Dr. Nimish Mohile:
Welcome to The ASCO Post Roundtable series on Personalizing Therapy for Patients With Glioma. I'm Dr. Nimish Mohile. I'm a Professor of Neurology at the University of Rochester. Joining me today are my colleagues Dr. Umemura and Dr. Bagley. Dr. Umemura, can you introduce yourself?
Dr. Yoshie Umemura:
Yes. My name is Yoshie Umemura. I am a neuro-oncologist. I am Chief of Neuro-Oncology at Barrow Neurological Institute and I'm also Chief Medical Officer at Ivy Brain Tumor Center.
Dr. Nimish Mohile:
Dr. Bagley.
Dr. Stephen Bagley:
Thanks. I'm Stephen Bagley. I'm an Assistant Professor at the University of Pennsylvania, also a neuro-oncologist and the Section Chief of Neuro-Oncology here.
Dr. Nimish Mohile:
Today we will be discussing the treatment and management of glioma with three patient case studies. Our first installment will focus on the treatment of low-grade oligodendroglioma.
Our first case is a 32-year-old woman with episodes of epigastric rising sensation that were lasting more than a year. She underwent a GI workup and was ultimately sent to neurology who suspected seizures. At the time, she had a normal neurologic examination. She was started on levetiracetam and the episodes stopped. An MRI demonstrated a right temporal lobe, non-enhancing mass. She underwent a gross total resection as seen on a postoperative MRI. At her first visit, we have incomplete pathology results. Histology demonstrated uniform round-to-oval neoplastic glial cells with clear perinuclear halos. Areas of microcalcification and low mitotic activity. The immunohistochemistry demonstrated Olig2 staining, an IDH1 mutation, and retention of ATRX expression. Other molecular tests and tumor sequencing are pending at this time. Dr. Bagley, based on what we're seeing so far, what do you think are the possible diagnoses and the most likely diagnosis for this case?
Dr. Stephen Bagley:
So I think that we can say so far that this individual has an IDH-mutant glioma. We can see just based on histology that this is a glial tumor and we do have positivity for R132H by immunohistochemistry, which is by far the most common IDH1 mutation, so common that there isn't an IHC stain developed for it. I think beyond saying that this is an IDH-mutant glioma, I would not want to convey a grade yet to this patient even though it does appear low-grade histologically. And I also would not want to differentiate between astrocytoma and oligodendroglioma with certainty, although there are some features here that would lean strongly towards oligodendroglioma, including the perinuclear halos, the fact that ATRX is expressed, whereas it would typically be lost in an astrocytoma, so most likely leaning towards a low-grade oligodendroglioma, but the molecular criteria are critical and still pending here.
Dr. Nimish Mohile:
Dr. Umemura, do you agree with that? And are you also faced with this challenge at your institution where you have partial results of pathology when you're first seeing a patient?
Dr. Yoshie Umemura:
Yes, I would agree with Dr. Bagley 100% about conveying what we do know and not delve too much into something that we currently have a good idea but don't know yet for sure, because like you said, the partial results are often the case early on when there are additional staining happening. It is good to know something than nothing, but they can't always sign everything out at the same time. With that said, I think I'm sure the patients would be quite anxious to know the full results. I think they can be eased, the anxiety can be eased by talking about things we can do at that moment, which would be seizure control, educating them what seizures are, what things can put them higher at risk for additional seizures and things like that so they feel a little more in control.
Dr. Nimish Mohile:
Great. So we then see the patient at a second visit and we have some additional testing that comes back and we find that she has a 1p/19q co-deletion and a TERT promoter mutation. And so the pathologists give this a final integrated diagnosis and call this an oligodendroglioma IDH-mutant 1p/19q co-deleted CNS WHO grade 2 or something that we might term a low-grade oligodendroglioma or a grade 2 oligodendroglioma. So Dr. Umemura, given this information, what would you counsel the patient about in terms of prognosis?
Dr. Yoshie Umemura:
I usually shy away from giving them specific numbers unless they really want to talk numbers, because I feel specific numerical numbers are really not representative of how people do. What I usually counsel them is that this is a tumor of oligodendrocyte origin and I'll talk about what glial cells are. I'll also talk about how this is not a curative disease and that this is something that they will be dealing with lifelong. In terms of prognosis, I do tell them that this is something that we want to achieve stability of, so we can prolong the time before the tumor enlarges again or we have to do something else again, and that this is something that we will have to deal with over time. And at one point I will also introduce the idea that this is a life-shortening disease. And by saying these things, I usually feel that we can achieve the same purpose of making sure that we're on the same page about the prognosis of gliomas rather than focusing on median survival, which is not their own life expectancy.
Dr. Nimish Mohile:
Dr. Bagley, do you have anything to add to that? Many of these patients come to us with the term benign and thinking that this is a benign disease and is it important as Dr. Umemura says to re-educate them about that?
Dr. Stephen Bagley:
Yes, absolutely. I think that I am very clear about that, the fact that this is a primary brain cancer and I will make a pretty clear distinction early on that this is not a benign tumor and that it is in fact malignant. As Dr. Umemura pointed out, I tend to stress, especially for a low-grade oligodendroglioma, that this is going to be a long-term condition this patient is dealing with and I highlight both the good and the bad of that. The bad of course is that for a young person, this is likely going to be life-limiting. The good news is that of all of the other gliomas that we see, this is by far the most responsive to therapy. And for this particular patient who's had a gross total resection of a grade 2 tumor, the prognosis, although not curable, is excellent. This person may live for decades. And so I'm also quick to point that out as well.
Dr. Nimish Mohile:
So Dr. Umemura, she is 32, she has a low-grade 1p/19q co-deleted oligodendroglioma and she had a gross total resection. What do we think the treatment options are here?
Dr. Yoshie Umemura:
I think traditionally the treatment option often would've been observation, but with the current indication of newly approved IDH inhibitor vorasidenib, I think a lot of neuro-oncologists, including myself, who recommend consideration of maintenance therapy with vorasidenib instead of purely observation.
Dr. Nimish Mohile:
And Dr. Bagley, do you agree with that?
Dr. Stephen Bagley:
Yeah, I certainly would discuss the IDH inhibitor option with this patient. I also would present what I view as an equally reasonable and maybe more reasonable approach in some cases, which is observation. I think we can get into the data a little bit, but in the INDIGO trial, all of the patients were required to have measurable residual tumor after their surgery, which this individual did not. The FDA label for the drug does include patients who've had gross totally resected disease like this. So this is a gray area in practice where you have an FDA indication, but not necessarily high level data supporting use in this scenario. So I think the patient's own goals and values are an important part of this discussion.
One of the main challenges here is that if we commit to vorasidenib in this young person, they may be on that sort of indefinitely and potentially for a very long time with implications for symptoms, although it is typically a pretty well-tolerated drug, the liver test abnormalities can be challenging sometimes. And then of course fertility concerns and whether this is an individual who is looking to conceive a child in the near future and how we take all of that together to help this person decide between observation and active therapy with vorasidenib.
Dr. Nimish Mohile:
And Dr. Umemura, is it fair to say that you would not consider radiation and chemotherapy in this case? And why?
Dr. Yoshie Umemura:
To answer that question, I would first consider observation and if doing more, doing vorasidenib because I don't think there is an indication to treat gross totally resected low-grade oligodendroglioma upfront with chemotherapy and radiation. With that said, I realized patients oftentimes want to be doing something, although I agree with Dr. Bagley about how observation is appropriate given that in the INDIGO, patients have measurable disease, these drugs are now available to them. And so if it does fit the patient's goals after discussing their goals in family planning or what they want to do, and probably also taking into consideration if their seizures are well controlled or not. And I think that's how we would decide observation vs maintenance therapy to delay the time until radiation and chemotherapy.
Dr. Nimish Mohile:
Yeah, so I agree with both of you. As we think about observation, we're typically thinking of that category that we call low-risk, low-grade glioma, and these are the patients who've had a gross total resection and they're under the age of 40, don't have any other concerning features either on imaging or histology. The new development of IDH inhibitors has made this a little bit more complicated, I think as both of you have brought up. And we think of these, using this in patients where per the trial, a watch-and-wait approach was considered appropriate. And that's not really clear exactly what that means, because that can mean different things to different people, and I think that that's where we struggle with this decision between observation with vorasidenib.
So I think as both of you pointed out, important to think about toxicities, what does it mean to be on a drug indefinitely? And what kind of impact might this have on fertility? And we typically would save the radiation and chemotherapy for those who we consider high-risk, which means there's either residual disease, they're older, there might be other features that are concerning.
Both of you talked about some considerations with vorasidenib in terms of toxicity in your clinical practices. Are you noticing any challenges or problems as you've started to use this? I'll start with Dr. Bagley.
Dr. Stephen Bagley:
I think what I mentioned previously, the transaminitis is probably the most commonly encountered issue and it's typically not accompanied by symptoms, although I have had a couple of patients complain of right upper quadrant discomfort and I think that usually very manageable in holding the drug and waiting for resolution. Although I'll say that due to the drug's long half-life, it can take quite a while in some cases for the LFTs to normalize. And so you can imagine from the patient perspective, that's time where they're not on therapy and maybe concerned. So I think very well-tolerated drug in general. But the LFTs, that has been the one thing in practice that has I think, hampered on therapy time the most for me so far. Interested in what Dr. Umemura's perspective is also.
Dr. Yoshie Umemura:
It's probably similar, the most commonly, but not everyone, but most commonly encountered issues are liver function testing number elevations. And I have not had anyone who are symptomatic from that and they all have resolved and improved. And I haven't had anyone not tolerate the drug after either dose reduction or interruption. I haven't had anyone who required secession of the drug. I have heard a few times from patients who noted very mild fatigue early on, which went away after about a month or two being on the drug. And in addition, I did note a couple of patients with nausea during the trial. But I would say on the trial I believe the patients had to take the drug on empty stomach and these were also patients who got nausea from any medication on empty stomach, including vitamins. Whereas I have not encountered any nausea off trial use.
Dr. Nimish Mohile:
So with vorasidenib in our arsenal now, I think important for folks to understand that this delayed time to next intervention according to the INDIGO study, it's a generally well-tolerated drug. Our main toxicities are related to the liver, and so we need to monitor LFTs. There remain some unknowns with long-term fertility and that's important particularly in this young population. But the positive ideas of this is are we able to better preserve brain health by avoiding or delaying radiation therapy. There's some suggestions that this may improve seizure control, but we struggle with the fact that we don't really have clear guidance on how long to treat patients for this.
And our key takeaways from this case are that low-grade oligodendrogliomas with favorable features, we may defer the use of radiation and chemotherapy and discuss these observations of observation vs vorasidenib. Vorasidenib is generally well tolerated, but we need to be discussing reproductive plans and monitoring for toxicity and vorasidenib may also contribute to neurocognitive preservation and possible seizure control. This brings us to the end of this case. Please see the other segments for further discussion about the latest research in glioma or visit ascopost.com.
