Table 2.
Nitrosourea trials in recurrent or progressive glioblastomaa
| Reference | Study Design/Population | TMZ Pretreatment | Nitrosourea Regimen | n | Radiographic Response (%) | PFS6 (%) | mPFS* (mo) | mOS* (mo) | WHO Grades 3/4 Toxicities (n) |
|---|---|---|---|---|---|---|---|---|---|
| Monotherapy | |||||||||
| van den Bent et al.25 | Phase II, randomized. Median age: 54 y |
Some (not clearly specified) | BCNU 60 mg/m2 on days 1–3 q8wk for max 5 cycles or TMZ 200 mg/m2 on days 1–5 q4wk in chemotherapy-naive pts or 150 mg/m2 on days 1–5 q4wk after prior adjuvant chemotherapy, with dose escalation to 200 mg/m2 in absence of significant toxicity (only combined data [cntrl] for BCNU and TMZ reported) or ERL 150 mg/d, with dose escalation to 200 mg/d if no toxicity |
29 27 (52 evaluable in cntrl) 54 |
CR: 0 PR: Cntrl: 5 vs ERL: 2 SD: Cntrl:18 vs ERL: 9 |
Cntrl: 24.1 vs ERL: 11.4 | Cntrl: 2.4 vs ERL:1.8 | Cntrl: 7.3 vs ERL:7.7 |
Hematologic: BCNU: 13 TMZ: 4 ERL: 1 Nonhematologic: BCNU: 8 TMZ: 4 ERL: 11 |
| Brandes et al.26 | Phase II. Median age: 49.7 y; median KPS: 70 |
No | BCNU 80 mg/m2 on days 1–3 q8wk for max 6 cycles | 40 |
CR: 0 PR: 6 SD: 9 PD: NA |
17.5 | NA | 7.53 |
Hematologic: NA Nonhematologic: 9 |
| Reithmeier et al.27 | Retrospective analysis. Median age: 53 y; median KPS: 70; 1st relapse: n = 30; 2nd relapse: n = 4; 4th relapse: n = 1 |
24 (69%) | BCNU 80 mg/m2 i.v. on days 1–3 q8wk for max 6 cycles | 35 |
CR: 0 PR: 2 SD: 19 PD: 11 |
13 | 2.6 | 5.1 |
Hematologic: 10 Nonhematologic: 4 |
| Wick et al.28 | Phase III open-label, randomized 2:1. 1st relapse: CCNU: n = 70; enzastaurin: n = 129 2nd relapse: CCNU: n = 21; enzastaurin: n = 45 |
NA | CCNU 100–130 mg/m2 on day 1 q6wk; Enzastaurin 500 mg p.o. daily (1125-mg loading dose on day 1) |
92 174 |
CR: 0 PR: 4 SD: 33 PD: 38 CR: 0 PR: 5 SD: 67 PD: 72 |
19.0 11.1 |
1.6 1.5 |
7.1 6.1 |
Hematologic: 46 Nonhematologic: 3 Hematologic: 1 Nonhematologic: 13 (P < .007 for hematologic toxicities) |
| Ahluwalia et al.,29 Batchelor et al.30 |
Phase III, multicenter, double-blind, randomized 1:2:2. Median age: 54 y |
Yes | CCNU 110 mg/m2 q6wk + placebo or CED 30 mg/d or CED 20 mg/d + CCNU 110 mg/m2 q6wk | 65 131 129 |
CR: 0 PR: 5 SD: 23 PD: 23 CR: 1 PR: 17 SD: 76 PD: 10 CR: 2 PR: 19 SD: 67 PD: 19 |
24.5 16 34.5 |
2.73 3.1 4.2 |
9.8 8.0 9.4 |
Hematologic: 30 Nonhematologic: 16 Hematologic: 7 Nonhematologic: 66 Hematologic: 116 Nonhematologic: 57 |
| Happold et al.31 | Retrospective analysis 2003–2008, after failed therapy with TMZ or recurrence | Yes | ACNU 72–90 mg/m2/d i.v. in 6-wk cycles, alone or in combination | 14 alone or 18 in combination |
CR: 0b PR: 2b SD: 5b PD: NAb |
20b | 2.7b | 6.7b |
Hematologic: 16b Nonhematologic: 3b |
| Addeo et al.33 | Phase II, multicenter, nonrandomized, single-arm. Median age: 52.8 y; median KPS: 90; 1st relapse: 100% |
Yes | FOT i.v. 80 mg/m2 on days 1, 15, 30, 45, and 60 (induction), then 80 mg/m2 q4wk (maintenance) | 40 |
CR: 1 PR: 9 SD: 16 PD: 14 |
61 | 6.7 | 11.1 |
Hematologic: Induction: 5; maintenance: 5 Nonhematologic: Induction: 0; maintenance: 3 |
| Brandes et al.34 | Phase II, nonrandomized, single-arm. Median age: 51 y; median KPS: 90 |
Yes | FOT 75–100 mg/m2 for 3 weekly doses followed, after a 5-wk rest, by 100 mg/m2 q3wk for ≤1 y | 43 |
CR: 0 PR: 3 SD: 15 |
20.9 | 1.7 | 6.0 |
Hematologic: Induction (100 mg/m2): 24; amended induction (75 mg/m2): 19; maintenance: 8 Nonhematologic: NA |
| Scoccianti et al.35 | Phase II, multicenter, single-arm. Median age: 56 y; median KPS: 80; 1st recurrence: 100% |
Yes | FOT i.v. 100 mg/m2 qwk for 3 consecutive wk (induction), then q3wk (maintenance) | 27 |
CR: 0 PR: 8 SD: 5 PD: 14 |
48.2 | 5.7 | 9.1 |
Hematologic: 4 pts Nonhematologic: 0 |
| Fabrini et al.36 | Phase II, multicenter, prospective, open-label, noncomparative. Median age: 56.8 y; median KPS: 90 |
Yes | FOT 100 mg/m2 i.v. on days 1, 8, and 15, followed by 4- to 6-wk rest period (induction). In nonprogressive pts, FOT 100 mg/m2 i.v. q3wk (maintenance) |
50 |
CR: 1 PR: 8 SD: 22 PD: 19 |
52 | 6.1 | 8.1 |
Hematologic: 7 pts Nonhematologic: 0 |
| Combination Regimens | |||||||||
| Kappelle et al.38 | Multicenter retrospective, 1994–1998. Median age: 46 y; median KPS: 80 |
Only 4 pts | Standard or intensified PRO, CCNU, and VIN | 63 |
CR: 3 PR: 8 SD: 25 |
29 | NA | 7.7 |
Hematologic: NA Nonhematologic: NA |
| Schmidt et al.37 | Retrospective chart review, 1994–2003. Median age: 49 y; 1st relapse: 100% |
Only 12 pts | PRO 60 mg/m2 p.o. days 8–21, CCNU 110 mg/m2 p.o. day 1, VIN 1.4 mg/m2 [max 2 mg] i.v. days 8 and 29; given in 8-wk cycles | 86 |
CR: 0 PR: 3 SD: 45 PD: 18 |
38.4 | 4.0 | 7.8 |
Hematologic: 30 pts Nonhematologic: 0 |
Abbreviations: ACNU, nimustine; BCNU, carmustine; CCNU, lomustine; CED, cediranib; cntrl, control arm; CR, complete response; ERL, erlotinib; FOT, fotemustine; max, maximum; KPS, Karnofsky performance score; mOS, median overall survival; mPFS, median progression-free survival; NA, not available; PD, progressive disease; PFS6, 6-month PFS rate; PR, partial response; PRO, procarbazine; pts, patients; SD, stable disease; VIN, vincristine.
For the most part, only glioblastoma 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.
aAll data are presented for glioblastoma patients only.
bData for ACNU alone were not available; the numbers listed represent responses for all patients (ACNU alone and in combination).