Re-irradiation for high-grade gliomas: Has anything changed?

Table 1 Summary of selected publications reporting radiosurgery as salvage treatment in recurrent high-grade gliomas

Ref.	Study type	No. patients	Histology	Re-irradiation		Median interval	Median tumor volume	Median PFS2	Median OS2	Severe toxicity	Radionecrosis
				Total dose, median	Dose/fr, median
Combs et al[28], 2005	R	32	All GBM	15 Gy	63.8 Gy	10 mo	10 mL	7 mo	10 mo	0%	0%
Hsieh et al[104], 2005	R	26	All GBM	12 Gy	42 Gy	NR	21.6 mL	NR	10 mo	NR	31.3% by image
Kong et al[34], 2008	P	114	65 GBM, 49 G3G	16 Gy	72 Gy	NR	10.6 mL	4.6 mo (GBM), 8.6 mo (G3G)	13 mo (GBM), 26 mo (G3G)	0%	24.4% by image
Patel et al[68], 2009	R	26	All GBM	18 Gy	90 Gy	12.5 mo	10.4 mL	NR	8.4 mo	Limited toxicity	NR
Skeie et al[30], 2012	R	51	All GBM	12.2 Gy	43.3 Gy	11 mo	12.4 mL	6 mo	12 mo	0%	0%
Martínez-Carrillo et al[31], 2014	R	87	46 GBM, 41 G3G	18 Gy	90 Gy	13.8 mo	8.7 mL	NR	7.5 mo (GBM); 17 mo (G3G)	0%	0%
Kim et al[105], 2015	R	29	All GBM	15 Gy	63.8 Gy	8.8 mo	11 mL	3.6 mo	9.2 mo	NR	NR

α/β = 2; EQD2: Equivalent dose at 2 Gy fractions; G3G: Grade III glioma; GBM: Glioblastoma; NR: Not reported; OS2: Overall survival from re-irradiation; P: Prospective; PFS2: Progression free survival from re-irradiation; R: Retrospective.

Table 2 Summary of selected publications reporting hypofractionated stereotactic radiosurgery as salvage treatment in recurrent gliomas

Ref.	Study type	No. patients	Histology	Re-irradiation			Median interval	Median tumor volume	Median PFS2/actuarial PFS2	Median OS2	Severe toxicity	Radionecrosis
				Total dose, median	Dose/fr, median	EQD2
Selch et al[106], 2000	R	21	15 GBM, 3 G3G, 2 G2G, 1 no biopsy	25 Gy	5 Gy	43.8 Gy	11 mo	12 mL	5 mo	6.7 mo	0%	0%
Vordermark et al[107], 2005	R	19	9 GBM, 10 G2G	30 Gy	5 Gy	52.5 Gy	19 mo	15 mL	4.9 mo, 4.6 mo (GBM)	9.3 mo, 7.9 mo (GBM)	10.5% other than necrosis	0%
Ernst-stecken et al[108], 2007	P	15	10 GBM, 3 G3G. 2 G2G	35 Gy	7 Gy	78.7 Gy	10 mo	22.4 mL	15 mo	12 mo	20% need to increase steroids dose without evidence of progressive disease	NR
Fokas et al[78], 2009	P	53	All GBM	30 Gy	3 Gy	37.5 Gy	NR	35 mL	22% at 12 mo	9 mo	0%	0%
Fogh et al[29], 2010	R	147	105 GBM, 42 G3G	35 Gy	3.5 Gy	48.1 Gy	8 mo	22 mL	NR	11 mo (GBM)	0.7% toxicity (severe headaches)	0%
Mckenzie et al[69], 2013	P	33	29 GBM, 4 G3G	30 Gy	5 Gy	52.5 Gy	NR	8.54 mL	62% at 6 mo	8.6 mo	9% toxicity other than necrosis	9% by image
Ogura et al[80], 2013	R	30	15 GBM, 9 G3G. 6 G2G	35 Gy	7 Gy	78.7 Gy	NR	9 mL	3 mo	10.2 mo	13.3% need to increase steroids dose without evidence of progressive disease	6.1% by image
Miwa et al[109], 2014	P	21	All GBM	30 Gy	5 Gy	52.5 Gy	12 mo	27.4 mL	NR	11 mo	4.8%	9.5%
Dincoglan et al[110], 2015	R	28	All GBM	25 Gy	5 Gy	43.8 Gy	11.2 mo	36.5 mL	5.8 mo	10.3 mo	0%	11% G2 by image

α/β = 2; EQD2: Equivalent dose at 2 Gy fractions; G: Grade; G2G: Grade II glioma; G3G: Grade III glioma; GBM: Glioblastoma; NR: Not reported; OS2: Overall survival from re-irradiation; P: Prospective; R: Retrospective; PFS2: Progression free survival from re-irradiation.

Table 3 Summary of selected publications reporting re-irradiation plus temozolomide as salvage treatment in recurrent high-grade gliomas

Ref.	Study type	No. patients	Histology	Re-irradiation			Median interval	Median tumor volume	Median PFS2/actuarial PFS2	Median OS2/actuarial OS2	Severe toxicity	Radionecrosis
				Total dose, median	Dose/fr, median	EQD2
Grosu et al[49], 2005	P	44 (TMZ 29)	34 GBM, 2 Gliosarcomas, 8 G3G	30 Gy	5 Gy	52.5 Gy	16 mo	15 mL	NR	8 mo (11 mo RT + TMZ vs 6 mo without TMZ)	0%	0%
Combs et al[81], 2008	R	25	8 GBM, 10 G3G, 7 G2G	36 Gy	2 Gy	36 Gy	36 mo	50 mL	5 mo; 16% at 12 mo	8 mo; 25% at 12 mo	0%	NR
Minniti et al[45], 2011	R	36	All GBM	37.5 Gy	2.5 Gy	42.2 Gy	14 mo	13.1 mL	5 mo; 8% at 12 mo	9.7 mo; 33% at 12 mo	Thrombocytopenia G3: 2.8%	8% by image
Conti et al[47], 2012	R	23 (TMZ 12)	All GBM	20 Gy	10 Gy	60 Gy	7 mo	< 30 mL	7 mo (TMZ) vs 4 mo (no TMZ)	12 mo (TMZ) vs 7 mo (without TMZ)	≥ G3 hematological toxicity > 40%	4.3%
Minniti et al[46], 2013	R	54	38 GBM, 16 G3G	30 Gy	6 Gy	60 Gy	15.5 mo	9.8 mL	6 mo (4 mo GBM)	12.4 mo (11.4 mo GBM)	Thrombocytopenia G3: 3.7%, leukopenia G3: 3.7%	7% by image
Greenspoon et al[111], 2014	P	31	All GBM	30 Gy	5 Gy	52.5 Gy	At least 6 mo	12 mL	7 mo	9 mo	NR	G3: 9.6%, G4: 3.2%
Aktan et al[48], 2015	R	21 (17 TMZ)	18 GBM, 3 G3G	54 Gy	2 Gy	54 Gy	39.4 mo	Recurrent tumor size was median 5.5 cm	NR	18 mo (G3G) and 14.1 mo (GBM)	0%	0%

α/β = 2; EQD2: Equivalent dose at 2 Gy fractions; G2G: Grade II glioma; G3G: Grade III glioma; G: Grade; GBM: Glioblastoma; NR: Not reported; OS2: Overall survival from re-irradiation; P: Prospective; R: Retrospective; PFS2: Progression free survival from re-irradiation; TMZ: Temozolomide.

Table 4 Summary of selected publications reporting re-irradiation plus bevacizumab as salvage treatment in recurrent high-grade gliomas

Ref.	Study type	No. patients	Histology	Re-irradiation			Median interval	Median tumor volume	Median PFS2	Median OS2	Severe toxicity	Radionecrosis
				Total dose, median	Dose/fr, median	EQD2
Gutin et al[56], 2009	P	25	20 GBM, 5 G3G	30 Gy	6 Gy	60 Gy	14.5 mo	34 mL	7.3 mo	12.5 mo	G3: 1 hemorrhage; G4: 3 (1 bowel perforation, 1 wound dehiscence and 1 GI bleed)	0%
Cuneo et al[54], 2012	R	63 (41 BEV)	49 GBM, 8 G3G, 6 prior G2G	15 Gy	15 Gy	63.8 Gy	21 mo	4.8 mL	GBM: 5.2 mo (BEV) vs 2.1 mo (without BEV). 6 mo whole series	GBM: 11.2 mo (BEV) vs 3.9 mo (without BEV). 10 mo whole series	11%	10%
Niyazi et al[52], 2012	R	30 (20 BEV)	22 GBM, 8 G3G	36 Gy	2 Gy	36 Gy	NR	NR	8 mo	Mean 12 mo	G3:1; G4: 1 wound dehiscence	0%
Shapiro et al[112], 2013	R	24	20 GBM, 1 G3G, 3 G2G	30 Gy	6 Gy	60 Gy	12.6 mo	35.3 mL	7.5 mo (6.8 mo GBM)	12.2 mo (whole series and GBM)	Toxicity BEV: G4: 12.5%	0%
Cabrera et al[113], 2013	P	15	8 GBM, 7 G3G	18 Gy. 25 Gy	18 Gy. 5 Gy	90 Gy. 43.8 Gy	20 mo	NR (< 5 cm)	3.9 mo	14.4 mo	G3:1	0%
Flieger et al[57], 2014	P	71 (57 BEV)	52 GBM, 19 G3G and G2G	36 Gy	2 Gy	36 Gy	NR	NR	5.6 mo (BEV) vs 2.5 mo (without BEV)	GBM: 9.3 mo (BEV) vs 6.1 mo (without BEV)	Toxicity BEV: G4: 5.3%	4.2% (BEV) by image or histologically

α/β = 2; BEV: Bevacizumab; EQD2: Equivalent dose at 2 Gy fractions; G: Grade; GBM: Glioblastoma; G2G: Grade II glioma; G3G: Grade III glioma; NR: Not reported; OS2: Overall survival from re-irradiation; P: Prospective; PFS2: Progression free survival from re-irradiation; R: Retrospective.

Table 5 Scoring scheme and new prognostic groups of the “New Combs Score”

Prognostic factors	Prognostic value
Primary histology
Glioblastoma, WHO IV	2
Anaplastic glioma, WHO III	1
Low-grade glioma, WHO I/II	0
Age
≥ 50 yr	1
< 50 yr	0
Time between primary RT and re-RT
≤ 12 meses	1
> 12 meses	0
Re-resection performed
No	1
Yes	0
KPS
< 80%	1
≥ 80%	0
Tumor volume (PTV)
> 47 mL	1
≤ 47 mL	0
Scoring group	Scoring value/mOS
a	0–1/19.5 mo
b	2–3/11.3 mo
c	4–5/8.1 mo
d	6–7/5.5 mo

KPS: Karnofsky performance status; mOS: Median overall survival; PTV: Planning target volume; RT: Irradiation; WHO: World Health Organization.