In an interview with Targeted Oncology, Stephen M. Karlovits, MD, discussed key developments that researchers have made in the primary brain tumor treatment landscape in recent years and upcoming trials with potential to improve outcomes for patients.
May is Brain Cancer Awareness Month, and ongoing advances in this field have offered more treatment options for a wider range of patients with primary brain tumors. Combinations of radiotherapy, surgery, chemotherapy, and targeted therapies are being refined to offer the most benefit to survival.
Chemoradiotherapy using temozolomide (Temodar) is the current standard of care for glioblastoma multiforme (GBM), one of the most common types of primary brain tumors. The phase 3 EORTC 26981–22981/NCIC CE3 trial demonstrated that adding temozolomide to radiotherapy significantly improved survival outcomes.1
Another major improvement is the introduction of tumor-treating field (TTF) therapy using alternating electric fields. The EF-14 trial (NCT00916409) compared maintenance chemotherapy plus TTF versus chemotherapy alone in patients with newly-diagnosed glioblastoma and found a median overall survival [OS] of 11.8 months with TTF versus 9.2 months with chemotherapy alone (HR, 0.70; 95% CI, 0.48 to 1.00; P = .049) with no higher-grade adverse events (AEs).2
Other developments include the use of targeted therapies, as well as improved modalities for delivering radiotherapy.
In an interview with Targeted OncologyTM, Stephen M. Karlovits, MD, of the Allegheny Health Network (AHN) radiation oncology division, director of the central nervous system tumor and information technology programs, and director of the AHN radiation oncology residency program, discussed key developments that researchers have made in the primary brain tumor treatment landscape in recent years and upcoming trials with potential to improve outcomes for patients.
Targeted OncologyTM: How has the field of primary brain tumor treatment changed compared with 10 years ago?
The main change that has occurred is within tumor classification. Instead of utilizing classic pathology—looking at the tumor underneath the microscope—tumor classification and treatment is now based on the actual molecular makeup of the individual tumors. So, in other words, we're looking at the tumor DNA, RNA, and protein expression levels, and that now guides our treatment.
Which trials over the past few years were the most practice changing in terms of introducing new standards of care this setting?
As far as the primary brain tumors are concerned, the most common one that we treat is called GBM. One of the trials that guides our current standard therapy is RTOG 0525. This was an international randomized phase 3 trial previously open at Allegheny General Hospital which looked at maximal safe resection, followed by radiation therapy and regular versus dose dense temozolomide chemotherapy. This trial helped define the current schedule for adjuvant chemotherapy.3
The other trial is called EF-14 and it was a TTF trial. TTFs create magnetic fields that are specifically targeted to your tumor that block cell division. In this trial, patients received chemoradiotherapy with temozolomide following maximal safe resection. After the radiation therapy was complete, half of the patients received TTFs in addition to temozolomide. And what they found was that there was [an increase of 8 percentage points in terms of OS rate] at 5 years in patients who had the TTF therapy.2
The current standard of care is maximal safe resection, followed by chemoradiotherapy with temozolomide, and then that is followed by additional temozolomide with the TTFs.4
How has the role of targeted therapies changed in the past few years in primary brain tumors? What notable trials are investigating targeted therapies?
Targeted therapy is currently in the process of changing. The first way is with the tumor classification. When we're determining what type of tumor the patient has, we look at the molecular makeup of the tumor and this guides treatment. We had a trial that we also participated in at Allegheny General Hospital called the GBM AGILE trial [NCT03970447]. It was a biomarker and molecular characteristic–driven trial. But those results are still pending, so we are awaiting the outcome.
Another trial that is currently available within Allegheny Health Network is NRG-BN007 [NCT04396860], a phase 3 intergroup trial, looking at adjuvant radiation with either chemotherapy or immunotherapy. Both regimens include maximal safe resection, followed by either radiotherapy with temozolomide, followed by additional temozolomide with or without TTF versus radiotherapy with immunotherapy followed by additional immunotherapy. The immunotherapy agents are ipilimumab [Yervoy] and nivolumab [Opdivo]. This trial is specifically for patients with a particular subtype of GBM called an unmethylated MGMT form. That's an active trial, so we don't have the results, but we've enrolled numerous patients onto this trial.
Another trial that's going to be opening up shortly at AHN, is EF-32 [NCT04471844]. It's also called the TRIDENT trial. As previously discussed, the current standard of care for GBM is maximal safe resection followed by chemoradiotherapy followed by additional adjuvant temozolomide and TTF. In this randomized trial, half of the enrollees will follow the current standard and the other half will start the TTF at the same time as the chemoradiotherapy and continue the TTF with the additional adjuvant temozolomide.
What we're trying to determine is, would it be better if we started the TTFs ‘right off the bat’ and deliver the radiation therapy with the TTF cap on rather than waiting 6 weeks for the radiation to complete before starting the TTFs. This and the other trials that I have listed so far are all national trials.
What is available for community oncologists to improve the quality of treatment and care for patients with brain cancers?
[At Allegheny Health Network], we have a multidisciplinary tumor board for neuro-oncology [that meets] every week. At this tumor board, we have physicians representing the specialties of neuroradiology, neuropathology, neurosurgery, neuro-oncology, and radiation oncology. During this tumor board, each individual patient is presented and then imaging, pathology, molecular testing, and potential clinical trial eligibility is reviewed followed by consensus treatment plan recommendation. We also provide navigation services for occupational therapy, physical therapy, home health, as well as psychological support. [Community oncologists] need to know that they are welcome to present their patients at our tumor board if they want a multidisciplinary opinion on how best to proceed.
What new options for treatment has your institution introduced recently?
For those patients that experience a recurrence, we have multiple different options, and we generally present all those cases at the multidisciplinary tumor board. We determine whether they're a candidate for resection of the lesion or whether they're a candidate for laser interstitial thermal therapy with our neurosurgery team. We also determine whether they're a candidate for any additional radiation therapy, sometimes in the form of standard radiation therapy, sometimes in the form of Gamma Knife [brain stereotactic radiosurgery].
One novel attribute about Allegheny General Hospital compared with some other Gamma Knife programs is that the vast majority of our patients are treated with a frameless approach. Therefore, they don't have to have a head frame or ‘halo’ fixated to their skull to receive the Gamma Knife treatment.
We are able to treat 90% of our patients frameless because we have the expertise and most advanced Gamma Knife available: the Gamma Knife Icon. It has a built-in imaging system that does 2 things. First, we're able to do what's called a cone-beam CT prior to treatment to make sure everything's in perfect alignment before we start the Gamma Knife treatment. The second thing is that we have an infrared camera as part of the imaging system that watches the patient and looks for fine movements and if a predetermined threshold is exceeded the treatment is temporarily stopped and the patient is repositioned. We have been able to change a technically invasive procedure into a non-invasive procedure.
We also have an Elekta Unity MRL. MRL stands for MRI-Linac [linear accelerator]. We are currently in the process of opening the [phase 2] UNITED trial [NCT04726397]. It's a trial which will use the targeting precision of the MRI-Linac to help reduce the amount of margin that we treat around primary brain tumors, specifically glioblastomas. By reducing the margin around what we're treating, we're reducing the volume that we treat, and thus, we're reducing the AEs that the patient may experience. The reason that we're able to do that with the MRI linear accelerator is that the patient is undergoing an MRI the entire time during radiation delivery. If there are any movements of the tumor, which there can be, or if there's any movement of the patient, we detect that right away and we can stop the treatment, reset, and then resume the treatment. We're one of  sites in the country that have this unit.
1. Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352(10):987-996. doi:10.1056/NEJMoa043330
2. Stupp R, Taillibert S, Kanner A, et al. Effect of tumor-treating fields plus maintenance temozolomide vs maintenance temozolomide alone on survival in patients with glioblastoma: a randomized clinical trial. JAMA. 2017;318(23):2306-2316. doi:10.1001/jama.2017.18718
3. Gilbert MR, Wang M, Aldape KD, et al. Dose-dense temozolomide for newly diagnosed glioblastoma: a randomized phase III clinical trial. J Clin Oncol. 2013;31(32):4085-4091. doi:10.1200/JCO.2013.49.6968
4. NCCN. Clinical Practice Guidelines for Oncology. Central nervous system cancers, version 2.2021. Accessed May 10, 2022. https://bit.ly/3FvCh4e