial open, but all patients get the immunotherapy. The real challenge is that neuroblastoma is an orphan disease. It only affects 700 patients each year in the United States, and right now there is no biotechnology company or pharmaceutical company that owns the rights to this antibody. The antibody was made in a laboratory at the National Cancer Institute, and what that means is there’s no commercial supply. We are working with the National Cancer Institute and with some biotech companies to get this commercialized. We have to assure that there is this immunotherapy regimen available and that it’s going to be available moving forward, and that really is where all of our efforts have gone into since discovering this result.
How long has it been since there’s been a positive movement in terms of neuroblastoma?
Dr. Maris: The last clinical trial that showed a new treatment improving outcome was published in 1999, which means the study ended in about 1996. That was the one that showed that transplant helped and that Accutane helped, so it’s been a long time.
How would you characterize what you and your fellow researchers have discovered?
Dr. Maris: I think it’s a major step forward in the field of neuroblastoma, and I would also dare say that it’s a very important discovery for cancer immunotherapy, cancer therapy in general. In this disease, neuroblastoma, this study also, besides being basically a home run for children who have this disease, it is the first time that an immunotherapy against basically a sugar-fat molecule – it’s a glyco-lipid that’s on the cell’s surface – has been proven to be effective. That may sound trivial, but there’s been a lot of debate in the cancer therapy about what makes a good tumor anogen, or what is sticking out of a cell makes sense to try to attack. This is the first time that we’ve shown that this class of a chemical is good to attack. Secondly, for the cancer community in general, this is the first study to show that adding in the cytokines, the chemicals to rev up the immune system, are an important piece of the picture. Now, we didn’t study whether or not antibody alone, or if you need the GMCSF or the IL2 or both. We may never know that, but what we do know is that the whole package is effective, so now our obligation is to build on that, and our future clinical trials will take this result and try to improve upon that.
Prior to these findings, when you’re talking about this high-risk population of patients, what was their prognosis?
Dr. Maris: In the study from 1999 – that showed that the last major advance. The children who got the best therapy had about a one-third chance of surviving. We’re hoping that even though there hasn’t been a major advance, we have improved therapy, we have made incremental progress through this decade, but we’re certainly hopeful that a child who presents today who receives the most modern therapy in terms of the best chemotherapy, the best sort of supportive care, and this immunotherapy regimen, that the cure rates will finally be past that 50 percent mark, and maybe significantly past that 50 percent mark. I think it’s important to emphasize that the job is far from done. The therapy is still very toxic and there are still children who do not go into remission, and there are still children who are going to relapse despite getting in remission, so even though I use the word home run, it’s probably not. I mean, it’s a major advance, that’s for sure, it’s the best result we’ve had in a long, long time in this disease, but there is still a very significant amount of work that needs to be done to get more precise, more effective, and at the same time, less toxic in what we’re doing because it’s not all about cure rates – children that survive have a high risk of having significant long-term side effects from the therapy that we’re providing.
What are some of the side effects?
Dr. Maris: The intensity of the chemotherapy and the radiation therapy make it so that at least two-thirds of the children have some long-term side effect, and up to one out of four children have a significant life-threatening sort of side effect, so the potential side effects of this therapy are broad and have to do with the different drugs that are used and whether the radiation was in the abdomen or in the chest, but they’re significant. Almost all these children have hormonal difficulties. Almost all the children will have problems with fertility or be sterile. The most horrific side effect is inducing or causing a cancer and some of these children are at risk for a second malignancy, so as much as we’re happy with this result and think that the immunotherapy is not adding significantly to the potential long-term side effects, we don’t know that for sure yet, and we have to stay cognizant of the concept of it’s not just about cure, it’s cure with quality, as we think about new treatment regimens moving forward.
What was the situation with your patient, Elizabeth?
Dr. Maris: The thing that I would like to emphasize about Elizabeth’s case is no matter how hard you try to design a clinical trial to be inclusive, there are always going to be individual children that fall through the cracks. The thing that was most striking about Elizabeth is that even though we, as physicians here at CHOP, had a patient like her in mind when we were designing the immunotherapy, she, through technicalities, was not eligible for the clinical trial. It’s a long and complicated reason, and it has to do with some unique aspects of her case, but she was not eligible, so Dr. Steven Grup and I here, because we had the belief that it would be the potentially important part of a curative regimen for her, we were able to petition the National Cancer Institute to have the immunotherapy regimen released to us on a compassionate basis to be used in her particular case, not part of the clinical trial. I think it was a gratifying result, certainly for me professionally, but I think that’s the understatement of the year. For the parents to see the results of this trial, to validate that the effort that they went through to get her access to this drug, watching her go through the side effects of this drug were worth it in the end, at least statistically.
Is she in remission at this point?
Dr. Maris: Elizabeth is in remission now, and she’s remained in remission, off of therapy now, for quite some time, and she is a normal, healthy appearing young lady, and we have high hopes and aspirations for her prognosis. The tricky thing about this immunotherapy and for the families that allow their children to be randomized is that it’s very different than a new diagnosis where you can see the child being sick, you can see the tumor, you can see the abnormal scan. These children were in remission when they went on, and the only thing that the parent could go on was what everyone had been telling them was that the risk for relapse was really high. There was a lot of reluctance when it was known how sick this therapy made you, especially after everything the children had been on up to that point. That’s why part of our obligation in reopening this clinical trial is that for families that enrolled a child on this trial, but they were randomized to the control arm or the retinoic acid arm, they are being given the opportunity now to come back and get the immunotherapy.
As we sit here today, there’s only enough antibody to treat 150 patients, so there is this ticking clock that we all hear. We’re trying to ramp up production at the National Cancer Institute, but there is a fear that we’re going to run out of this stuff. That would be a real problem to prove that something is effective, that it’s helpful, and not to have it as a nightmare scenario. We’re trying to collect more safety information in order to make it easier for a biotech company to go to the FDA