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 a 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 an Associate Professor and Chief of Neuro-Oncology at Barrow Neurological Institute, as well as Chief Medical Officer at Ivy Brain Tumor Center.
Dr. Nimish Mohile:
Dr. Bagley?
Dr. Stephen Bagley:
Hi, I'm Stephen Bagley. I'm an Assistant Professor at the University of Pennsylvania, and I'm a Neuro-Oncologist there and Section Chief of Neuro-Oncology.
Dr. Nimish Mohile:
Today we will be discussing the treatment and management of glioma with three patient case studies. Our third and final installment will focus on the treatment of a high-grade astrocytoma.
This is a case of a 58-year-old woman who comes to the ED after her husband notices a left facial droop. She undergoes a CT head that demonstrates a right frontal hemorrhagic lesion, with surrounding edema. An MRI is done and demonstrates a heterogeneously contrast-enhancing tumor with some intratumoral blood and surrounding edema. She undergoes a resection, and operative note states that this is a complete resection but no postoperative MRI is done.
I'm going to pause there for one second. What do we think about this case in terms of being able to tell whether there's a complete resection or not? In our previous cases, whether there was a complete resection or not was important, both for prognosis and our decisions about treatment. What do we think about this with no postoperative MRI? Dr. Umemura?
Dr. Yoshie Umemura:
I would take it as a grain of salt that there was likely... hopefully a good amount of resection. And I think it also depends on where it was done, so I know the practice tendencies of the surgeon, hopefully. But I would look at the preoperative imaging and try to assert if there was likely gross total or not, given what the patient's symptoms are in eloquent areas. If I feel comfortably that this likely was a gross total resection, I would likely pick up the phone and speak with the surgeon and ask the surgeon if there is a plan to get postoperative MRI before discharge or not, and the reason for the surgeon to feel that it was a complete resection in the operative note.
Dr. Nimish Mohile:
The patient sees us postoperatively in the clinic, and their preliminary histology shows astrocytic morphology with mild to moderate cellularity. There's minimal nuclear atypia, there's no evidence of necrosis or microvascular proliferation, and a low mitotic index. Immunohistochemistry does show an IDH1 mutation, and this is a GFAP-positive on immunohistochemistry. Tumor sequencing is pending. Dr. Bagley, what do we know about this so far and what are the possible diagnoses?
Dr. Stephen Bagley:
So far we know that this is an IDH-mutant glioma, but we really don't know yet what the grade is going to be here. It does appear low-grade histologically, but we don't have sequencing available yet. And this is a case that was enhancing on the preoperative MRI, and so there's some concern about high-grade. But we need the CDKN2A/B homozygous deletion status, which if present would automatically make this a grade 4 tumor. So again, like similar cases, we are hesitant to present this patient with a definitive grade and diagnosis until we have the full molecular profile.
Dr. Nimish Mohile:
Dr. Umemura, anything to add to that?
Dr. Yoshie Umemura:
I would agree with Dr. Bagley. I think other than discussing that there is IDH mutation present, I would hold off on talking about the grade with the patient.
Dr. Nimish Mohile:
So we see them again a couple of weeks later. Tumor sequencing results are back, and this confirms the IDH1 mutation but also demonstrates a homozygous CDKN2A/B deletion. Dr. Bagley, what does this mean?
Dr. Stephen Bagley:
So we have a case here where the presence of the homozygous CDKN2A/B deletion, that actually automatically bumps this up to a grade 4 tumor, despite the lack of high-grade morphology on pathology. And this is based on actually numerous studies now demonstrating that these patients carry a prognosis and clinical course that mirrors a grade 4 IDH-mutant astrocytoma that actually has those high-grade features on the pathological basis.
So we give these patients a grade 4 diagnosis and manage them as a grade 4 diagnosis. And unfortunately, even though it's clearly a better diagnosis than an IDH-wildtype glioblastoma, most of these patients are not going to live over the 5-year mark. So it's still a very challenging diagnosis.
Dr. Nimish Mohile:
So the technical term for this on the integrated diagnosis that shows up on the path report is astrocytoma, IDH-mutant CNS WHO grade 4. We would also consider this or term this a high-grade glioma. In the old days we might've called this a secondary glioblastoma, though we didn't have quite the molecular features to confirm that. And we'd also term this as a grade 4 astrocytoma.
Dr. Umemura, as you talk to the patient, what is the prognosis for this patient and what do you think are the key treatment options?
Dr. Yoshie Umemura:
I would talk about how this is not a curable disease, and that it is aggressive and malignant. I would, however, discuss that treatment goals being trying to achieve stability and trying to maximize their quality of life. And also, although the prognosis and median survivals are there, I believe the median survival is around 2 year for these patient and certainly less than a majority of people would not live past 5 years, there are of course a big range. So in patients in their 40s and 50s, I think it's important that they understand the direness of this disease but not so much get bogged down on the specific median survival number.
Dr. Nimish Mohile:
And Dr. Bagley, how would you approach treatment?
Dr. Stephen Bagley:
These are cases where there is some controversy. I tend to treat many of them similar to a glioblastoma, using the typical Stupp protocol, which is radiation with concomitant temozolomide, followed by adjuvant temozolomide cycles. However, there are other cases that I may manage more like a grade 3 IDH-mutant astrocytoma, following CATNON, which is generally going to be radiation followed by 12 cycles of temozolomide.
Making that distinction for me is partially a discussion with patients. It's also I tend to think about cases like the one we're talking about right now as being a little bit more like a grade 3, just on the basis of not having microvascular proliferation and necrosis on pathology. And I probably would manage this patient a little bit more like a grade 3, with radiation followed by temozolomide. I think the cases where you can see pathologically that there is microvascular proliferation and necrosis, this is an extremely high-grade lesion that I tend to treat more like a run-of-the-mill glioblastoma. But I think this is a gray zone where it would be wonderful to have some prospective trial data that we really just don't have. So curious to hear, Dr. Umemura, how you would think about this one.
Dr. Yoshie Umemura:
I agree with you, there's a little gray zone. I tend to use a slight hybrid approach where I will discuss the glioblastoma-like approach, given that it is grade 4. But I will have a very low threshold to stop temozolomide during concurrent time, if they're having a lot of issues with constipation from Zofran for example, or any fatigue. Because I think that's the gray area. And so that's how it would make it a hybrid.
Dr. Nimish Mohile:
Yeah. So we really lack true prospective data on this specific tumor, on the grade 4s. They were included... They might've been included in Stupp as a small subset, as well as probably included in RTOG 9802 as a small subset, 'cause we didn't do the molecular testing back then.
And we're faced with two kind of slightly different treatment options. There's the work from CATNON that would suggest we should treat these patients with RT and adjuvant temozolomide, a radiation regimen in 33 fractions. And then there's the work from Stupp that suggests that we should do RT with concurrent and adjuvant temozolomide. Here we're doing 60 gray in 30 fractions. Most of our data regarding that regimen suggests that we should probably stop at 6 months and that there's not a benefit beyond 6 months. But then in the CATNON regimen we go up to 12 months.
So I'll just say for me, this has been a source of... I think there's a source of confusion about what the best option is, here. This is something that's really confusing to explain to our fellows and trainees on why we might choose one option or another. Do you think there's a meaningful difference between these regimens?
Dr. Yoshie Umemura:
I don't think I have enough to say there is a meaningful difference or not. However, I think what I do is I try to base my decision based on what the patient receives. So if the patient ended up not doing temozolomide during radiation, or I inherit them after radiation from a second opinion or move, I tend to aim for 12 cycles. Although I would twist their arm and really get through the first 6 cycles and then be okay if they want to stop, especially if there's some sort of maintenance trial that we do have going on right now. Because that is modeling after the CATNON, and the data for the adjuvant therapy was shown with the 12 cycle design.
However, I also know the 12 cycle design was designed based on the historical preferences for patients to receive around that many. But the data for temozolomide prior to that was due to the 6 cycle regimen. So I really don't think there is really anything I can fall back to to make that distinction. But if they have gotten temozolomide during radiation, I'll be okay 6 cycles after the radiation.
Dr. Nimish Mohile:
Dr. Bagley, anything to add to that?
Dr. Stephen Bagley:
Just one interesting thing that I think about sometimes is the fact that the temozolomide concomitant with radiotherapy, in some subset of patients that's going to result in significant and prolonged myelosuppression such that you may not even be able to get them on adjuvant cycles either on time or ever in some cases.
And I think based on the CATNON data that we talked about before, the adjuvant temozolomide is probably more important for these IDH-mutant patients than the concomitant phase. So I do worry sometimes that there may be some group of patients where they're not really getting the full adjuvant course because they had such a rough time with concomitant, which does affect blood counts differently in some patients versus the 5-days-on, 23-day-off period. So I just keep that in mind when I'm making these decisions.
Dr. Nimish Mohile:
That's helpful. So our key clinical takeaways for this case are that homozygous CDKN2A deletions are associated with aggressive tumor biology, and that results in us upgrading these tumors to a grade 4, and despite histologic findings of a lower-grade tumor. There's no clear evidence that tells us whether to follow a regimen from CATNON versus Stupp, and some of this is individual and based on the patients and needs to be informed decision-making between a physician and their patient. And it's important for patients to know that the survival expectations for grade 4 IDH-mutant astrocytoma are better than they are for glioblastoma, but they are likely poorer than they are for grade 3 or grade 2 astrocytomas.
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.
