ASTRO Releases Clinical Guidelines on the Treatment of IDH-Mutated Grade 2/3 Diffuse Glioma

The American Society for Radiation Oncology (ASTRO) has released clinical recommendations for the treatment of patients who have been diagnosed with IDH-mutated grade 2/3 diffuse glioma based on World Health Organization (WHO) 2021 criteria, according to a clinical practice guideline update published in Pro Practical Radiation Oncology.¹

Close surveillance was strongly recommended for those with IDH-mutant, 1p/19q codeleted oligodendroglioma of WHO grade 2 following gross total section and no high-risk features. For those with grade 2 disease and high-risk features, ASTRO conditionally recommended adjuvant radiotherapy and strongly recommended treatment for WHO grade 3 oligodendroglioma. For those with WHO grade 2 astrocytoma with high-risk features, adjuvant radiotherapy was conditionally recommended with a strong recommendation for those with WHO grade 3 disease.

“Adjuvant radiotherapy after surgery remains a cornerstone of therapy for patients with IDH-mutant grade 2 and grade 3 diffuse glioma to improve PFS [progression-free survival],” the investigators wrote. “However, the optimal timing of radiotherapy remains controversial. Based on the available evidence, this guideline recommends that some low-risk patients, including those with gross total resection and lacking high-risk features, should be initially observed with the understanding that most patients will require radiotherapy during their disease course.”

The guideline recommendations were produced with the goal of improving patients care quality and outcomes based on systemic methods to assess and classify evidence with a focus on patient-centric care and shared decision making. Task force members included a multidisciplinary panel of key opinion leaders from various geographic regions and across different genders, races, practice settings, and areas of expertise. The guidelines were developed using evidence-based methodologies in concordance with standards from the National Academy of Medicine. Factors such as population, intervention, comparator, outcomes, timing, and setting framework comprised the evidence.

The task force noted that strategies focused on patients with IDH-mutated grade 2 and 3 diffuse glioma have been a point of contention when considering that clinical trials highlighting a PFS and/or overall survival improvement often use various interventions. Understanding how to interpret data has been complex due to heterogeneous study populations until the advent of molecular markers which has resulted in a more meaningful prognostication.

The task force included radiation oncologists, neuro-oncologists, a neurosurgeon, a neuropathologist, a radiation oncologist resident, and a patient advocate. A total of 14 individuals peer reviewed the guidelines and made appropriate updates. For the evidence review, the task force conducted a systemic search for human clinical trials via the Ovid MEDLINE database. To be included in the literature review, studies needed to be in adult patient populations who had been diagnosed with WHO grade 2 or 3 glioma. Patients who were under the age of 18 years; were reirradiated; had an IDH wild-type glioblastoma with WHO grade 4; had an IDH-mutant astrocytoma and CDKN2A/B homozygous deletion with WHO grade 4; had a circumscribed astrocytic glioma; had a glioneuronal and neuronal tumors; had a ependymal tumors; or had a disseminated disease were not included in the guideline recommendations.

Recommendations for Low- and High-Grade Gliomas

In particular, optimal indications and timing for radiotherapy are based on randomized controlled trials with a focus on patients with low-grade glioma, such as grade 2 oligodendroglioma and astrocytoma. Although many trials did not test for IDH mutations and 1p/19q codeletion, many included patients with IDH-mutant grade 2 and 3 disease. In a population of patients with grade 2 glioma, adjuvant radiotherapy significantly improved PFS compared with radiotherapy at progression. Based on this, patients with low-grade disease are recommended to undergo observation, while those with high-risk disease have been recommended for adjuvant radiotherapy.

The Benefit of Adjuvant Therapy for Grade 2 Oligodendroglioma

In the past, treatment for patients with grade 2 oligodendroglioma was only administered upon progression. Current data support early adjuvant treatment strategies among those with high-risk features and close surveillance for the low-risk population. Notably, the recommendation is conditional as current data highlight a lack of OS benefit following treatment with adjuvant radiotherapy compared with surveillance. Moreover, for grade 3 or anaplastic oligodendroglioma, radiotherapy is favored by conventional clinical practice for those who experienced radiotherapy delays or interruptions compared with individuals who never received the treatment.³

However, the authors indicated that chemotherapy recommendations were beyond the guideline’s scope and that data from the phase 3 CODEL trial (NCT00887146), assessing adjuvant radiotherapy plus subsequence procarbazine, lomustine, and vincristine vs temozolomide in co-deleted anaplastic glioma or low-grade glioma, may help to guide future decisions.⁴

Recommendations for Those With IDH-Mutated Astrocytoma

In the IDH-mutated astrocytoma population, a conditional recommendation has been made for adjuvant radiotherapy for those with high-risk features and WHO grade 2 disease. Sequential or sequential/concurrent chemotherapy are included in the recommendation and covers those with high-risk, grade 2 astrocytoma, oligodendroglioma, and oligoastrocytoma. Although studies supporting adjuvant chemotherapy and radiotherapy have been published regarding patients with grade 3 IDH-mutant astrocytoma, timing of radiotherapy still needs to be determined.

References

1. Halasz LM, Attia A, Bradfield L, et al. Radiation therapy for IDH-mutant grade 2 and grade 3 diffuse glioma: an ASTRO clinical practice guideline. Pro Prac Rad Onc. 2022;12(5):370-386. doi:10.1016/j.prro.2022.05.004
2. Karim ABMF, Afra D, Cornu P, et al. Randomized trial on the efficacy of radiotherapy for cerebral low-grade glioma in the adult: European Organization for Research and Treatment of cancer study 22845 with the Medical Research Council study BRO4: an interim analysis. Int J Rad Onc Bio Phys. 2002;52(2):316-324. doi:10.1016/S0360-3016(01)02692-X
3. van de Bent MJ, Carpentier AF, Sanson M, et al. Adjuvant procarbazine, lomustine, and vincristine improves progression-free survival but not overall survival in newly diagnosed anaplastic oligodendrogliomas and oligoastrocytomas: a randomized European Organisation for Research and Treatment of Cancer phase III Trial. J Clin Oncol. 2006;24(18):2715-2722. doi:10.1200/JCO.2005.04.6078
4. Jaeckle KA, Ballman KV, van den Bent M, et al. CODEL: phase III study of RT, RT + TMZ, or TMZ for newly diagnosed 1p/19q codeleted oligodendroglioma. Analysis from the initial study design. Neuro Oncol. 2021;23(3):457-467. doi:10.1093/neuonc/noaa168.