Focus on current and emerging treatment options for glioma: A comprehensive review

Table 1 World Health Organization classification of gliomas

Grade	Name	Description and characteristics
I	Pilocytic astrocytoma	Well-differentiated, often cystic, slow-growing, generally benign
II	Diffuse astrocytoma	Infiltrative, moderately cellular, tends to recur, can progress to higher grades
II	Oligodendroglioma	Composed of oligodendrocyte-like cells, often associated with 1p/19q co-deletion
II	Mixed oligoastrocytoma	Combination of features of oligodendroglioma and diffuse astrocytoma
III	Anaplastic astrocytoma	Higher grade astrocytoma with increased cellularity and mitotic activity
III	Anaplastic oligodendroglioma	Higher grade oligodendroglioma with increased cellularity and atypia
III	Anaplastic oligoastrocytoma	Higher grade mixed tumor with features of both anaplastic astrocytoma and anaplastic oligodendroglioma
IV	Glioblastoma	Highly aggressive, necrosis, endothelial proliferation, molecular heterogeneity

Table 2 List of Immunotherapy

Ref.	Completion year	Demographics	Study phase	Identifier	Experimental drug	Sample size	Primary endpoint/outcomes	Results for primary outcome
BRAF/MEK inhibitors
Nicolaides et al[107], 2020	2023	Pediatrics	Phase 2	NCT01748149 (Ongoing Trial)	Vemurafenib	40	Safety and pharmacokinetics	Not yet reported
Hargrave et al[108], 2019	2020	Pediatrics	Phase 1/2a	NCT01677741	Dabrafenib	32	Objective response rates and safety	Objective response rate was 44% and 91% experienced adverse effects
Kaley et al[109], 2018	2016	Adults	Phase 2	NCT01524978	Vemurafenib	24	Confirmed objective response rate, PFS, OS and safety	Confirmed objective response rate was 25% and median PFS was 5.5 months
FGFR inhibitors
Lassman et al[110], 2022	2018	Adults	Phase 2	NCT01975701	Infigratinib	26	6-month PFS	6-month PFS rate was 16.0%
Bahleda et al[111], 2019	2017	Adults	Phase 1	NCT01703481	Erdafitinib	187	Safety	Most common treatment-related adverse events were hyperphosphatemia, dry mouth, and asthenia, generally grade 1/2 severity
HDAC inhibitors
Wood et al[112], 2018	2018	Pediatrics	Phase 1	ACTRN12609000978268	Panobinostat	9	Safety and pharmacokinetics	2 patients experienced Grade 3-4 thrombocytopenia, 1 experienced Grade 3 anemia, and 2 experienced Grade 3 neutropenia
Imipridone
Arrillaga-Romany et al[113], 2020	2023		Phase 2	NCT02525692 (Ongoing Trial)	ONC201	89	6-month PFS	Not yet reported
PI3K/mTOR inhibitors
Wen et al[114], 2022	2023	Adults	Phase 2	NCT03522298	Paxalisib	32	Safety and pharmacokinetics	Well-tolerated with adverse events consistent with other PI3K inhibitors
Wen et al[115], 2020	2020	Adults	Phase 1	NCT01547546	GDC-0084	47	Safety and pharmacokinetics	Well-tolerated with adverse events consistent with other PI3K inhibitors
Franz et al[116], 2015	2014	Adults/Pediatrics	Phase 1/2	NCT00411619	Enviroximes	28	6-month change in the volume of sub ependymal giant-cell astrocytoma	Statistically significant reduction in the volume of the primary sub ependymal giant-cell astrocytoma at 6 months
NTRK/ALK inhibitors
NCT02637687[117]	2026	Pediatrics	Phase 1/2	NCT02637687 (Ongoing Trial)	Larotrectinib	155	Objective response rates	Not yet reported
NCT02576431[118]	2025	Adults/Pediatrics	Phase 2	NCT02576431 (Ongoing Trial)	Larotrectinib	204	Objective response rates, PFS, OS, Safety	Not yet reported
Desai et al[119], 2022	2025	Adults/Pediatrics	Phase 1/2	NCT02650401 (Ongoing Trial)	Entrectinib	69	Maximum Tolerated Dose and Objective response rates	Not yet reported
IDH inhibitors
NCT05588141[120]	2029	Adults	Phase 1/2	NCT05588141 (Ongoing Trial)	Zotiraciclib	96	12-months PFS	Not yet reported
Mellinghoff et al[121], 2023	2027	Adults	Phase 3	NCT04164901	Vorasidenib	340	PFS	Significantly improved PFS
Mellinghoff et al[122], 2019	2024	Adults	Phase 1	NCT03343197	AG-120, AG881	49	2-hydroxyglutarate concentrationin resectedtumors	decreased tumorcell proliferationand immune cellactivation
EGFR inhibitors
Weller et al[123], 2017	2016	Adults	Phase 3	NCT01480479	Rindopepimut/Temozolomide	745	OS	Median OS was 20.1 months in the Rindopepimut group versus 20.0 months in the control group
Lassman et al[124], 2023	2022	Adults	Phase 3	NCT02573324	Depatuxizumab mafodotin	691	OS	No OS benefit for depatux-m in treating EGFR-amp newly diagnosed GBM

PFS: Progression-free survival; OS: Overall survival.

Table 3 Supratentorial surgical treatment options for glioma, n (%)

Ref.	Study origin	Study design	Total number of patients	Supratotal resection sample	Male, %	Age atresection	Permanent neurological deficits	Progression-free survival	Overall survival
Gajjar et al[63], 1997	United States	Cohort study	142	48 (68/142)	61	7 median (0.17-19)	Not reported	70 ± 5 at 4 years	90 ± 3 at 4 years
Fisher et al[67], 2008	United States	Cohort study	278	19 (52/278)	58	9.1 ± 0.3	Not reported	55 ± 3 at 5 years	87 ± 2 at 5 years
Wisoff et al[125], 2010	United States	Prospective trial	518	64 (332/518)	54	7.9 median (0.6-20.5)	Not reported	78 ± 2 at 8 years	96 ± 0.9 at 8 years
Yordanova et al[93], 2011	France	Case series	15	100.00	53.3	36.4 (24-59)	2, 13.3	73.3 at 38 months	100 at study end
Youland et al[11], 2013	United States	Retrospective cohort	351	67 (235/351)	55	10.9 (0.05-19.6)	Not reported	75.8 at 5 years	94.9 at 5 years
Lima et al[126], 2015	France	Case series	21	19.0 (4/21)	28.57	35 (18-57)	0, 0	100 at study end	100 at study end
Duffau et al[127], 2016	France	Cohort study	16	100.00	43.75	41.3 (26-63)	0, 0	50 relapse rate (avg 70 months)	100 at study end
Lima et al[92], 2017	France	Two-center prospective study	19	26.3 (5/19)	42.1	31.2 (19-51)	0, 0	100 at study end	100 at study end
Rossi et al[86], 2019	Italy	Case series	449	32 (145/449)	53.1	37.9 (median 36.5)	1, 0.69 (SupTR group)	Not reported	Not reported
Ng et al[128], 2020	France	Case series	74	28 (21/74)	41.89	35.7 (18-66)	0, 0	Not reported	100 at 5 years
Ng et al[129], 2020	France	Case series	47	26 (12/47)	34.04	39.2 ± 11.3	0, 0	Not reported	100 at study end
Goel et al[130], 2021	India	Cohort study	74	34 (25/74)	62.16	33 (21-55)	0, 0	98.7 at 2 years	100 at study end
Rossi et al[94], 2021	Italy	Case series	319	35 (110/319)	61.1	38.9 (18-75)	6, 1.9	94 at 92 months (SupTR group)	100 at 80 months (SupTR group)
Ius et al[131], 2022	United States, Canada, France, and Italy	Four center retrospective review	267	9 (24/267)	41.9	39.2 (18-71)	8, 3.1	Not reported	100 at 100 months (SupTR)