Key Takeaways
- Treatment choices for relapsed or progressive pediatric low-grade glioma (pLGG) include surgery, traditional chemotherapy, and radiation therapy. Many clinical trials of targeted therapy for glioma are underway.
- The decision to use radiation therapy often depends on tumor location. When radiation therapy is used, proton therapy is preferred because it results in less exposure of healthy brain tissue to radiation compared with proton therapy.
- Traditional chemotherapy puts a significant logistical burden on patients and their families. Targeted therapies offer the potential for more convenient treatment regimens.
- The length of time between completion of radiation therapy and observed glioma progression can help clinicians to differentiate between true disease progression and pseudoprogression.
Amar Gajjar, MD, is the director of the neuro-oncology division at St. Jude Children’s Research Hospital, Memphis, Tennessee. Dr Gajjar is the co-chair of the department of oncology and chair of the department of pediatric medicine at St. Jude. Dr Gajjar is an active participant in the Pediatric Brain Tumor Consortium, the Pediatric Neuro-oncology Consortium, and the Children’s Oncology Group. He is heavily involved in clinical trials featuring novel treatments for pediatric brain tumors.
What is the current treatment landscape for unresectable pLGG or pLGG that progresses after surgical resection?
There are many treatment options involving conventional chemotherapy, radiation therapy, and new targeted therapy agents. Conventional chemotherapy includes regimens of carboplatin and vincristine; thioguanine, procarbazine, lomustine, and vincristine (TPCV); or vinblastine monotherapy.1,2 Fortunately, ongoing shortages of vincristine and vinblastine have not presented us with any difficulties thus far, and we are able to select a treatment regimen without taking that into consideration. When radiation therapy is appropriate, modalities such as proton radiation, photon radiation, and stereotactic radiation have all demonstrated local control of glioma.3-5
Targeted therapies for pLGG are currently only available through patient enrollment in a clinical trial. Selumetinib (ClinicalTrials.gov Identifier: NCT01089101), tovorafenib (ClinicalTrials.gov Identifier: NCT04775485), binimetinib (ClinicalTrials.gov Identifier: NCT3231306), and mirdametinib (ClinicalTrials.gov Identifier: NCT04923126) are just a few of the many targeted therapies currently under investigation for use in the treatment of pLGG.
What is your approach to balancing the benefits of different medications or radiation therapy against potentially harmful effects of treatment, such as the impact on patients’ physical and cognitive development?
Unlike high-grade gliomas, low-grade gliomas are slow-growing, meaning very aggressive therapy is not warranted in most cases. We try to avoid radiation therapy entirely in very young patients because of the potential for late toxicities.3 There is not an expert consensus as to what age a patient should be before radiation therapy is considered appropriate.
The decision to use radiation therapy may be influenced by the location of the glioma. For example, if a patient has a chiasmatic/hypothalamic glioma or optic pathway glioma, then the patient may be rapidly losing visual acuity. In order to halt this loss in visual acuity, we are more likely to treat such patients with radiation therapy. Unfortunately, sometimes patients present at our hospital late in the disease process and have become completely blind due to forgoing radiation treatment (instead receiving only traditional chemotherapy), despite having tumors that were causing rapid vision loss. When radiation therapy is indicated, the use of proton radiation therapy rather than photon radiation therapy results in a little less damage to surrounding healthy brain tissue.
In adults with low-grade gliomas, radiation therapy helps to improve seizure control. That benefit is not observed in pLGG, however, and radiation therapy is not indicated as a means to minimize seizures associated with pLGG. Treatment of pediatric patients with glioma comprises traditional chemotherapy in conjunction with antiseizure medications.
A variety of agents that target the mitogen-activated protein kinase (MAPK) pathway, such as MEK or BRAF inhibitors, are being tested in pLGG clinical trials. Therapies targeting the activated Ras/Raf/MEK pathway in pLGG offer a novel mechanism of tumor control, with potentially lower toxicity. How do you envision the impact of emerging targeted agents on the pLGG treatment landscape?
Every treatment option, whether it be traditional chemotherapy or targeted therapy, has associated adverse effects. Targeted agents, if shown to be better — or at least noninferior — at treating the tumor, it will carry their own toxicities and complications. These include, but are certainly not limited to, skin rashes, elevated creatine phosphokinase levels, cardiomyopathies, and vision changes.6
The primary benefit of targeted therapy is that there are oral therapy options. Traditional chemotherapy often requires an all-day clinic visit with required labs and chemotherapy infusions. For every treatment day, the young patient is being removed from school, the parent is missing a day of work, and this is happening repeatedly over the course of many months. Some employers are not as flexible as others regarding parents’ need to take their child to multiple treatment appointments, and the entire process can pose a very large socioeconomic burden to families.
Some of the treatment decisions, at least in regard to choosing between traditional chemotherapy and targeted therapy, is going to come down to the relative convenience of oral medications.
What is the current role of genetic testing in choosing a treatment regimen?
The 2021 World Health Organization (WHO) guidelines for the management of central nervous system (CNS) tumors state that molecular testing should be performed on every patient with glioma.7 The process of completing the test can be difficult for clinicians at smaller sites, who perhaps do not see as many patients with pLGG; hence there is a potential for error. Historically, we would start treatment and then do molecular testing, but under current WHO classification of gliomas, molecular testing is now the first step. It currently takes a couple of weeks to receive the results. At that point, we can use the patient’s histologic information and molecular characteristics to advise on enrollment in an appropriate clinical trial.
Despite the availability of molecular testing for patients with pLGG, it is still unclear whether a specific molecular event carries the same prognostic significance across different pLGG subtypes. What is your approach to integrating histologic tumor classifications with molecular findings?
This is emerging knowledge, and more information will be generated as more patients are treated prospectively with targeted agents; it is known, however, that patients with tumors that have a CDKN2A deletion along with the BRAF V600E mutation have a poorer prognosis.
The new WHO CNS tumor classification guidelines advise on generating an integrated diagnosis that includes molecular and histopathologic information.7 The classification and nomenclature were also updated in 2021 to reflect this integration. For example, Diffuse low-grade glioma, MAPK pathway-altered cites an additional subtype indicating the specific molecular alteration. Also, the WHO CNS grading now includes combined histologic and molecular parameters, and grading is assigned within the tumor type.
A recent study indicated that in patients with pLGG, pseudoprogression frequently occurs after radiation therapy.8 How is the difference between pseudoprogression and true progression determined, and what is the impact on treatment decisions?
Pseudoprogression is very common after radiation therapy and can happen up to 18 to 24 months after the patient has completed therapy. If there is pseudoprogression, we will adjust the frequency of imaging in an effort to monitor the situation more closely. If the patient with tumor pseudoprogression is symptomatic, steroids are very effective for symptomatic relief.
This Q&A was edited for clarity and length.
Disclosure
Amar Gajjar, MD, reported affiliations with Genentech, Inc.; QED Therapeutics Inc.; Day One Biopharmaceuticals, Inc.; Geanno Bio, and Kazia Therapeutics, Ltd.
References
1. Ater JL, Zhou T, Holmes E, et al. Randomized study of two chemotherapy regimens for treatment of low-grade glioma in young children: a report from the Children’s Oncology Group. J Clin Oncol. 2012;30(21):2641-2647. doi:10.1200/JCO.2011.36.6054
2. Lassaletta A, Scheinemann K, Zelcer SM, et al. Phase II weekly vinblastine for chemotherapy-naive children with progressive low-grade glioma: a Canadian Pediatric Brain Tumor Consortium Study. J Clin Oncol. 2016;34(29):3537-3543. doi:10.1200/JCO.2016.68.1585
3. Greenberger BA, Pulsifer MB, Ebb DH, et al. Clinical outcomes and late endocrine, neurocognitive, and visual profiles of proton radiation for pediatric low-grade gliomas. Int J Radiat Oncol Biol Phys. 2014;89(5):P1060-P1068. doi:10.1016/j.ijrobp.2014.04.053
4. Paulino AC, Mazloom A, Terashima K, et al. Intensity-modulated radiotherapy (IMRT) in pediatric low-grade glioma. Cancer. 2013;119(14):2654-2659. doi:10.1002/cncr.28118
5. Marcus KJ, Goumnerova L, Billett AL, et al. Stereotactic radiotherapy for localized low-grade gliomas in children: final results of a prospective trial. Int J Radiat Oncol Biol Phys. 2005;61(2):P374-P379. doi:10.1016/j.ijrobp.2004.06.012
6. Fangusaro J, Onar-Thomas A, Young Poussaint T, et al. Selumetinib in paediatric patients with BRAF-aberrant or neurofibromatosis type 1-associated recurrent, refractory, or progressive low-grade glioma: a multicentre, phase 2 trial. Lancet Oncol. 2019;20(7):1011-1022. doi:10.1016/S1470-2045(19)30277-3
7. Louis DN, Perry A, Wesseling P, et al. The 2021 WHO classification of tumors of the central nervous system: a summary. Neuro-Oncology. 2021;23(8):1231-1251. doi:10.1093/neuonc/noab106
8. Stock A, Hancken C-V, Kandels D, et al. Pseudoprogression is frequent after front-line radiation therapy in pediatric low-grade glioma: results from the German Low-Grade Glioma Cohort. Int J Radiation Oncol Biol Phys. 2022;112(5):P1190-P1202. doi:10.1016/j.ijrobp.2021.12.007
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Reviewed September 2022
