Management of A Patient With BRAF-Mutated Pilocytic Astrocytoma

Nicholas Whipple, MD, MPH, Primary Children’s Hospital, Salt Lake City, Utah, describes a case of a patient with a BRAF-V600E mutant pilocytic astrocytoma. Dr Whipple explains the treatment course that was taken, from initial treatment with carboplatin-vincristine to trametinib monotherapy and finally dabrafenib-trametinib combination. 

While the patient is stable and has discontinued dabrafenib-trametinib, Dr Whipple highlights the treatment options available should the patient require further therapy in the future, including a return to dabrafenib-trametinib, cytotoxic chemotherapy with or without bevacizumab, radiation therapy, and tovorafenib.

Transcript:

My name is Dr Nicholas Whipple, and I'm a pediatric neuro-oncologist at Primary Children's Hospital, the University of Utah and the Huntsman Cancer Institute. I have the privilege of caring for children and young adults who are diagnosed with brain and spinal cord tumors of any variety, and I really enjoyed taking care of this patient population.

This is an interesting case of a young girl who presented with a very extensive optic pathway glioma that was affecting various significant structures in her brain. Many optic pathway gliomas involved just one specific segment of the optic pathway, and this one at presentation really involved almost the entire optic pathway, including optic nerve chasm, hypothalamus optic tracks, and the bilateral thalami. This case has been very interesting to follow and help care for, and we're happy that this young girl is doing well. I wanted to talk just a little bit about the specifics of this case and perhaps provide a little insight into some of our treatment decision-making and how I would think about treating this tumor in the event that we need to repeat treatment.

As you've read from the case, initially this patient was given standard of care cytotoxic chemotherapy with carboplatin-vincristine, but she had a mixed response: part of the tumor while stable after that treatment, which is great, other portions of the tumor grew and we felt like we needed to treat that, that we needed to intervene and switch therapy because of that progressive disease.

When the patient's tumor progressed again while on a MEK inhibitor, we felt the need to really get some tissue and confirm what are we dealing with. What's the histology of this tumor and what are the molecular findings of this tumor? When we found that it had a BRAF-V600E mutation, we felt compelled to add a BRAF-inhibitor dabrafenib onto the trametinib, to try and achieve a superior response. As we know, dabrafenib and trametinib combined therapy is FDA-approved for the treatment of pediatric low-grade glioma with BRAF-V600E alterations, and we've seen great success in using this combination in our patients. When we started using that combined therapy, we saw an immediate stabilization followed by shrinkage of the tumor and we were very pleased. And, of course, this was thrilling to the family who had tried a couple of other prior therapies and who were of course worried about the overall outcome of this disease for their daughter, in terms of tumor spread and visual function.

The question at hand here for the case is a young girl, she's still young and she's been on a few different therapies now. I almost expect that at some point tumor is going to progress. Again, the natural history of this type of tumor is that it often progresses multiple times during the first decades of life, requiring multiple interventions until hopefully we see a biologic senescence sometime in the patient's twenties. That's different for various patients, but that's kind of how I think about it and how I describe it to families.

Let’s say this tumor recurs and progresses in early childhood, and let's say that it reaches that threshold that we feel we need to intervene. I want to provide the caveat that some mild growth over long periods of time that's not clinically significant can just be watched. We don't have to intervene and initiate a new treatment at every subtle increase in tumor size on an MRI. We want to be aware that a slow growing tumor can sometimes be watched. The rate of growth is important to consider when considering when to reinitiate therapy. New areas of disease are important to consider when considering whether to reinitiate therapy and of course ophthalmologic exam is important if there are declining visual symptoms, findings, that's of course very telling and important to know when deciding to reinitiate therapy.

Let’s say we've decided we're going to reinitiate therapy. I've provided a few different options here of things to consider, not necessarily a comprehensive list. There are multiple tools in our toolbox of what we can use to treat a pediatric low-grade glioma, and I think they all have a place. I asked the specific question, which of the following treatment options would generally be considered the least desirable next treatment option given the patient's young age, extensive tumor location and available alternative treatment options?

Option one, dabrafenib-trametinib. Some might think, well, the patient was already on this, why would you restart it and give the same therapy? And to that, I would say it's a good therapy. It's worked for this patient. It provided tumor control and a hopefully lengthy drug holiday where the patient was off. Reinitiating dabrafenib-trametinib and knowing that we already know how the patient responded to it, they're familiar with the side effects, family's comfortable with it, it's a viable option. The family patient has not failed this therapy simply because tumor progresses again in the future. So, a viable option, reinitiate dabrafenib trametinib.

A second consideration is using a cytotoxic chemotherapy that the patient has not yet seen. This patient progressed while on carboplatin and vincristine, so I wouldn't strongly consider using that again. But other cytotoxic chemotherapies have been studied such as vinblastine. And bevacizumab has an increasing body of evidence that it may be helpful in preserving vision visual outcomes. I've seen many colleagues use a combination of vinblastine with bevacizumab or vinblastine monotherapy to treat these tumors. There's good evidence and some clinical trial support in using this treatment option, and I would consider that that's always a viable recurrent treatment option for this patient population.

The third consideration I put on this question was the use of radiation. I want to come back to that one last because that's the answer that I would select as probably the least desirable next treatment step. So I'm going to come back to that one in just a minute.

The fourth choice is tovorafenib. Tovorafenib has a recent FDA approval. It’s a pan-RAF inhibitor, and we know that there's good evidence in this patient population with optic pathway glioma that it can help to stabilize and treat this disease. And there's even evidence that visual outcomes may be improved in a meaningful percent of the population who have this tumor type when this treatment is used. So BRAF-V600E mutation, absolutely you could use tovorafenib and it would be a really viable treatment option. And I might even say that many families I think would prefer this treatment option because it's something they've not yet tried. Families may feel very compelled to try something new when they have disease progression yet again, and the once weekly dosing is very enticing.

There are pros and cons to all of these treatments and side effects that differ with all of them, and those are important considerations to have. It’s very important to have a really open and robust conversation with family about what they think about each treatment option. I think families should have a significant say in which treatment their child uses when multiple treatment options exist that are good.

Now, the fourth treatment option radiation, that's the answer I would've selected. Radiation is a really effective treatment for pediatric low-grade glioma, so I don't want to dismiss using it at all. It has its place, and perhaps this patient could even need it at some point. But the reason I chose this one as the least desirable next step was for a couple of different reasons. One, the tumor location for this patient is very large. In order to radiate the entirety of this tumor, it's going to require quite a large radiation field that encompasses optic nerves that encompasses the hypothalamus, and really significant, if not all of the area of the pituitary gland. Now, radiation techniques have improved and probably portions of that pituitary axis could be spared, but radiating the hypothalamus would be required because that's where tumor is, and there's the risk in doing that of causing endocrinopathies for this patient, such as growth hormone deficiency or thyroid deficiency.

So we want to be cautious about what are the side effects of each treatment and how could that treatment impact the patient most significantly at this early stage. And given the extensive tumor location, I would say that endocrinopathies are a real concern with that treatment. I would say that vasculopathies are also a concern for this, given the location of the tumor. We shouldn't neglect the idea that a radiation therapy could potentially cause some visual disturbance in radiating such as significant portion of the optic apparatus. Neurocognition, I think would be a concern for this patient because given the very large area of tumor, I think that cortex would necessarily be involved in at least part of the radiation field. And at such a young age, we want to be cautious of how large that radiation field would need to be. And perhaps lastly, I'm sure there's some other pros and cons, but lastly, risk of secondary malignancy is something we always think about when we think of using when radiation, especially in a young patient.

These other treatment options, including at least one that hasn't been used, tovorafenib, are treatment options that I think are still really viable for this patient that are on the table immediately that perhaps have a more appropriate side effect profile at this stage for the patient at this young age and given the extensive disease as well. But all of these options are appropriate treatment options to consider, and there's always the possibility that others have a different viewpoint of which of these treatments they might prefer or which treatments the family would prefer.

That's my thought process in looking at this tumor type and how I would approach treatment selection and what I would offer to family and what I might reserve for at least a later time period if we needed to use radiation at some point in the future.

Thanks so much for taking part in this case.