Temozolomide for treatment of brain metastases: A review of 21 clinical trials

Table 1 Study characteristics of the studies that used temozolomide as a single agent

Trial	Publication information(author/yr/country)	Patient characteristic			Cancer	Prior treatment
		Total number	Median age	Gender (male/female)
1	Abrey et al[16]/2001/United States	41 (341)	60	11/30	NSCLC (n = 22)	WBRT (n = 41)
					Breast (n = 10)	Stereotactic RT (n = 9)
					Melanoma (n = 3)	Chemotherapy (n = 35)
					SCLC (n = 2)	Surgery (n = 11)
					Rectal (n = 2)
					Ovarian (n = 1)
					Endometrial (n = 1)
2	Siena et al[20]/2009/Italy	157	51.14/53.93/59.12	72/85	Melanoma (n = 53)	WBRT (n = 41)
					Breast cancer (n = 51)	Chemotherapy (n = 98)
					NSCLC (n = 53)	Radiotherapy (n = 34)
3	Schadendorf et al[21]/2006/Germany	45 (405/376)	54.5	29/16	Melanoma	Chemotherapy (n = 21)
4	Giorgio et al[19]/2005/Italy	30	65	23/7	NSCLC	WBRT (n = 30)
						Stereotactic radio surgery (n = 1)
						Chemotherapy (n = 30)
5	Christodoulou et al[17]/2000/Greece	28 (241)	56	19/9	NSCLC (n = 12)	WBRT (n = 23)
					SCLC (n = 5)	Radiation(other sites) (n = 5)
					Breast (n = 4)	Surgery (n = 4)
					Other (n = 7)	Chemotherapy (n = 22)
						Biologic therapy(n = 1)
6	Agarwala et al[15]/2004/United States	151 (1221)	537/46.58	95/56	Melanoma	Chemotherapy (n = 34)
						Immunotherapy (n = 237/218)
7	Dziadziuszko et al[18]/2003/Poland	12 (111)	57	6/6	NSCLC	WBRT (n = 4)
						Chemotherapy (n = 1)
						Surgery (NA)
						Radiotherapy (NA)

¹The number of patients eligible for the assessment of clinical outcomes;

²Non–small cell lung cancer (NSCLC);

³Breast cancer;

⁴Melanoma;

⁵The number of patients eligible for the assessment of brain lesion response;

⁶The number of patients eligible for the assessment of extracerebral response;

⁷No prior chemotherapy;

⁸Prior chemotherapy. NA: Not available; SCLC: Small cell lung cancer; WBRT: Whole-brain radiotherapy.

Table 2 Study characteristics of the studies that combined temozolomide with radiotherapy and/or other agents

Trial	Publication information(author/yr/country)	Patient characteristic			Cancer	Prior treatment
		Total number	Median age	Gender (male/female)
8	Addeo et al[22]/2008/Italy	27	55	13/14	NSCLC (n = 15) Breast (n = 12)	Chemotherapy (n = 20) Surgery (n = 20) Radiotherapy (n = 12)
9	Mikkelsen et al[23]/2010/United States	17	65.4	10/7	Lung (n = 13) Colon (n=1) Melanoma (n = 1) Mixed (prostate, bladder, lung) (n = 1) Unknown (probably lung) (n = 1)	Chemotherapy (n = 7) Surgery (n = 1) Stereotactic radiosurgery (n = 2)
10	Kouvaris et al[24]/2007/Greece	33	66	22/11	SCLC (n = 4) NSCLC (n = 10) Breast (n = 7) Rectal (n =5) Melanoma (n = 5) Oral cavity (n = 1) Unknown (n = 1)	NA
11	Hofmann et al[25]/2006/Germany	35 (341)	53	19/16	Melanoma	Chemotherapy (n = 7) Immunotherapy (n = 4) Chemoimmunotherapy (n = 3) Surgery/radiosurgery (n = 4)
12	Antonadou et al[26]/2002/Greece	25 (241)	49	25/14	Melanoma	NA
13	Atkins et al[29]/2008/United States	39	61	29/10	Melanoma	Immunotherapy (n = 12) Radiotherapy (n = 7)
14	Cortot et al[28]/2006/France	50 (472/333/474)	57	40/10	NSCLC	Surgery (n = 40) Radiotherapy (n = 3)
15	Iwamoto et al[31]/2007/United States	38 (361)	57	15/23	NSCLC (n = 17) SCLC (n = 3) Breast (n = 11) Colon (n = 2) Renal (n = 2) Endometrial (n = 1) Bladder (n = 1) Head and neck (n = 1)	Chemotherapy (n = 37) WBRT (n = 30) Surgery (n = 20) Stereotactic radiosurgery (n = 18)
16	Larkin et al[32]/2006/United Kingdom	26 (141)	50	14/12	Melanoma	Immunotherapy (n = 7) Radiosurgery (n = 1) Surgery (n = 1)
17	Caraglia et al[33]/2005/Italy	19	63	7/12	Breast (n = 8) NSCLC (n = 6) Colo-rectal (n = 3) Melanoma (n = 1) Ovarian (n = 1)	Systemic treatment (n = 12 ) Radiotherapy(out of brain) (n = 3) WBRT (n = 13)
18	Bael et al[34]/2007/United States	11 (51)	50	8/3	Melanoma	Immunotherapy (n = 3)
19	Christodoulou et al[35]/2005/Greece	32 (211)	53	11/21	Breast (n = 15) NSCLC (n = 11) SCLC (n = 1) Gastric (n = 1) Melanoma (n = 3) Unknown (n = 1)	Chemotherapy (n = 27) Radiotherapy (n = 17) Surgery (n = 1)
20	Hwu et al[30]/2005/United States	26 (142/153)	60	14/12	Melanoma	WBRT (n = 8) Stereotactic radiosurgery (n = 4) Surgery (n = 4)
21	Bafaloukos et al[27]/2004/Greece	25 (241)	48	15/10	Melanoma	NA

¹The number of patients eligible for the assessment of clinical outcomes;

²The number of patients eligible for the assessment of brain lesion response;

³The number of patients eligible for the assessment of extracerebral response;

⁴The number of patients eligible for the assessment of global response. TMZ: Temozolomide; NA: Not available; NSCLC: Non–small cell lung cancer; WBRT: Whole-brain radiotherapy.

Table 3 Treatment administration and clinical outcomes of the studies that used temozolomide as a single agent

Trial	Cancer	Treatment administration			Clinical outcomes
		Drug	Dose regimen	Mediancycles	CR	PR	OR	ORR	SD	PD	Other (median1)
1	NSCLC (n = 22) Breast (n = 10) Melanoma (n = 3) SCLC (n = 2) Rectal (n = 2) Ovarian (n = 1) Endometrial (n = 1)	TMZ	150-200 mg/m2 per day, days 1-5/28-d cycle	NA	0	22	2	0.059	15 (82/43/34)	17 (92/33/54)	TTP: 1.97 mo OS: 6.62 mo
2	Melanoma (n = 53) Breast cancer (n = 51) NSCLC (n = 53)	TMZ	150 mg/m2 per day, days 1-7, 15-21/28- or 35-d cycle	NA	12	9 (55/23/22)	10	0.064	31 (125/83/112)	116 (365/413/392)	PFS: 56 d5/58 d3/66 d2 OS: 100 d5/172 d2
3	Melanoma	TMZ	125-150 mg/m2 per day, days 1-7, 15-21/28-d cycle	48 d	0/06	2/16	2/16	0.044/ 0.0276	5/56	33/316	OS: 4.1 mo (3.6 mo8/4.3 mo7)
4	NSCLC	TMZ	150-200 mg/m2 per day, days 1-5/28-d cycle	6	2	1	3	0.1	3	24	TTP: 3.6 mo OS: 6 mo
5	NSCLC (n = 12) SCLC (n = 5) Breast (n = 4) Other (n = 7)	TMZ	150 mg/m2 per day, days 1-5/28-d cycle	NA	0	1	1	0.042	4	19	TTP: 3 mo OS: 4.5 mo
6	Melanoma	TMZ	150-200 mg/m2 per day, days 1-5/28-d cycle	NA	1	8	9	0.074	40	73	PFS: 1.2 mo7/1.0 mo8 OS: 3.5 mo7/2.2 mo8
7	NSCLC	TMZ	200 mg/m2 per day , days 1-5/28-d cycle	1	0	0	0	0	3	8	NA

¹Median: Data here are median values;

²NSCLC;

³Breast cancer;

⁴Other cancer;

⁵Melanoma;

⁶Extracerebral response;

⁷No prior chemotherapy;

⁸Prior chemotherapy. TMZ: Temozolomide; NA: Not available; NSCLC: Non–small cell lung cancer; SCLC: Small cell lung cancer; SD: Stable disease; PR: Partial response; CR: Complete response; OR: Objective response; ORR: Objective response rate; PD: Progressive disease; PFS: Progression-free survival; TTP: Time to progression; OS: Overall survival.

Table 4 Treatment administration and clinical outcomes of the studies that combined temozolomide with radiotherapy and/or other agents

Trial	Cancer	Treatment administration			Clinical outcomes
		Drug	Dose regimen	Mediancycles	CR	PR	OR	ORR	SD	PD	Other (Median1)
8	NSCLC (n = 15) Breast (n = 12)	TMZ, WBRT	WBRT 30 Gy, TMZ 75 mg/m2 per day, days 1-10; subsequent TMZ 75 mg/m2 per day, days 1-21/28-d cycle	4.2	2 (12/13)	11 (52/63)	13	0.481	6 (32/33)	8 (62/23)	PFS: 6 mo OS: 8.8 mo
9	Lung (n = 13) Colon (n = 1) Melanoma (n = 1) Mixed (prostate, bladder, lung) (n = 1) Unknown (probably lung) (n = 1)	TMZ, WBRT	WBRT 30 Gy, TMZ 95 mg/m2 per day, days 1-14	NA	0	3	3	0.176	10	4	PFS: 2.4 mo OS: 4.1 mo
10	SCLC (n = 4) NSCLC (n = 10) Breast (n = 7) Rectal (n = 5) Melanoma (n = 5) Oral cavity (n = 1) Unknown (n = 1)	TMZ, WBRT	WBRT 36Gy, TMZ 60 mg/m2 per day, days 1-16; subsequent TMZ 200 mg/m2 per day, days 1-5/28-d cycle	NA	8 (32/24 /13/25)	11 (52/26/13 /15/17/18)	19	0.545	2 (15/16)	12 (32/14 /26/53 /15)	PFS: 11 mo OS: 12 mo
11	Melanoma	TMZ, WBRT	WBRT 20 or 30 Gy, TMZ 200 mg/m2 per day, days 1-5/28-d cycle	NA	19	29	39	0.0889	99	179	OS: 8 mo mixed response10: 5
12	NSCLC (n = 16) SCLC (n = 5) Breast (n = 2) Unknown (n = 2)	TMZ, WBRT	WBRT 40 Gy 5 d/wk, TMZ 75 mg/m2 per day, days 1-28; subsequent TMZ 200 mg/m2 per day, days 1-5/28-d cycle	NA	9	14	23	0.959	1	0	OS: 8.6 mo
13	Melanoma	TMZ, WBRT, Thalidomide	WBRT 30 Gy, days 1-5/8-12; TMZ 75 mg/m2 per day, Weeks 1-6; thalidomide 100 mg/d, Weeks 1-4, 100-400 mg/d Weeks 5, 7, 9	NA	1	2	3	0.077	7	29	TTP: 7 wk OS: 4 mo
14	NSCLC	TMZ, WBRT, Cisplatin	WBRT, TMZ 200 mg/m2 per day, days 1-5/28-d cycle, cisplatin 75 mg/m2, day 1/28-d cycle	NA	12/03/04	52/63/84	62/63/84	0.1282 /0.1813 /0.174	212/163 /104	202/113 /294	TTP: 2.3 mo OS: 5 mo
15	NSCLC (n = 17) SCLC (n = 3) Breast (n = 11) Colon (n = 2) Renal (n = 2) Endometrial (n = 1) Bladder (n = 1) Head and neck (n = 1)	TMZ, Vinorelbine	TMZ 150 mg/m2 per day, days 1-7, 15-21/28-d cycle; vinorelbine 25 or 30 mg/m2 per day, days 1, 8/28-d cycle	2	1 (NSCLC)	1 (breast)	2	0.055	5	29	PFS: 1.9 mo OS: 5 mo
16	Melanoma	TMZ, Lomustine	TMZ 150 mg/m2 per day, days 1-5/28-d cycle; lomustine 60 mg/m2 per day, day 5/56-d cycle	NA	09	09	09	09	19	139	OS: 2 mo
17	Breast (n = 8) NSCLC (n = 6) Colo-rectal (n = 3) Melanoma (n = 1) Ovarian (n = 1)	TMZ, Doxorubicin	TMZ 200 mg/m2 per day, days 1-5/28-d cycle; pegylated liposomal doxorubicin 35 mg/m2 per day, day 1/28-d cycle	NA	3	4	7	0.368	8	4	PFS: 5.5 mo OS: 10.0 mo
18	Melanoma	TMZ, arsenic trioxide (ATO)	ATO 0.25 mg/kg per day, days 1-5 in week 0 + 0.35 mg/kg twice weekly/8-wk cycle; TMZ 200 mg/m2 per day, days 1-5 in weeks 1, 5/8-wk cycle	NA	0	0	0	0	0	5	NA
19	Breast (n = 15) NSCLC (n = 11) SCLC (n = 1) Gastric (n = 1) Melanoma (n = 3) Unknown (n = 1)	TMZ, Cisplatin	TMZ 150-200 mg/m2 per day, days 1-5/28-d cycle; cisplatin 75 mg/m2 per day, day 1/28-d cycle	3	19 (NSCLC)	1/89	99	0.428	59	69	TTP: 2.9 mo OS: 5.5 mo
20	Melanoma	TMZ, Thalidomide	TMZ 75 mg/m2 per day, days 1-42/8-wk cycle; thalidomide 200-400 or 100-250 mg/d, days 1-42/8-wk cycle	1	2/011	1/011	3/011	0.214 /011	7/511	4/1011	OS: 6 mo
21	Melanoma	A: TMZ, Docetaxel B: TMZ C: TMZ, Cisplatin	A: TMZ 150 mg/m2 per day, days 1-5/28-d cycle, docetaxel 80 mg/m2 per day, day 1/28-d cycle; B: TMZ200 mg/m2 per day, days 1-5/28-d cycle; C: TMZ 200 mg/m2 per day, days 1-5/28-d cycle, CDDP 75 mg/m2 per day, day 1/28-d cycle	NA	0/211	6/511	6/711	0.25/ 0.29111	5	13	TTP: 2 mo OS: 4.7 mo

¹Median: Data here are median values; Drugs: Chemotherapy and/or radiotherapy;

²NSCLC;

³Breast cancer;

⁴SCLC;

⁵Melanoma;

⁶Rectal cancer;

⁷Unknown;

⁸Oral cavity cancer;

⁹Global response;

¹⁰Mixed response: PR or SD in the brain and PD at other locations;

¹¹Extracerebral response. TMZ: Temozolomide; NA: Not available; NSCLC: Non–small cell lung cancer; SD: Stable disease; PR: Partial response; CR: Complete response; OR: Objective response; ORR: Objective response rate; PD: Progressive disease; PFS: Progression-free survival; TTP: Time to progression; OS: Overall survival.