Defining Brain Tumor Progression: Balancing Clinical Symptoms and Imaging

Monitoring brain tumor progression is a complex balancing act between objective imaging and subjective clinical changes. In a virtual Case-Based Roundtable moderated by John De Groot, MD, neuro-oncologist at UCSF Health, explored the nuances of transitioning patients from targeted therapy to more intensive options like radiation or chemotherapy.

The conversation delves into the limitations of traditional RANO criteria for nonenhancing tumors, the weight of seizure recurrence as a marker of biologic growth, and why the rate of change across multiple scans is often more telling than a single measurement. By weighing subtle radiographic shifts against difficult-to-control clinical symptoms, these experts outline how they determine when a treatment has truly stopped working.

This is part 2 of a 2-part series.

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CASE SUMMARY

The patient is a 44-year-old engineer living independently with a Karnofsky performance status of 100. He has resumed full-time work since resection and reports excellent cognitive function. Over the past 6 months, he has noticed increased fatigue and short-term memory lapses, attributed to sleep disruption from seizure activity. No new neurologic deficits. Seizures remain focal aware events lasting < 60 seconds. He drives only with restrictions per local law.

History

• April 2022: subtotal resection (STR) of left frontal tumor
• Path: Astrocytoma IDH1-mutant, grade 2; 1p/19q non-codeleted; MGMT methylated
• Postoperative MRI: small residual T2/FLAIR; no enhancement
• 2022–2024: Observation with MRI; no symptoms until recent months

Current Imaging and Laboratory Work-Up

• MRI (April 2024): Expanding FLAIR lesion along left superior frontal gyrus; no enhancement, no diffusion restriction, no mass effect.
• Magnetic resonance (MR) spectroscopy shows persistent elevated 2-hydroxyglutarate peak consistent with active IDH-mutant metabolism.
• EEG shows occasional left frontal spikes.
• Routine labs and liver function tests normal. No evidence of infection or inflammation. Findings collectively support radiographic progression after a period of observation.
• Seizures still ongoing despite antiepileptic drugs

DISCUSSION QUESTION

What criteria do you use to define progression that requires a change from targeted therapy to radiation or chemotherapy?

John De Groot, MD: These are the diseases we think are probably always changing and always progressing, just at variable speeds. Is it safe to wait until a patient develops worsening neurologic function before you proceed with more definitive like radiation or chemotherapy?

Robert Yoo, DO: I still follow RANO,¹ if possible. Most of these tumors don't really enhance, so it's tough to say, but if the patient has convincing clinical symptoms that's an absolute yes, even if there's a subtle T2/FLAIR, I would say they are maybe progressing.

De Groot: So even if the patient had a 10% increase in FLAIR but no symptoms, that would be something you watch, whereas if they have 10% increase in FLAIR and they've got progressive, difficult-to-control seizures, maybe you would think about that differently.

Yoo: Yes, that's correct.

Karan Dixit, MD: I use rate of change. It’s not just 1 scan. If 1 scan shows a 10% change, what does the next scan show? I think with these patients, you can usually wait 3 months to get a sense of what's going on. If it's a consistent growth, that means, in my mind, the treatment is not doing what it needs to do. I think clinical symptoms, seizures, are a clear clinical sign. If I have a clinical trial [the patient is eligible for], I'll maybe be bit more favorable of switching therapy early because that's something you know is available for them.

DISCUSSION QUESTION

Do you consider seizure recurrence a clinical marker of biologic progression even without radiographic change?

Dixit: [I think it depends on] the trajectory of tumor growth. I’m more worried if I know something's going to grow into motor pathway and seeing if I can do something earlier to prevent that. These patients often aren't focally weak, because the neuroplasticity aspect of the disease and tumor location are a big part of it. If people with frontal lobe tumors or executive network involvement, I do everything possible to delay the timeline of radiotherapy. There’s some give in allowing some amount of growth, but if tumor is growing at a meaningful pace that multiple scans and close interval in 6 months shows progression, then we need to be a bit more aggressive.

To differentiate treatment progression from treatment effect and biologic fluctuation, it's consistency of change. It's a hard one to measure, I'm sure, all the clinical results. It's hard to even collect the data in a systematic fashion to incorporate into our metrics. If there's a clear difference in their outcomes, and I think it's from tumor growth, I do think that should play a role in in treatment change. But what is that metric? Is it an attention span? Something else you can treat through supportive care, potentially?

DISCUSSION QUESTION

How do you approach patient anxiety and decision fatigue during long periods of radiographic monitoring?

Leia Nghiemphu, MD: I think this is where neurological symptoms help. If the patient is asymptomatic, not having more seizures, it's a little easier to keep them going with this radiographic monitoring. But I think this is where having more motor weakness, speech aphasia, cognitive problems, doing scans more often, perhaps if we're starting to see some radiographic change with some symptoms emerging, I think that helps the patient to know that we're watching more carefully.

Dixit: I let patients know this is a chronic medication. Like you treat diabetes or high blood pressure, you just have to stay on it, and we continue until it stops working. And then at that point, we switch to something else. I tell them that they’re going to need radiation/chemotherapy at some point; we’re just trying to push it off for as long as possible. I haven’t had pushback from You're going to need radiation, chemotherapy. At some point that is going to happen. It's just we're trying to push it off for as long as possible.

De Groot: How do you differentiate true progression from treatment effect or biologic fluctuation and nonenhancing disease?

Yoo: For us, we order MR spectroscopy occasionally, but I think it is sometimes unreliable for more enhancing or high-grade disease. Obviously, perfusion will be nicer, but I found perfusion doesn’t help that much. I think it’s difficult, but MR spectroscopy is at least better than nothing.

De Groot: Is it safe to wait until a patient develops worsening neurologic function before you proceed with more definitive treatment like radiation or chemotherapy? At what point do you consider neurocognitive testing or health-related quality of life metrics as primary indicators for therapy change?

Dixit: For me, it's dependent on lesion location. If I know someone's going to develop motor weakness because something invades in a certain pathway, that's a bit different. To differentiate treatment progression from treatment effect and biologic fluctuation, it's consistency of change.

We tried neurocognitive testing once a year for our patients, and they hate doing it. This is where tumor location and how it impacts neurocognitive function and language, depending on which networks are affected, matter. It's hard to measure. It’s hard to even collect the data in a systematic fashion to incorporate into our metrics. If there’s a clear difference in their outcomes, and I think it's from tumor growth, I do think that should play a role in in treatment change. But what is that metric? Is it an attention span? Is it something else you can treat through supportive care?

REFERENCE

1. Wen P, van den Bent M, Youssef G, et al. RANO 2.0: Update to the response assessment in neuro-oncology criteria for high- and low-grade gliomas in adults. J Clin Oncol. 41, 5187-5199(2023). DOI:10.1200/JCO.23.01059