Table 3.

Temozolomide monotherapy trials in recurrent or progressive glioblastoma^a

Reference	Study Design/Population	TMZ Pretreatment	TMZ Regimen	n	Radiographic Response (%)	PFS6* (%)	mPFS* (mo)	mOS* (mo)	WHO Grades 3/4 Toxicities (n)
Temozolomide-Naive Population
Brada et al.24	Phase II, open-label, uncontrolled TMZ at 1st relapse. Median age: 54 y; median time to 1st relapse: 8.1 mo	No (40% of pts had prior nitrosourea-containing chemo-therapy)	Chemotherapy-naive pts: 200 mg/m2/d p.o. for 1st 5 d of 28-d cycle. Pts with previous nitrosourea-containing adjuvant chemotherapy: 150 mg/m2/d for 1st 5 d of 28-d cycle	126	CR: 2 PR: 8 SD: 57	18	2.1	5.4	Hematologic: 30 Nonhematologic: 30
Brandes et al.39	Phase II, 2nd relapse	No (previous PCV)	150 mg/m2/d for 5 d q28d	22	CR: 2 PR: 3 SD: 4	31.8		7.6	Hematologic: 4 Nonhematologic: 2
Brandes et al.40	Phase II. Mean age: 48.4 y; median KPS: 80. 2nd relapse	No (previous PCV)	150 mg/m2/d for 5 d q28d	42	CR: 2 PR: 6 SD: 9 PD: NA	24	NA	7.0	Hematologic: 1 Nonhematologic: 0
Khan et al.41	Phase II, prospective, extended, low-dose, single-center	No	75 mg/m2/d for 42 d q70d	28	CR: 0 PR: 0 SD: 11 PD: 17	19	2.3	7.7	Hematologic: 8 Nonhematologic: 0
Wick et al.46	Phase II, nonrandomized, prospective	No	150 mg/m2 on days 1–7 and days 15–21 of 28-d cycles for max 12 cycles	21	CR: 0 PR: 2 SD: 17 PD: 2	48	4.9	NA	Hematologic: 10 Nonhematologic: 7
Chan et al.42	Prospective, open-label, compassionate use in Chinese pts	No	200 mg/m2/d for 5 d q28d for 4 cycles	13	NA	21.0	NA	NA	Hematologic: 0 Nonhematologic: 0
Brandes et al.43	Phase II. Median age: 57 y; Median KPS: 90	No	75 mg/m2/d for 21 d q28d	33	CR: 1 PR: 2 SD: 17	30.3	3.8	9.3	Hematologic: 14 Nonhematologic: 4
Nagane et al.44	Prospective, open-label. Mean age: 48.2 y; Median KPS: 70	No (89.5% had previous nitrosourea-based therapy)	150–200 mg/m2/d for 5 d q28d	19	CR: 1 PR: 3 SD: 6 PD: 7	22.2	2.2	9.9	Hematologic: 5 Nonhematologic: 9
Balmaceda et al.45	Phase II, single-arm, multicenter. Median age: 43 y; 1st relapse: n = 48; ≥2 relapses: n = 20	No (previous non-nitrosourea: n = 7; nitrosourea: n = 33; none: n = 28)	200 mg/m2 initial dose, then 9 consecutive doses at 90 mg/m2 q12h for 28 d; increased to 100 mg/m2 q12h in absence of toxicity	68	CR: 3 PR: 18 SD: 22 PD: 19	35	4.0	9.0	NA
Temozolomide-Pretreated Population
Franceschi et al.48	Retrospective analysis	Yes	150–200 mg/m2/d for 5 d, q28d in 13 pts, 25 mg/m2/d continuously in 1 pt	9	CR: 2 PR: 2 SD: 2 PD: 3	NA	7.0	12+	Hematologic: 1 Nonhematologic: 0
Kong et al.49	Pilot study, metronomic. Median age: 48.3 y	Yes	40 mg/m2/d (3 mo)	12	CR: 0 PR: 2 SD: 5 PD: 5	58.3	6.0	11	Hematologic: 0 Nonhematologic: 0
Wick et al.47	Prospective, nonrandomized: alternating weekly regimen. Median age: 51 y	9/64 pts had received TMZ (+ CCNU)	150 mg/m2 on days 1–7 and days 15–21 q28d (1-wk on, 1-wk off)	64	NA	43.8	5.5	NA	NA
Wick et al.54b	Retrospective analysis, 3 centers, 2000–2007. Median age: 52 y. 2 cohorts: TMZ escalation with progression during TMZ vs TMZ rechallenge after SD and disease-free interval	Yes	75 mg/m2/d (days 1–42 during radiotherapy), plus 150–200 mg/m2/d for 5 d q28d or 150–200 mg/m2/d for 5 d q28d or 150 mg/m2/d for 1-wk on, 1-wk off or 75 mg/m2/d for 21 d q28d or 40 mg/d continuousc	47	NA	27.7 (progressive cohort 26.3 vs stable cohort 28.6%)		5.8 (progressive cohort 6.6 vs stable cohort 5.3)	Hematologic: 22 Nonhematologic: 10
Berrocal et al.50	Phase II, multicenter	Yes	85 mg/m2 for 21 d q28d	GB: 27 AA: 15 Misc: 5	CR: 0 PR: 2 SD: 15a PD: 30a	0	NA	5.1a	NA
Perry et al.51	Phase II, continuous, dose-intense (RESCUE study), multicenter. Pts prospectively divided into 3 groups (early, extended, and rechallenge) per timing of progression during adjuvant therapy	Yes	50 mg/m2/d continuous for max 1 y or progression	91	NA	23.9 (early 27.3; extended 7.4; rechallenge 35.7)	NA (early 3.6; extended 1.8; rechallenge 3.7)	9.3	NA
Kong et al.52	Phase II, low-dose, continuous (metronomic). Median age: 51 y	Yes	40–50 mg/m2/d	38	CR: 0 PR: 2 SD: 21	32.5	4.0	9.6	Hematologic: 4 Nonhematologic: 0
Hammond et al.53 (prelim results only)	Phase II, dose-intense, single-arm, 1st recurrence. Median age: 57 y; median KPS: 90	Yes	75–100 mg/m2/d for 21 d q28d	47	CR: 0 PR: 6 SD: 18	23	2.3	13	Hematologic: 7 Nonhematologic: NA
Randomized Studies
Yung et al.23	Phase II, randomized, multicenter, open-label. Median age: 51–52 y; 1st relapse: 100%	No (65%–68% of pts received prior nitrosourea)	TMZ 150–200 mg/m2/d for 5 d q28d or procarbazine 150 mg/m2/d (or 125 mg/m2/d if prior chemotherapy) p.o. for 28 d, repeated q56d	112 113	CR: 0 PR: 6 SD: 45 CR: 0 PR: 6 SD: 31	21 8	2.9 1.9	NA	Hematologic: 14 Nonhematologic: 12 Hematologic: 9 Nonhematologic: 17
Brada et al.55	Prospective, randomized 1st progression: 100%	No (chemotherapy-naive)	TMZ 200 mg/m2 for 5 d or TMZ 100 mg/m2 for 21 d or PCV	GB: 72 AA: 15 GB: 66 AA: 15 GB: 139 AA: 23	NA	NA	5.0a 4.2a 3.6a	8.5a 6.6a 6.7a	Hematologic: 38a Nonhematologic: 37a Hematologic: 28a Nonhematologic: 38a Hematologic: 57a Nonhematologic: 64a

Abbreviations: AA, anaplastic astrocytoma; CCNU, lomustine; CR, complete response; GB, glioblastoma; KPS, Karnofsky performance score; mOS, median overall survival; mPFS, median progression-free survival; PCV, procarbazine, CCNU, and vincristine; PD, progressive disease; PFS6, 6-month PFS rate; PR, partial response; pts, patients; SD, stable disease.

For the most part, only GB data are presented in the table. We have reported enrollment numbers for different patient populations only when all data in a paper are presented for combined patient populations.

*Disease PFS and OS were calculated from beginning of retreatment with TMZ.

^aData are presented for GB patients only except for the Berrocal study,⁵⁰ where 27 patients had GB, 15 had AA, and 5 had miscellaneous brain tumors, and the Brada study,⁵⁵ where 277 patients had GB, 53 had AA, and 20 had miscellaneous brain tumors.

^bRetrospective study.

^c11 patients also received 13-cis-retinoic acid or pegylated liposomal doxorubicin.