Background
Methods
Study selection criteria
Types of studies
Types of participants
Search strategy for identification of studies
Critical evaluation of the selected studies
Data extraction
Analysis and presentation of results
Results
Reasons for exclusion | |
---|---|
Lee 2012 [72] | Nonrandomized (cost-effectiveness analysis) |
Shiroiwa 2010 [73] | Nonrandomized (cost-effectiveness analysis) |
Zhang 2012 [74] | Nonrandomized |
Adjuvant treatment | |
Ducreux 2009 [77] | Different comparison (bevacizumab in both arms) |
Pectasides 2012 [78] | Different comparison (bevacizumab in both arms) |
Souglakos 2012 [79] | Different comparison (bevacizumab in both arms) |
Díaz-Rubio 2012 [80] | Different comparison (bevacizumab in both arms) |
Price 2012 [81] | Subgroup analysis of another study |
Moehler 2009 [82] | Nonrandomized |
Study |
n
| Type of study | Patients | Comparison | Primary endpoint |
---|---|---|---|---|---|
Regimens containing irinotecan with/without bevacizumab
| |||||
813 | Randomized, multicenter, phase III | mCRC, ECOG PS 0–1, ≥ 18 years | IFL/Bev (5 mg/kg) | OS | |
IFL/placebo | |||||
Guan 2011 [24] (ARTIST) | 203 | Randomized, multicenter, phase III | mCRC, ECOG PS 0–1, ≥ 18 years | IFL/Bev (5 mg/kg) | PFS and PFS rate in 6 months |
IFL | |||||
Stathopoulos 2010 [44] | 222 | Randomized, phase III | mCRC, ECOG PS 0–2, ≥ 18 years | IFL/Bev (7.5 mg/kg) | OS |
IFL | |||||
Regimens containing oxaliplatin with/without bevacizumab
| |||||
1400 | Randomized, multicenter, phase III | mCRC, ECOG PS 0–1, ≥ 18 years | XELOX or FOLFOX/Bev (5 mg/kg or 7.5 mg/kg) | PFS | |
XELOX or FOLFOX/placebo | |||||
Regimens containing oxaliplatin or irinotecan with/without bevacizumab
| |||||
370 | Randomized, multicenter, phase III | mCRC, ECOG PS 0–2, ≥ 18 years | FOLFOX or FOLFIRI/Bev (5 mg/kg) | PFS | |
FOLFOX or FOLFIRI | |||||
Regimens containing only 5-FU with/without bevacizumab
| |||||
Kabinnavar 2003 [47] | 104 | Randomized, multicenter, phase III | mCRC, ECOG PS 0–1, ≥ 18 years | 5-FU/LV | TTP and ORR |
5-FU/LV/Bev (5 mg/kg) | |||||
5-FU/LV/Bev (10 mg/kg) | |||||
Kabinnavar 2005 [48] | 209 | Randomized, multicenter, phase III | mCRC, ECOG PS 1–2, ≥ 65 years | 5-FU/LV/Bev (5 mg/kg) | OS |
5-FU/LV/placebo | |||||
Regimens containing only capecitabine with/without bevacizumab
| |||||
Tebutt 2010 [40] (MAX) | 313a | Randomized, multicenter, phase III | mCRC, ECOG PS 0–2, ≥ 18 years | Capecitabine/Bev (7.5 mg/kg) | PFS |
Capecitabine | |||||
Cunningham 2013 [22] (AVEX) | 280 | Randomized, multicenter, phase III | mCRC, ECOG PS 0–2, ≥ 70 years | Capecitabine/Bev (7.5 mg/kg) | PFS |
Capecitabine | |||||
Chemotherapy protocols: | |||||
IFL/Placebo: 5-FU: 500 mg/m2, bolus + LV: 20 mg/m2, during 2 h + irinotecan: 125 mg/m2, once/week for 4 weeks every 6 weeks. | |||||
IFL/Bev: same chemotherapy regimen + bevacizumab: 5 mg/kg intravenously every 15 days until progression. | |||||
Guan 2011 [24] - (ARTIST) | |||||
IFL/Placebo: 5-FU: 500 mg/m2 + LV: 20 mg/m2 (infusion: 6–8 h) + irinotecan: 125 mg/m2, once/week for 4 weeks every 6 weeks. | |||||
IFL/Bev: same chemotherapy regimen + bevacizumab: 5 mg/kg intravenously every 15 days until progression. | |||||
Stathopoulos 2010 [44] | |||||
IFL: 5-FU: 500 mg/m2 + LV: 200 mg/m2 + irinotecan: 135 mg/m2, in Day 1 (D1) every 3 weeks. | |||||
IFL/Bev: same chemotherapy regimen + bevacizumab: 7.5 mg/kg intravenously every 3 weeks until progression. | |||||
FOLFOX/placebo: LV: 200 mg/m2/day intravenously in 2 h + 5-FU: 400 mg/m2/day in bolus, followed by 600 mg/m2/day in 22 h in Days 1 and 2 + oxaliplatin: 85 mg/m2, in 2 h, in D1; | |||||
FOLFOX/Bev: same chemotherapy regimen + bevacizumab: 5 mg/kg, Day 1; every 15 days; | |||||
XELOX/placebo: capecitabine: 1000 mg/m2 orally, twice/day, for 14 days + oxaliplatin: 130 mg/m2 intravenously in D1; | |||||
XELOX/Bev: same chemotherapy regimen + bevacizumab: 7.5 mg/kg in D1; every 21 days, until progression. | |||||
FOLFOX: LV: 100 mg/m2/day intravenously D1 and D2 + 5-FU: 400 mg/m2/day in bolus D1 and D2, followed by 600 mg/m2 in 22 h in Days 1 and 2 + oxaliplatin: 85 mg/m2, in 2 h, in D1; | |||||
FOLFIRI: LV: 100 mg/m2/day intravenously D1 and D2 + 5-FU: 400 mg/m2/day in bolus D1 and D2, followed by 600 mg/m2 in 22 h in Days 1 and 2 + irinotecan 180 mg/m2, in D1; | |||||
FOLFOX or FOLFIRI/Bev: same chemotherapy regimen + bevacizumab: 5 mg/kg, Day 1; every 15 day; | |||||
Kabinnavar 2003 [47] | |||||
5-FU/LV: 5-FU: 500 mg/m2/LV: 500 mg/m2, weekly for 6 weeks every 8 weeks. | |||||
5-FU/LV/Bev (5 mg/kg): same chemotherapy regimen + bevacizumab: 5 mg/kg, Day 1, every 15 day; | |||||
5-FU/LV/Bev (10 mg/kg): same chemotherapy regimen + bevacizumab: 10 mg/kg, Day 1, every 15 day; | |||||
Kabinnavar 2005 [48] | |||||
5-FU/LV: 5-FU: 500 mg/m2/LV: 500 mg/m2, weekly for 6 weeks every 8 weeks + placebo every 15 day. | |||||
5-FU/LV/Bev (5 mg/kg): same chemotherapy regimen + bevacizumab: 5 mg/kg, Day 1, every 15 day; | |||||
Tebutt 2010 [40] (MAX)a | |||||
Capecitabine: 1000–1250 mg/m2 orally, twice/day, for 14 days; | |||||
Capecitabine/Bev: same chemotherapy regimen + bevacizumab: 7.5 mg/kg D1; every 21 days, until progression. | |||||
Cunningham 2013 [22] - (AVEX) | |||||
Capecitabine: 1000 mg/m2 orally, twice/day, for 14 days; | |||||
Capecitabine/Bev: same chemotherapy regimen + bevacizumab: 7.5 mg/kg D1; every 21 days, until progression. |
Characteristics and results of included studies
Studies containing chemotherapy (irinotecan-based) + bevacizumab
AVF 2107 trial
Study | n (ITT) | Comparison | Response rate | PFS | OS |
---|---|---|---|---|---|
HR (95 % CI) | HR (95 % CI) | ||||
Regimens containing irinotecan with/without bevacizumab
| |||||
402 | IFL/Bev | 44.8 % | 10.6 months | 20.3 months | |
411 | IFL/placebo | 34.8 % | 6.2 months | 15.6 months | |
p = 0.004 | HR: 0.54 (0.37–0.78) | HR: 0.66 (0.52–0.85) | |||
Guan 2011 [24] (ARTIST) | 139 | IFL/Bev | 35.3 % | 8.3 months | 18.7 months |
64 | IFL | 17.2 % | 4.2 months | 13.4 months | |
p = 0.013 | HR: 0.44 (0.31–0.63) | HR: 0.62 (0.41–0.95) | |||
Stathopoulos 2010 [44] | 114 | IFL/Bev | 36.8 % | NR | 22 months |
108 | IFL | 35.2 % | 25 months | ||
p = NS | HR: 1.05 (0.81–1.36)b | ||||
Regimens containing oxaliplatin with/without bevacizumab
| |||||
699 | XELOX or FOLFOX/Bev | 47 % | 9.4 months | 21.3 months | |
701 | XELOX or FOLFOX/placebo | 49 % | 8.0 months | 19.9 months | |
p = 0.31 | HR: 0.83 (0.72–0.95)a | HR: 0.89 (0.76–1.03) | |||
Regimens containing oxaliplatin or irinotecan with/without bevacizumab
| |||||
176 | FOLFOX or FOLFIRI/Bev | 50.6 % | 9.6 months | 20.8 months | |
194 | FOLFOX or FOLFIRI | 50 % | 8.4 months | 21.3 months | |
p = 0.865 | HR: 0.86 (0.70-1.07) | HR: 1.13 (0.89-1.43) | |||
Regimens containing only 5-FU with/without bevacizumab
| |||||
Kabinnavar 2003 [47] (AVF0780) | 35 | 5-FU/LV/Bev (5 mg/kg) | 40 % | 9.0 months | 21.5 months |
33 | 5-FU/LV/Bev (10 mg/kg) | 24 % | 7.2 months | 16.1 months | |
36 | 5-FU/LV | 17 % | 5.2 months | 13.8 months | |
(p = 0.08) | HR: 0.54 (0.33–0.88) | HR: NR | |||
Kabinnavar 2005 [48] (AVF2192) | 104 | 5-FU/LV/Bev | 26 % | 9.2 months | 16.6 months |
105 | 5-FU/LV | 15.2 % | 5.5 months | 12.9 months | |
p = 0.055 | HR: 0.50 (0.35–0.73) | HR: 0.79 (0.56–1.10) | |||
Regimens containing only capecitabine with/without bevacizumab
| |||||
Tebutt 2010 [40] (MAX) | 157 | Capecitabine/Bev | 38.1 % | 8.5 months | NR |
156 | Capecitabine | 30.3 % | 5.7 months | ||
p = 0.16 | HR: 0.63 (0.50–0.79) | HR: 0.88 (0.68–1.13) | |||
Cunningham 2013 [22] (AVEX) | 140 | Capecitabine/Bev | 19 % | 9.1 months | 20.7 months |
140 | Capecitabine | 10 % | 5.1 months | 16.8 months | |
p = 0.04 | HR: 0.53 (0.41–0.69) | HR: 0.79 (0.57–1.09) |
ARTIST trial
Stathopoulos et al. trial
Studies containing chemotherapy (oxaliplatin-based) + bevacizumab
NO16966 trial
Studies containing chemotherapy (irinotecan or oxaliplatin-based) + bevacizumab
ITACA trial
Studies containing chemotherapy (only 5-FU) + bevacizumab
AVF0780 trial
n
| Anemia | Neutropenia | Febrile neutropenia | Thrombocytopenia | |
---|---|---|---|---|---|
Regimens containing irinotecan with/without bevacizumab
| |||||
IFL/Bev | 393 | NR | 37.0 % | NR | NR |
IFL/placebo | 397 | 31.1 % | |||
Guan 2011 [24] (ARTIST) | |||||
IFL/Bev | 141 | 4 % | 33 % | 2 % | 3 % |
IFL | 70 | 1 % | 19 % | 2 % | 4 % |
Stathopoulos 2010 [44] | |||||
IFL/Bev | 114 | NR | NR | NR | NR |
IFL | 108 | ||||
Regimens containing oxaliplatin with/without bevacizumab
| |||||
XELOX or FOLFOX/Bev | 694 | NR | NR | NR | NR |
XELOX or FOLFOX/placebo | 675 | ||||
Regimens containing oxaliplatin or irinotecan with/without bevacizumab
| |||||
FOLFOX or FOLFIRI/Bev | 176 | 1.1 % | 39.6 % | 0.6 % | 2.3 % |
FOLFOX or FOLFIRI | 194 | 2.6 % | 42.3 % | 2.1 % | 1.0 % |
Regimens containing only 5-FU with/without bevacizumab
| |||||
Kabinnavar 2003 [47] (AVF0780) | |||||
5-FU/LV/Bev (5 mg/kg) | 35 | NR | 5.7 % | NR | NR |
5-FU/LV/Bev (10 mg/kg) | 32 | 3.1 % | |||
5-FU/LV | 35 | 2.85 % | |||
Kabinnavar 2005 [48] (AVF2192) | |||||
5-FU/LV/Bev | 100 | NR | 5 % | NR | NR |
5-FU/LV | 104 | 7 % | |||
Regimens containing only capecitabine with/without bevacizumab
| |||||
Tebutt 2010 [40] (MAX) | |||||
Capecitabine/Bev | 157 | NR | 0 % | 2.5 % | 0 % |
Capecitabine | 156 | 1.3 % | 1.9 % | 0 % | |
Cunningham 2013 [22] (AVEX) | |||||
Capecitabine/Bev | 134 | NR | 1 % | NR | NR |
Capecitabine | 136 | 1 % |
n
| Diarrhea | Hypertension | Proteinuria | Gastrointestinal perforation | Nausea/vomiting | Any thromboembolic events | Bleeding | |
---|---|---|---|---|---|---|---|---|
Regimens containing irinotecan with/without bevacizumab
| ||||||||
IFL/Bev | 393 | 32.4 % | 11.0 % | 0.8 % | 1.5 % | NR | 19.4 % | 3.1 % |
IFL/placebo | 397 | 24.7 % | 2.3 % | 0.8 % | 0 % | 16.2 % | 2.5 % | |
Guan 2011 [24] (ARTIST) | ||||||||
IFL/Bev | 141 | 26 % | 4 % | 1 % | 1 % | 13 % | 1 % | 1 % |
IFL | 70 | 21 % | 0 % | 0 % | 0 % | 12 % | 0 % | 1 % |
Stathopoulos 2010 [44] | ||||||||
IFL/Bev | 114 | NR | NR | NR | NR | NR | NR | NR |
IFL | 108 | |||||||
Regimens containing oxaliplatin with/without bevacizumab
| ||||||||
XELOX or FOLFOX/Bev | 694 | NR | 4 % | <1 % | <1 % | NR | 10 % | 2 % |
XELOX or FOLFOX/placebo | 675 | 1 % | 0 % | <1 % | 6 % | 1 % | ||
Regimens containing oxaliplatin or irinotecan with/without bevacizumab
| ||||||||
FOLFOX or FOLFIRI/Bev | 176 | 8.0 % | 27.8 % | 22.2 % | NR | 5.2 % | 21 % | 17.0 % |
FOLFOX or FOLFIRI | 194 | 5.7 % | 10.8 % | 13.4 % | 3.7 % | 12.9 % | 4.6 % | |
Regimens containing only 5-FU with/without bevacizumab
| ||||||||
Kabinnavar 2003 [47] (AVF0780) | ||||||||
5-FU/LV/Bev (5 mg/kg) | 35 | 28.6 % | 8.6 % | NR | NR | NR | 14.3 % | 0 % |
5-FU/LV/Bev (10 mg/kg) | 32 | 31.2 % | 25 % | 6.2 % | 9.3 % | |||
5-FU/LV | 35 | 37.1 % | 0 % | 2.8 % | 0%a | |||
Kabinnavar 2005 [48] (AVF2192) | ||||||||
5-FU/LV/Bev | 100 | 39 % | 16 % | 1 % | 2 % | NR | 18 % | 5 % |
5-FU/LV | 104 | 40 % | 3 % | 0 % | 0 % | 18 % | 3 % | |
Regimens containing only capecitabine with/without bevacizumab
| ||||||||
Tebutt 2010 [40] (MAX) | ||||||||
Capecitabine/Bev | 157 | 17 % | 3.8 % | 3.2 % | 1.9 % | 10.2 % | 12.1 % | 1.3 % |
Capecitabine | 156 | 11 % | 0.6 % | 0.6 % | 0.6 % | 10.9 % | 7.1 % | 2.6 % |
Cunningham 2013 [22] (AVEX) | ||||||||
Capecitabine/Bev | 134 | 7 % | 2 % | 1 % | 0 % | 3 % | 11 % | 0 % |
Capecitabine | 136 | 6 % | 1 % | 0 % | 0 % | 1 % | 5 % | 1 % |