Addressing Unmet Needs in Brain Tumor Care: A Conversation With Raj Singh, MD

For all the progress oncology has made across most solid tumors in the past decades, glioblastoma has remained stubbornly resistant to that momentum. The standard of care established in the early 2000s is, in most respects, still the standard of care today—a fact that frustrates physicians like Raj Singh, MD, a radiation oncologist at the Eugene M. and Christine E. Lynn Cancer Institute, part of Baptist Health South Florida.

Asked about the biggest unmet needs in brain tumor care, Singh doesn't hesitate before pointing to systemic therapy. "In the glioma space specifically—glioblastoma—we're still trying to find effective systemic therapies beyond the Stupp protocol, which is really still where we've remained since the early 2000s," he said in an interview with Targeted Oncology. "That's still the optimal treatment approach for glioblastoma. We have yet to find a new systemic therapy that has really evolved the treatment paradigm significantly."

A Pattern of Promise That Doesn't Hold

It isn't that nothing has been tried. Singh points to tumor-treating fields, delivered through a device called Optune, as a genuine, if modest, advance. "There's certainly some promise in increasing the median survival," he said. But other leads haven't panned out the way researchers hoped. "We were hoping that there would be a signal as well in the MGMT-methylated population with lomustine, based on some initial promising smaller randomized trials—that doesn't quite seem to be tracking with the larger trials for that signal."

That gap between early data and confirmatory trials, Singh said, is close to the defining frustration of the field. "I think with glioblastoma, we always see these really promising signals in either single-arm phase 2 trials or smaller phase 3 [trials] that just don't tend to translate—from what we've seen so far—to large prospective trials." He sees faster, more adaptive trial designs as part of the answer going forward.

Meningioma: A Tumor With No Backup Plan

If glioblastoma's problem is a stalled systemic-therapy pipeline, meningioma's problem is the near-total absence of one. Despite being, in Singh's words, "the most benign brain tumor that we see," meningioma leaves patients with almost nowhere to turn once standard local treatment fails. "Those patients have incredibly limited options after surgery and/or radiation," Singh said. "What's unmet is really that population of patients once they've exhausted local therapy options. As of yet, we really have nothing from a systemic standpoint for aggressive, radio-refractory, and surgical-refractory patients with meningioma."

He frames the contrast with other cancer types directly. "We always talk about the next lines of therapy in extracranial primary disease. We really need to develop that in intracranial primary disease, where really it's local therapy that still remains the primary therapy. We need better salvage options for patients moving forward."

Sorting Patients by Biology, Not Just Appearance

Asked where the field is heading, Singh sees the most immediate progress coming not from new drugs but from better ways of identifying which patients actually need aggressive treatment in the first place, particularly in meningioma.

"Further characterization of the tumors [will help] better characterize patients who maybe don't even need as much therapy as we would traditionally recommend, based on traditional clinical characteristics, such as the grade of the tumor [and] the extent of resection," he said. The shift, in his view, is toward molecular profiling. "Instead of just looking at those factors, [we're] instead looking at the molecular level, at methylation profiling. That'll really be, I think, the next phase of meningioma research."

For glioblastoma, Singh is measured about how quickly similar progress will come, largely because of the disease's underlying biology. "That's taking a bit more time, and that's just because there's so much heterogeneity inherent in glioblastoma," he said. Immunotherapy, a strategy many hoped might finally break the field's long plateau, hasn't delivered yet. "We've looked at immunotherapy potential as a way to take advantage of that, and so far, trials that have looked at immunotherapy, both in methylated and unmethylated patients, have not proven to show a benefit." The search continues. "We're still trying to find, I think, that magic bullet, so to speak... and hopefully we will get there at some point."

Treating Younger Patients

Brain tumors in adolescents and young adults raise a distinct set of concerns, and Singh has seen the patient population evolve alongside the field's molecular classification systems. "As the molecular stratification [methods] have improved, there's now this new entity called the IDH-mutant grade 4 astrocytoma, which previously we would have called glioblastoma, but really it's its own unique entity that we see in a younger population," he said—one that still follows the broader glioblastoma treatment paradigm. Where IDH inhibitors like vorasidenib (Voranigo) might eventually fit into that paradigm is still an open question for this specific subgroup. "There's interest in where might that play into the treatment paradigm for these grade 4 IDH-mutant [tumors], and we still don't quite know that answer,” he said. Some neuro-oncology colleagues, he noted, have leaned toward adding vorasidenib alongside the standard regimen in select younger, robust patients given its relatively favorable toxicity profile, even before more definitive data is available.

Because the radiation fields used for these tumors are large, comparable to standard glioblastoma treatment, younger patients face real long-term risks. "Patients are certainly at significant risk of long-term radionecrosis and neurocognitive sequelae, both affecting short- and long-term memory, delayed verbal recall, etc," Singh said. Age matters here too. "The older a patient is, as opposed to, let's say, a developing child, the impact is less in an adult than it is in a child. But the effect that edema can have on a patient long-term, particularly if they have chronic radionecrosis requiring steroids long-term, or [bevacizumab (Avastin)], or other medications to manage it, can be quite severe."

Predicting who will face the worst of these effects remains difficult. "I am very honest with patients—I always encourage activity and continuing to pursue a career as feasibly tolerated, based on what one's line of work is, but with the caveat that it's hard to know and predict. That's one thing we're trying to get better at as well." Early intervention, in his experience, can make a meaningful difference. "What I've done quite a bit in my practice, actually, is if we see radiographic changes of necrosis but we're not seeing any symptoms yet... you can use natural supplements." He points specifically to Boswellia serrata, an extract studied in a German randomized trial roughly 2 decades ago for its ability to penetrate the brain and help manage cerebral edema. "In my younger patients particularly, it's something that we talk about quite a bit as a way of trying to reduce that risk, to maintain their quality of life."

Fertility preservation is another conversation that has to happen quickly with younger patients, without delaying treatment unnecessarily. "We try to do extensive counseling and have all of that done in as quick a time frame as we can, while still not delaying adjuvant therapy following surgery as much as we can," Singh said. When a patient does choose to pursue fertility preservation, his team compensates with closer monitoring rather than simply waiting. "Sometimes what we'll do is do very close MRIs during that period to make sure that there's not, let's say, a rapidly progressive event that we're missing, that might inform their decision-making about whether they want to pursue that route or not."