Anaplastic Gliomas

Question 1

ANAPLASTIC GLIOMAS

Answer 1

WHO grade III gliomas are referred to as anaplastic gliomas. While historically considered more aggressive than grade II gliomas, molecular classification has allowed for more granular prognostication among subgroups. Anaplastic gliomas include anaplastic oligodendroglioma (AO) IDH-mutant and 1p19q codeleted, anaplastic astrocytoma (AA) IDH-mutant, and AA IDH-wild-type. The general treatment paradigm includes maximal safe surgical resection followed by adjuvant RT and CHT. The randomized trials that established a survival benefit from CHT used PCV. However, concurrent and adjuvant TMZ is given more often and is still subject to ongoing study. An improved understanding of genomics is rapidly informing the clinical behavior and treatment.

Question 2

What is the epidemiology?

Answer 2

Grade III gliomas account for 25% of high-grade gliomas; the majority are AAs.1 AOs account for 0.4% and AAs 1.7% of newly diagnosed gliomas.2 Oligodendrogliomas are more common in younger patients.

Question 3

What are the risk factors?

Answer 3

Previous ionizing radiation.4 Genetic syndromes (<5% of gliomas) associated with gliomas include NF1 (17q, café au lait spots, Lisch nodules, neurofibroma, optic glioma, astrocytoma), NF2 (22q, bilateral acoustic neuroma, glioma, meningioma, ependymoma), tuberous sclerosis (ash-leaf macules, subependymal giant cell astrocytoma, gliomas), Li–Fraumeni syndrome, and von Hippel–Lindau (hemangioblastoma).

Question 4

What is the anatomy?

Answer 4

Most arise in the cerebral hemispheres. The frontal lobe is more common than parietal/ temporal, which is more common than occipital. Cerebellar tumors are uncommon.

Question 5

What is the pathology?

Answer 5

Histologic subtypes include AA and AO. WHO grading is classically based on the presence of two of the following criteria (MEAN): high mitotic index, endothelial proliferation, nuclear atypia, or necrosis.5 WHO grade I: benign, none. Grade II: low grade, one feature. Grade III: anaplastic, two features. Grade IV: malignant, three to four features or necrosis.1 Currently, WHO classification is now performed by integrating the phenotypic and genetic/mutational signatures. See Chapter 3 for an expanded discussion of the 2016 WHO CNS classification update and the cIMPACT updates, which will inform the next WHO updat

Question 6

What are the genetics aspects?

Answer 6

Oligodendrogliomas are molecularly defined per the 2016 WHO CNS classification by allelic loss of the 1p and 19q chromosome arms (“1p19q codeletion”) as well as IDH mutation. AOs carry a relatively favorable prognosis of ~14 years.6 ATRX loss and TP53 mutation is characteristic of astrocytoma (but not required for diagnosis) and is mutually exclusive with 1p19q codeletion. AAs with an IDH mutation have an intermediate prognosis of 5.5 years. AAs without an IDH mutation have a prognosis similar to that of glioblastoma of ~1.5 years.

Question 7

What are the clinical presentations?

Answer 7

Headache and seizures are the most common symptoms. Other symptoms may include memory loss, motor weakness, visual symptoms, language deficit, and cognitive and personality changes. In general, size and location dictate presenting symptoms.

Question 8

What is the workup?

Answer 8

H&P with neurologic exam.

Question 9

What are the Labs?

Answer 9

CBC, pregnancy test in young females, other basic labs prior to CHT.

Question 10

What are the imaging aspects?

Answer 10

MRI with gadolinium contrast. Anaplastic gliomas are typically hypointense on T1 with heterogeneous enhancement with gadolinium (up to one third may not enhance). Following surgical resection, obtain a postoperative MRI within 72 hours (ideally 24–48 hours) to determine the extent of resection and residual disease

Question 11

What is the pathology?

Answer 11

Must obtain tissue diagnosis by biopsy or surgical resection.

Question 12

What are the prognostic factors?

Answer 12

Patient-Related: Historically, an RPA by the RTOG classified patients based on factors such as age (<50 vs. ≥50), KPS (<90 vs. 90–100), mental status changes, and duration of symptoms (>3 months better than >3 months).7–9 The most favorable RPA class (<50 y/o with AA and normal mental status) demonstrated an MS of 58.6 months.

Question 13

What are the prognostic factors?

Answer 13

Tumor-Related: AO has a better prognosis compared to AA. The following molecular genetic alterations are positive prognostic factors: IDH mutations, 1p19q codeletion, and MGMT promoter methylation.

Treatment-Related: Extent of surgical resection

Question 14

What are the prognostic factors?

Answer 14

NATURAL HISTORY: Anaplastic gliomas, like other gliomas, are locally aggressive and frequently cause symptoms related to local progression and edema of surrounding tissue by alterations in permeability of blood–brain barrier.

Question 15

What are the treatment paradigm?

Answer 15

Surgery: Maximal safe resection with neurologic preservation is standard. See Chapter 1 for further details.

Question 16

What are the treatment paradigm?

Answer 16

Chemotherapy: Randomized trials including RTOG 9402 and EORTC 26951 have established a survival benefit with the addition of PCV CHT to RT for IDH-mutant anaplastic gliomas (PCV: lomustine, procarbazine, and vincristine). The addition of adjuvant TMZ to RT improves OS for IDH-mutant AAs. TMZ vs. PCV is currently being compared on the CODEL trial for AOs. Some institutions favor TMZ over PCV given that it is better tolerated. TMZ is given 75 mg/m2 daily with RT including weekends, followed by 150 to 200 mg/m2 daily on days 1 through 5 of 28-day cycles, with the first cycle beginning 28 days after the completion of RT. Up to 12 cycles of adjuvant TMZ are administered. Subgroup analyses have demonstrated no benefit with the addition of CHT for IDH-wild-type AAs.

Question 17

What are the treatment paradigm?

Answer 17

Radiation Indications: Adjuvant RT improves overall survival after surgery compared to observation or CHT alone and is indicated for all high-grade gliomas. Dose: The most common dose is 59.4 Gy/33 fx per trials discussed in the following. Toxicity: Common acute side effects may include fatigue, headache, alopecia, skin erythema, nausea, memory changes, or cerebral edema. Late effects are dependent on tumor location but may include radiation necrosis, memory/cognitive changes, hearing loss, optic neuritis, cataracts, hypopituitarism.

Question 18

What is the role of RT in the management of anaplastic gliomas?

Answer 18

The role of RT was initially established in the 1970s and 1980s due to a survival benefit. Walker (J Neurosurg 1978, PMID 355604): 303 patients with anaplastic gliomas randomized to one of four arms: (a) best supportive care, (b) BCNU alone, (c) RT alone, (d) RT + BCNU. RT was delivered as 50 to 60 Gy to the whole brain. MS was 14 weeks, 18.5 weeks, 35 weeks, and 34.5 weeks, respectively.

Question 19

What is the role of CHT in addition to RT?

Answer 19

Two landmark studies from RTOG and EORTC established the utility of adding CHT (PCV) to RT in anaplastic gliomas. Subsequent subset analyses have shed light on the importance of melecular markers.

Cairncross, RTOG 9402 (JCO 2006, PMID 16782910; Update JCO 2013, PMID 23071247; Subset JCO 2014, PMID 24516018): PRT of 291 patients newly diagnosed with AO/AOA randomized after surgery to four cycles PCV prior to RT vs. RT alone. PCV was administered every 6 weeks. RT started within 6 weeks of completion of CHT. A dose of 59.4 Gy/33 fx was given: 50.4 Gy/28 fx to the resection cavity and any T2 abnormality + 2 cm and then a 9 Gy/5 fx boost to the resection cavity and any T1 postcontrast enhancement plus 1 cm; 79% of “RT alone” patients eventually received CHT (PCV or TMZ); only 46% of PCV + RT patients received all four cycles of CHT. Original analyses in 2006 did not demonstrate a survival benefit with chemoRT as compared to RT alone for the entire cohort (4.7 years vs. 4.6 years, respectively). However, on subset analysis in 2014, patients with IDH-mutated tumors lived longer after chemoRT as compared to those with RT alone. Within the IDH-mutated subgroup, patients with 1p19q codeletion lived the longest. For patients with IDHwild-type, chemoRT did not increase survival compared to RT alone.

Question 20

What is the role of CHT in addition to RT?

Answer 20

Question 21

What is the role of CHT in addition to RT?

Answer 21

van den Bent, EORTC 26951 (JCO 2006, PMID 16782911; update JCO 2013, PMID 23071237): PRT of 368 patients newly diagnosed with AO/AOA randomized after surgery to RT followed by PCV x 6C vs. RT alone. Patients received RT within 6 weeks of surgery. A dose of 59.4 Gy/33 fx was given: 45 Gy followed by 14.4 Gy boost. Six cycles of PCV were started within 1 month of completing RT and administered every 6 weeks. Thirty-eight percent of PCV patients discontinued CHT prematurely; 82% of RT alone patients received CHT (PCV > TMZ + others) at recurrence; 55% of RT + PCV patients received salvage CHT (TMZ > PCV + others). On post hoc path review, one third of patients were found to have GBM; MFU 140 months. OS significantly improved among the entire group with PCV: 42.3 vs. 30.6 months. Significant improvements in PFS noted in both 1p19q codeleted (157 vs. 50 months) and 1p19q intact (15 vs. 9 months). No long-term difference in QOL reported after PCV. IDH mutation and 1p19q codeletion were independently significant on multivariate prognostic model. MGMT methylation status was not an independent prognostic factor of survival

Question 22

What is the role of CHT in addition to RT?

Answer 22

Question 23

What is the management of AAs?

Answer 23

Though often categorized with AOs and AOAs, it is important to note that histologic AAs were not enrolled on either RTOG 9402 or EORTC 26951. Instead, the standard of care of chemoRT is derived from historical malignant glioma trials, of which AAs constituted a minority of patients. They also made up a small minority of the patients on the Stupp trial (see Chapter 1), from which the modern treatment paradigm is generally extrapolated. The only modern prospective randomized evidence in AAs comes from RTOG 9813. However, the contemporary definition of AA uses molecular markers, and subset analyses of RTOG 9402 or EORTC 26951 showed benefit to PCV for AA with IDH mutation.

Question 24

What is the management of AAs?

Answer 24

Chang, RTOG 9813 (Neuro Oncol 2017, PMID 27994066): PRT of 196 patients with AA or AOA (<25% oligo component) and KPS ≥60 was randomized to RT with concurrent and adjuvant TMZ vs. RT and nitrosourea (either BCNU or CCNU); RT was 59.4 cGy/ 33 fx. No difference in survival between arms (3.9 vs. 3.8 years, p = .36). The RT + NU arm had a significantly higher rate of worse overall grade ≥3 toxicity (75.8% vs. 47.9%, p < .001). Conclusion: RT + TMZ was not beneficial compared to RT + nitrosourea but was better tolerated.

Question 25

What is the role of TMZ for anaplastic gliomas?

Answer 25

Despite the survival advantage demonstrated with PCV in patients with AOs and AOAs, many substitute TMZ as it is easier to administer and generally better tolerated. RTOG 0131, NOA-04, and the early results of CATNON all suggest this is a reasonable substitution.

Vogelbaum, RTOG 0131 (J Neuroncol 2015, PMID 26088460): Phase II, single-arm trial including 48 patients undergoing TMZ x 6C followed by concurrent RT + TMZ (if disease progression seen on CT/MRI scans every 8 weeks while on pre-RT TMZ). RT 59.4 Gy/33 fx. MFU 8.7 years, median PFS 5.8 years, MS not reached. 1p19q status available in 37 cases. OS and PFS not reached for codeleted patients. Four patients (10%) achieved complete response. Conclusion: Pre-RT TMZ followed by concurrent RT and TMZ is indirectly comparable to PCV followed by RT.

Question 26

What is the role of TMZ for anaplastic gliomas?

Answer 26

Wick, NOA-04 (JCO 2009, PMID 19901110; Update Neuro Oncol 2016, PMID 27370396): PRT of 318 patients with anaplastic glioma randomly assigned 2:1:1 (A:B1:B2) to receive (A) RT 54 to 60 Gy, (B1) PCV, or (B2) TMZ. In arm A, patients received CHT after progression, and in arm B1 or B2, patients received RT after progression. The primary end point was TTF defined as progression after RT and one CHT in either sequence. The initial results reported in 2009 did not identify any difference in TTF, PFS, or OS between primary CHT compared to RT. This was confirmed with report of long-term results in 2016. The study also identified IDH1 mutation as a positive prognostic factor with a stronger impact as compared to 1p19q codeletion or MGMT methylation. Subset analysis demonstrated that AOs (IDH-mutant, 1p19q codeleted) had improved PFS with PCV vs. TMZ, suggesting PCV may be more effective in this subset.

Question 27

What is the role of TMZ for anaplastic gliomas?

Answer 27

van den Bent, EORTC CATNON (Lancet 2017, PMID 28801186; Update Lancet 2021, PMID 34000245): Phase III PRT of 748 patients with newly diagnosed anaplastic glioma with 1p19q intact randomized to 1 of 4 arms: (a) RT (59.4 Gy/33 fx) alone, (b) RT + concurrent TMZ, (c) RT alone + adjuvant TMZ, or (d) RT + concurrent and adjuvant TMZ. Stratified based on MGMT methylation, age, 1p loss of heterozygosity, presence of oligodendroglial elements, and performance status. Interim analysis with MFU 27 months and 99% enrollment at the time of analysis. HR for OS with adjuvant TMZ 0.65 (SS). 5-year OS 55.9% with adjuvant TMZ, 44.1% without adjuvant TMZ. Adjuvant TMZ improved PFS 42.8 vs. 19.0 months (p < .05). MGMT methylation was prognostic for OS but not predictive of improved outcome to adjuvant TMZ at this stage. At second interim analysis with MFU 55.7 months, futility of concurrent TMZ was declared (MS 66.9 months with concurrent TMZ vs. 60.4 months without). Adjuvant TMZ improved OS vs. not adjuvant TMZ (MS 82.3 months vs. 46.9 months). Conclusion: Adjuvant TMZ, but not concurrent TMZ, improved PFS and OS for 1p19q intact anaplastic gliomas.

Question 28

What is the role of TMZ for anaplastic gliomas?

Answer 28

Jaeckle, CODEL (Neuro Oncol 2020, PMID 32678879): PRT of 36 patients with 1p19q codeleted WHO grade III oligodendrogliomas randomized to RT (59.4 Gy) alone, RT with concurrent and adjuvant TMZ, or TMZ alone in the initial CODEL design. With 7.5-year follow-up, PFS was shorter with TMZ alone compared to the RT arms (HR 3.12, 95% CI: 1.26–7.69, p = .014). The comparison was underpowered to determine OS differences. No differences were observed in neurocognitive decline. Conclusion: Patients with 1p19q codeleted AOs had significantly shorter PFS when treated with TMZ alone compared to RT arms. The CODEL trial is now redesigned to compare RT + PCV vs. RT + TMZ, and is ongoing.