Round 2: Managing Suspected Pseudoprogression

The discussion turns to early post-treatment imaging changes, with panelists debating how to approach management when progression is suspected but not confirmed. Key considerations include clinical stability, interpretation of imaging, and balancing the risks of acting too early versus waiting for greater clarity.

To see arguments related to patient factors and treatment decision-making, see Round 1.

To see arguments related to biomarker-guided decision-making, see Round 3.

Dr Minesh Mehta: So this is now going to be the management of suspected pseudoprogression. So let me start with the case first. So this is the clinical summary of the patient. This is a 52-year-old man with a newly diagnosed GBM, also IDH wild type. Has also had a gross total resection, so again, favorable. Has a pretty good performance status, ECOG 1. MGMT promoter is again methylated, so we're giving all these favorable characteristics. And you will see that there's a reason for this in a second why the MGMT promoter is methylated. 

Again, the patient has completed concurrent chemoradiotherapy and now is tolerating therapy well without interruption of steroids. Patient now gets in to be 4 weeks post radiation. The MRI shows increased enhancement at the resection cavity margin. There is also some increase in the surrounding T2/FLAIR signal. Patient goes on to have an MR with perfusion, and the MR indicates that in the areas of increased contrast enhancement, those regions are hypoperfused—not hyper, but hypoperfused. Patient's clinically stable, transitioning to maintenance therapy at this point. Social history is not terribly unusual here. The patient's married, lives with the wife and 2 children. And the decision point now is selecting the maintenance therapy based on these imaging findings and how we interpret these imaging findings. 

Dr Ashley Parham Ghiaseddin: I'm glad that now I get to at least talk a little bit about why I would be using Tumor Treating Fields in a patient like this, but I think it's helpful to note, when you have a patient that's MGMT methylated and you get changes on the imaging, they're clinically stable, they're off of corticosteroids, they're within 12 weeks of completing their chemoradiation, that's a patient that I would suspect is more likely to have radiation-induced inflammatory changes from the initial treatment. And I would be more willing to want to go into adjuvant treatment as opposed to a situation where you may be considering whether or not the patient could benefit from a repeat resection. I think a key point here Dr Mehta pointed out was that the MR perfusion was hypoperfused so that you're not also seeing any indication of increased blood flow to the area of enhancing changes on the imaging. 

One of the things that I wanted to talk about here is, a lot of times in clinical trials like EF-14 was pointed out earlier in debate number 1, is what is the reproducibility of that data? And sometimes we critique that the patients that we're putting on clinical trials are the perfect patient so that we expect them to do well. And when they come into the real-world setting, the treatment that we're actually considering for those patients is not as beneficial. And a lot of that has to do with how we're recruiting our patients. So what I wanted to show here is the TIGER study, which was the largest prospective study in newly diagnosed GBM in the real-world practice setting. 

This was 429 patients who were going to be starting Tumor Treating Fields. They were over the age of 18, they had histologic confirmation of the disease, and they were within the first 3 cycles of maintenance chemotherapy. So that's again in the window of this patient. They've completed chemoradiation. They're within the 12 weeks that we would expect radiation-induced changes to really be at its most significant. Doesn't mean it can't happen later, but most significant period is within that 3 months. And they had a clinical indication for going on to Tumor Treating Fields therapy. Their baseline demographics were what we normally expect for someone with GBM.  

The survival benefit that you saw in the TIGER study was at 19.6 months, and this is very powerful to see in the real-world setting, results that mirror the clinical trial results. I'd go further to show you the progression-free survival as well, which was 10.2 months. And when you think back at the EF-14 data, importantly, their percentage of patients alive at 2 years was 43%. And you can see here in the TIGER study, 42%, virtually identical. 

I think it's important to also remember: What does the safety look like? This is something that, again, in clinical trials, you can see the safety, very little concerns, but what do we see in the real-world setting? And we actually saw that it maintained the positive safety profile that was established with the EF-14 study in TTFields use. Overall survival and progression-free survival were consistent with prior studies, and this was another way of showing a large prospective study in newly diagnosed GBM in the real-world setting, mirroring the groundbreaking trial of EF-14. When you look at that and say, this is our patient who's not in a clinical trial, who's MGMT methylated, who's within 12 weeks of completing chemoradiation, clinically without any symptoms that are concerning of progression, not on steroids, this is a patient that I would consider should go on to adjuvant therapy, use Tumor Treating Fields as well as maintenance temozolomide. 

I'd caution you that when you actually repeat the imaging, if you were to see further increases enhancement, remember that even Tumor Treating Fields can cause some element of pseudoprogression as well, meaning that there can be some inflammation related to the Tumor Treating Fields device as well. With that being said, I would definitely recommend the continuation of the adjuvant therapy that includes Tumor Treating Fields in this patient. 

Dr Rupesh Kotecha: So I think the challenge and the unique scenario of the second case in comparison to the first case is that it challenges us to just not reflexively apply the EF-14 data and not think about the patient's current scenario. So we have a patient who is 4 weeks out from concurrent chemoradiation therapy after having had a gross total resection and now has concerning findings for either pseudoprogression or true progression. The first point I would make is that our diagnostic imaging at this juncture unfortunately is imperfect. We don't do a good job of identifying those patients who are truly going to continue to benefit from maintenance treatment versus those patients who truly need to change to a salvage approach or a salvage therapy. Perfusion is worse, one aspect of evaluating imaging studies, but not all areas of the brain, for example, are going to be well-perfused, and so it may be difficult to determine. 

Number two is this patient had a gross total resection before, and so looking at the perfusion changes afterwards, especially when you just have enhancement lining the surgical cavity, is not as easy to use versus in somebody, for example, who had a subtotal resection and then has a growing area of disease or a bulky area of disease. And so I think the debate right now is TTFields and temozolomide or temozolomide alone at this juncture. I'm not saying never TTFields, I'm just saying not now. 

Why not now? Number one, you have this issue of pseudoprogression versus true progression, and the fact that pseudoprogression can potentially, as was mentioned, be worsened with the use of TTFields. So at this juncture, we should not add an additional therapy if we don't know it's appropriate for this patient, and it could potentially obscure additional imaging in the future. The next point I'd like to make is that this patient, as you heard on the initial slide, is now off corticosteroids. If you do things that worsen that pseudoprogression, the patient ultimately may need to go back on steroids, which have side effects of their own. 

My final point is the question: Is there a cost in survival if you just don't start TTFields now, but just wait for their next scan, make sure the patient's responding, and then start TTFields? If we go back to the EF-14 study, patients could go 7 weeks from completion of chemoradiation to randomization and then get TTFields. This patient's just 4 weeks out; get their next scan in 4 to 6 weeks, if it shows that they're responding, you can start TTFields at that point. That would be within the timeframe that patients were actually treated on the EF-14 study. 

And finally, if you're looking at the TIGER study, it was presented here, those patients actually started within the first 3 months, and that was during that maintenance time. So in clinical practice, not all patients start at 4 weeks. For patients who are having pseudoprogression, we wait to confirm that they are not having true progression, and then we start them with TTFields. And as was presented, we recapitulate the same survival benefit in TIGER that we saw in EF-14. So this patient, I would argue we just wait for right now. They start with temozolomide, they can add TTFields at their next cycle.