Navigating Therapeutic Options in Recurrent Pediatric Low-Grade Glioma
In this case-based discussion, Nathan Robison, MD, explores the management of recurrent pediatric low-grade glioma in a teenager with a progressive hypothalamic-chiasmatic tumor following years of relative stability after initial chemotherapy.
He reviews key considerations in determining when treatment is warranted and examines the benefits and limitations of surgery, chemotherapy, radiation, and targeted therapies, including tovorafenib and MEK inhibitors. Emphasizing shared decision-making, Dr Robison highlights the importance of balancing disease control with the goal of minimizing long-term treatment-related morbidity and preserving quality of life.
Transcript:
Hello, my name is Nathan Robison. I am interim section head of oncology and a practicing pediatric neuro-oncologist at Children's Hospital Los Angeles and Associate Professor of Clinical Pediatrics at the University of Southern California Keck School of Medicine.
Our case today involves a patient with a recurrent pediatric low-grade glioma. Specifically in this patient, he's a teenager with a hypothalamic-chiasmatic tumor who got initial treatment with chemotherapy and then had a long period of stability and then slow growth and now some symptoms. So really we just want to talk about what our options are for management of recurrent low-grade glioma. And I want to emphasize a couple of things.
First of all is that we have multiple options. There's a wide range of options--of good options--for this condition. And I also want to emphasize that the risk-benefit ratio of the considerations we make are very different from most of the oncologic diseases we treat in that pediatric low-grade gliomas are almost always ultimately a self-limiting disease. Due to oncogene induced senescence, a phenomenon we're starting to understand a bit better, these tumors ultimately burn out. They don't keep growing throughout life. And also they have a unpredictable growth pattern. They can grow and then stop growing and then grow again, just because a tumor's growing on one MRI doesn't mean it will still be growing at the same rate at the next MRI. And for all of these reasons, caution needs to be exercised. We don't want to just jump to treat because an MRI shows growth and also it's paramount that we do our best to avoid long-term morbidity and toxicity for our patients.
And so the first question always is whether even to treat at all. So this is a patient where we watched for a while as his tumor slowly grew intermittently and did not treat. It wasn't causing any symptoms. He unfortunately already had severe vision loss that was not getting worse. And so very reasonable to just watch and wait even with a continually slow growing tumor. However, we got to the point the tumor was causing symptoms. It wasn't quite clear was the headache actually due to the tumor or not, but there was enough concern that the tumor was contributing to these. Plus it was growing in a way that was becoming a bit more dangerous. We were seeing it start to press a little bit on the brainstem and all of those together with shared decision making, it seemed that treatment was clearly indicated.
First question always for low-grade gliomas: is surgery an option? So surgery when you can completely resect it can be curative. However, for a hypothalamic chiasmatic tumor, the only way to completely resect it would be to resect the hypothalamus and the chiasm leaving blindness and severe morbidity, which would be, as we talked about before, completely counterproductive. The goal is to preserve function, keep them as well as possible in the long term. So a complete resection is not an option.
A partial resection could be and could buy some time, could be very reasonable, but the tolerability for risk is going to be extremely low. So if the surgery is very risky, the answer for low-grade glioma is almost always going to be no. That takes us then to what really is usually our first consideration is chemotherapy. This patient got carboplatin and vincristine as a child and it was quite effective. He went many, many years without growth afterwards. And general principle in this disease is if it worked the first time, it will work the second time. Unfortunately for him, carboplatin is no longer an option because he had a severe reaction initially and desensitization protocols are available. But given that there are multiple other options, there would be no reason to do carboplatin in him again.
If it weren't for that issue, carboplatin and vincristine would've been a good option or monthly carboplatin is a reasonable alternative. Weekly vinblastine also an alternative chemotherapy that's been shown to be effective both upfront and then the recurrent setting. All of these good options. I would be cautious though about some chemotherapy, such as alkylators. Thioguanine, procarbazine, CCNU (lomustine), and vincristine, TPCV, a very effective treatment option, but the long-term risk morbidity from alkylators would be a concern. I would be very cautious about using TPCV, Temodar, or CCNU while we have other options. Similarly for the cisplatin etoposide. Again, a very effective low-grade glioma option used in Europe, but would not be my first choice for second-line therapy.
That does lead us into radiation, which for similar reasons I would try to avoid. Again, an effective option. It used to be our frontline, but it has very significant to long-term morbidity. And multiple population studies have shown that long-term risk of death goes up significantly if you give radiation predominantly due to the risk of malignant transformation of the tumor itself. So death to a disease that was supposed to have been a self-limiting disease, something we would obviously want to avoid. Radiation can have a role for low-grade glioma, but it's only in very select circumstances.
But that leads us then to the big topic, which is targeted therapy, molecular targeted therapy. And the first to mention is tovorafenib, which was approved 2 years ago, April of 2024. It is the only drug specifically approved by the FDA for children with recurrent or refractory low-grade glioma, children or adults with BRAF-altered low-grade glioma. So this is an FDA approved option. It's a once a week medication and certainly a reasonable option for this patient, which should be presented. Main side effect is dermatologic. It can cause acneiform in teenagers or dry skin and/or occimatus-like rash. The other big concern is that it very often causes growth suppression. There's data now that there is catch-up growth once the drug is stopped, but in this patient, he may have already stopped growing. He's 14, in which case that's not a concern, or he may be right at the end of his growth spurt, but still with some growing to do, in which case, if we started now by the time we finish, say in 2 years, he likely would have fused growth plates, and so catch-up growth wouldn't be an option for him. So that needs to be a consideration depending on the age, the growth suppression can be a significant factor.
Another alternative, very reasonable alternative, are the class of MEK inhibitors, which have also shown to be effective for this disease. They cause similar dermatologic toxicities. They also can usually cause paronychia, which can be very annoying, although not dangerous, but they typically don't cause the same degree of growth suppression. So that could be a reasonable alternative for that patient, including drugs like celemetinib and trametinib, which have been published as well as not yet published, but presented trials with what may be more drug penetrant drugs like bemetinib or mirtametinib. MEK inhibitors of note can also be used for patients with NF1-associated low-grade glioma or low-grade glioma that's thought to be MAP kinase driven but don't have a specific identified BRAF alteration. The tovorafenib is specifically for BRAF altered tumors.
Very important as a last point, I will mention that type 1 BRAF inhibitors, so the BRAF V600 inhibitors such as bimirrafenib or dabrafenib are only effective for BRAF V600-mutant tumors. In other MAP kinase-driven tumors like BRAF fusion tumors, they actually cause paradoxical activation of the pathway and can actually cause escalation of tumor growth. So these are very strongly contraindicated in tumors like our patient's, where they could actually have the opposite effect.
There are other options that I'm not mentioning here, things like bevacizumab, which have been shown to be effective in anecdotal experience. So again, a range of options. I think the take-home point just to conclude is that there are multiple different, very effective options for this disease and decisions should be made with shared decision-making, taking into account both personal patient preferences, psychosocial factors as well as medical factors. And the ultimate goal is really to minimize long-term morbidity, either of the treatment or of the disease.
