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 and neuro-oncologist at the University of Rochester. Joining me today are two of my colleagues, Dr. Umemura and Dr. Bagley. Dr. Umemura, do you want to introduce yourself?
Dr. Yoshie Umemura:
Thank you. My name is Yoshie Umemura. I'm Chief of Neuro-oncology at Barrow Neurological Institute, as well as Chief Medical Officer of Ivy Brain Tumor Center at the same institution.
Dr. Nimish Mohile:
Dr. Bagley?
Dr. Stephen Bagley:
Thank you. I'm Stephen Bagley. I'm an Assistant Professor at the University of Pennsylvania, neuro-oncologist and Section Chief of Neuro-oncology.
Dr. Nimish Mohile:
Thank you both for joining us. Today, we will be discussing the treatment and management of glioma with three patient case studies. Our second installment will focus on the treatment of a low-grade glioma.
C.R. is a 45-year-old man who is bumping into things on his right side and is found to have a field cut. An MRI of the brain revealed extensive left temporal parietal, non-enhancing mass. A functional MRI demonstrated language involvement near the anterior component of the mass.
He underwent a subtotal resection with approximately 50% removed and noted that a visual field deficit was worse after surgery and he was left with a left lower quadrantanopsia. At his first visit, his histology demonstrated an infiltrative tumor with moderately cellular glial tissue. He had astrocytes with elongated and pleomorphic nuclei, rare mitotic figures, but no evidence of microvascular proliferation or necrosis. Immunohistochemistry was GFAP positive and IDH1 immunostaining is negative. Tumor sequencing and other molecular studies are pending at this point. Dr. Bagley, what do you think about our initial results here?
Dr. Stephen Bagley:
So far, we can tell this patient that there's a glioma here, but beyond that I would be very hesitant to go into much more detail, given the lack of molecular data. This is a case where we have a negative staining for R132H, the most common IDH mutation, but that particular locus is only about 90%, so there's another 10% or so of cases that may have non-canonical IDH mutations either in IDH1 or IDH2. So an IDH mutant glioma is certainly on the table here. On the extreme flip side, there is actually a possibility this is a glioblastoma. We haven't seen molecular data yet, but depending on certain features that may be present on the sequencing, even though this doesn't meet classic histological criteria for a grade 4 tumor, there are certain molecular features that may bump it to be an IDH wild type glioblastoma. So very, very different diagnoses and I don't want to get it too deep with this patient until we have that data back.
Dr. Nimish Mohile:
So Dr. Umemura, you end up having a discussion with the patient as Dr. Bagley described, and then the patient calls you the next day because they went on ChatGPT and they entered their pathology report and was told that he had an IDH wild type glioblastoma and that median survival was just over a year. And in his message to you he says, "But my neurosurgeon assured me that this is a low-grade tumor." What do you tell him?
Dr. Yoshie Umemura:
I would first likely set up a phone or a video visit, so there is a bit of a control setting to have a conversation, preferably video visit so I can have a face-to-face conversation. I think that this is actually a not too uncommon situation that we run into. Neurosurgeons and neuro-oncologists and radiation oncologists, we all work very well as a team, but I think, because we all have a different role in what we do for these patients, a lot of overlapping, but slightly different. And oftentimes, we really appreciate neurosurgeons to really take these patients off the ledge in the emergency room when they're told of a lot of unknowns and really giving them reassurance. And I think it is fair sometimes things like this looks like low-grade or non-enhancing disease, a young patient gets told. But because of that, I think what happens is the more and more these ChatGPTs and Googles develop, people are going to be told more specific things that may or may not be accurate for those patients.
And so I will go over those things with the patient, talking about why the neurosurgeon may have said that this may look like low-grade tumor, that this was a non-enhancing disease on the MRI. I will also point out that likely that Dr. Bagley would've discussed that there are additional molecular testings that are pending and that that's just because they're staining for one most common mutation for IDH does not mean it's completely wild type. Although there is a possibility, we need to keep an open mind and wait for the final pathology to come out. And I would likely let them know around in what timeframe we would know that, so they're not just waiting in the limbo completely.
Dr. Nimish Mohile:
Dr. Bagley, the patient is concerned about urgency, do need to start treatment right away? Do we have time to wait for the sequencing results?
Dr. Stephen Bagley:
Yeah, I would stress to this patient that the diagnostic possibilities here are quite different and do inform the treatment plan. And so I would encourage them to be patient with this and reassure them that this is not going to take months to get results back. We're talking about days to weeks, and I think it is the right thing here to be patient and wait until we have an integrated diagnosis.
Dr. Nimish Mohile:
So he sees us again in a couple of weeks and his molecular gene sequencing testing is back and he does have an IDH1 mutation, no 1p19q deletion and no CDKN2A deletion. And he is given an integrated diagnosis of an astrocytoma IDH mutant CNS WHO grade 2, or in less complicated terms, what we would call a low grade astrocytoma, sometimes a diffuse astrocytoma or a grade 2 astrocytoma. So Dr. Bagley, what is the patient's prognosis here and what do you think are the key treatment options?
Dr. Stephen Bagley:
So here, we have a grade 2 IDH mutant astrocytoma that has been partially resected and it sounds like there is a significant amount of residual disease. So depending on exactly which study you look at, this patient likely has a median overall survival somewhere in the 10 to 12 year range. And as Dr. Umemura mentioned earlier, I wouldn't necessarily offer that data to the patient without being solicited to do so during that initial meeting, but stressing to them that, again, this is a malignancy. This is something that is going to require treatment and unfortunately is not curable. I think those are important points to discuss fairly early on. And in terms of the treatment here, this is an area of some uncertainty. So I think that most neuro-oncologists would agree that observation is not going to be a reasonable plan for an individual of this age with this amount of residual tumor.
And the question becomes do we follow the conventional route here of radiation followed by alkylating chemotherapy, either PCV or temozolomide. And this patient does have what would traditionally be considered high risk features with regard to age and extent of tumor that's residual. And more importantly though, we now have an IDH inhibitor and this individual is on the FDA label for that and would have met the eligibility criteria for the INDIGO trial.
There is some gray zone about treatment options here. There are some neuro-oncologists who would recommend jumping into radiation and chemotherapy for this patient and others who would favor starting with vorasidenib and then saving radiation and chemotherapy for future progression. I'm very interested to hear what Dr. Umemura thinks, but my general sense for this patient is that this is a significant amount of residual disease that is potentially close to language. And this is a person where, if there is progression early on during IDH inhibitor therapy, could become symptomatic, requiring radiation and chemotherapy at a time where there's significantly more tumor, more symptom burden.
And so this is a case where I would be open to discussing both, but would probably present a slightly stronger lean towards initiating radiation and chemotherapy in this individual. And I say that mainly because, if you look at the INDIGO data, there's about 40% or so of patients who have already progressed by the 2-year mark on that therapy and we don't have a biomarker yet to know who those individuals are. And so I ask myself, if this person is one of those folks who's going to progress early, what's that going to mean for them? And is that enough of a clinical importance for me to recommend radiation and chemotherapy now? So that's my general thought on this one. Dr. Umemura, what do you think?
Dr. Yoshie Umemura:
I tend to agree with you. I think IDH inhibitor is not necessarily off the table. There are some patients who have stability of tumor or occasionally even reduction in the volume, from what we can tell. But given that this is case, I believe, with extensive tumor and only about half were taken out and it is in a quite sensitive area, I think we would be quite nervous about any growth of that. With that said, if the patients are very nervous about doing radiation, what we don't want is for these patients to just completely get lost in follow-up because they were just afraid of treatment.
We sometimes run into that as well and I think it would be really important to lay it out so they know that there are two options, that they're not being pushed into one treatment or the other. But I agree with you, I think this would be concerning and you may want to pull out the definitive treatment with cytotoxic therapy. With that said, it is great too, and if the patient is doing well at the time of these counseling and also after having met with the radiation oncologist probably early on, given that this was initially considered maybe IDH wild type, I think the patient would've likely met with the radiation oncologist by then. So at the time of finalizing the treatment plan, just depends on how they're doing. I would probably talk about either IDH inhibitor alone or radiation with chemotherapy.
Dr. Nimish Mohile:
Yeah, this is a really tough case. I think we've got two different trials that give us some guidance here. So the INDIGO trial, which gives us some hope that we might be able to defer radiation in this patient. But then if we think about RTOG 9802 and the impact that RT and PCV has on patient survival, I think it becomes really hard, as a neuro-oncologist, to not consider that as almost a standard of care in these patients. And so I think it becomes a complicated discussion.
Part of this is about what to expect from radiation. And so what would he experience during and after radiation that we would worry about?
Dr. Yoshie Umemura:
During radiation, of course I would want them to talk with the radiation oncologist as well, but in my visit, I would always touch upon some of the things that they would expect to hear. I think it's always good that they hear things more than once, so it sticks without having to take meticulous notes. And so I would tell them the most common thing we hear about is fatigue that they experience gradually during the treatment and that may improve gradually after the treatment, as well as the hair loss in the area of the radiation, but we don't expect from chemotherapy that we use in this case; astrocytoma, so likely. Temozolomide maybe, or not with the current guideline. Now we're talking about another trial with the CATNON trial, of whether or not adding temozolomide during concurrent time or not. I probably would not necessarily get into too much about delayed radiation effect on these patient on those first visit from me because I think I would like to reserve that conversation for radiation oncologists first and then provide any follow-up conversation afterwards.
Dr. Nimish Mohile:
Dr. Bagley, what are your thoughts about this on discussion of the delayed effects? When we think about these delayed effects, so I've been in practice for 18 years now, so I have a lot of low-grade gliomas that I see in long-term follow up and they have the cognitive syndromes with impact on memory processing, executive function. I see the cavernous malformations, with causing seizures and hemorrhages, cataracts, hearing loss, occasionally a second tumor, and then impacts of radiation necrosis. When and how do we communicate that to patients?
Dr. Stephen Bagley:
Yeah, that's a really tough thing because I think it's the main feared long-term problem with this definitive therapy. When you're going to make that decision to embark on radiation and chemotherapy, that's what you are worried about, is what's going to happen to this person down the line from a neurocognitive standpoint. And I tend to, as Dr. Umemura said, not get into a ton of detailed information about that during the first or second visit because you can imagine that that would derail a lot of folks from getting this therapy that, when you weigh the risks and benefits, is still on many, many cases in favor of doing it.
But I think for the patients who are asking and want that information, I am pretty clear about it. And frank radiation necrosis, depending on the location and extent, can be sometimes more debilitating than the tumor itself. And I do have a handful of cases where they're long-term survivors of a low grade glioma, but are cognitively devastated from radiation necrosis and that is a terribly challenging situation. So I think we all have a healthy respect for radiation and in select cases where we think it's the right thing to do, having vorasidenib in our pocket now is quite nice to delay the time until radiation is necessary.
Dr. Yoshie Umemura:
I would like to add that I think it's important to give radiation oncologists a chance to discuss it in full before us tainting the risk too far. But at the same time, I do make it a point to discuss that, after radiation, to not be too concerned if things look worse. So I do talk about that with sometime, on the first couple visits.
Dr. Nimish Mohile:
And you mean that in terms of imaging or symptoms?
Dr. Yoshie Umemura:
On the imaging. On the imaging and then that there may be some symptoms associated with it, but I do think patients get so scared when they read a report saying progression from radiologists, so I do caution them ahead of time.
Dr. Nimish Mohile:
Yeah, good point. The final question in this patient, then, is if we decide to go ahead with radiation, is there a preferred chemotherapy regimen? We are typically faced with either PCV, which is procarbazine, CCNU and vincristine or temozolomide. Do you guys have a preference or do you think the data leads us in a particular direction? Let me start with you, Dr. Bagley.
Dr. Stephen Bagley:
Yeah, I think my general practice is that, for a patient like this with an astrocytoma, if I'm going to embark on radiation and chemotherapy, I tend to use temozolomide. For the oligodendrogliomas, as long as they are fit enough to handle it and I don't have concerns around medication compliance and other things, I tend to go for PCV. This is somewhat based on just my interpretation of RTOG 9802 and some of the post-hoc molecular breakdowns of that trial. And if you look at that data, it's stratified by 1p19q codeletion status. The hazard ratios are much lower for the oligodendrogliomas, which we would expect because we know those tumors are far more chemotherapy sensitive. And as we all know, temozolomide tends to be better tolerated, logistically easier for patients. And we do extrapolate the CATNON trial, which was in grade 3, IDH mutant astros towards the IDH mutant grade 2s. I recognize, though, that that is an area of controversy and there are many purists who would recommend PCV for these patients, which is reasonable also.
Dr. Nimish Mohile:
How about you, Dr. Umemura?
Dr. Yoshie Umemura:
For those evidence cited by Dr. Bagley, same reasons, but I would stick to temozolomide. I don't see an upside of PCV on astrocytoma. I think that there is a reason CATNON was just for astrocytoma. I think, though, there is, like I mentioned earlier, the concurrent use of temozolomide is now becoming the area of question mark, in terms of guideline and real-life practice. But I do tend to lean to temozolomide instead of PCV for astrocytomas.
Dr. Nimish Mohile:
Yeah, I'll say I have a pretty similar approach in my practice. When we think of PCV, I mean really strong data from RTOG 9802, with overall survival in all-comers more than 13 years, but does come with significant toxicities, resulting in cytopenias, neuropathy, some GI side effects. And as Dr. Bagley said, as you do a more detailed analysis of the data, maybe a stronger role here for oligodendrogliomas. And then looking at temozolomide, pretty strong data across a lot of gliomas now for its biological activity. And I think many will extrapolate from the CATNON studies and other glioma studies demonstrating that activity, and tends to be generally well tolerated and something that you can finish out a whole course on without too many challenges, particularly in a person this age.
Our key clinical takeaways from this case are that grade 2 astrocytoma tends to be more aggressive than the grade 2 oligodendroglioma. Age over 40 years and residual disease put this patient, in particular, into a higher risk category. The standard of care, based on trials for grade 2 astrocytoma in this situation is radiotherapy and adjuvant chemotherapy. The evidence is most supportive of PCV, but the choice depends on patient and clinician preferences. And as we discussed, there is some data supporting temozolomide in this setting as well, but important to know that PCV is associated with some notable toxicities that may impact quality of life. 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.
