Background
Methods
Search strategy
Selection criteria
Data extraction
Quality assessment
Statistical analysis
Results
Search results and study quality assessment
Study | Selection | Comparability | Exposure | Randomization | Masking | Accountability of all patients | Quality (score) | |
---|---|---|---|---|---|---|---|---|
Randomized controlled trial | ||||||||
2012 | Kim [26] | ★★ | ★ | ★ | 4 | |||
2016 | Urata [10] | ★★ | ★★ | ★ | 5 | |||
2017 | Yang [11] | ★★ | ★★ | ★ | 5 | |||
Retrospective study | ||||||||
2010 | Kim [19] | ★★★ | ★★ | ★★ | 7 | |||
2010 | Hotta [20] | ★★★★ | ★★ | ★★★ | 9 | |||
2010 | Hong [21] | ★★★ | ★★ | ★★ | 7 | |||
2011 | Wu [22] | ★★★★ | ★★ | ★★★ | 9 | |||
2011 | Shin [12] | ★★★ | ★★ | ★★ | 7 | |||
2011 | Togashi [23] | ★★★★ | ★★ | ★★ | 8 | |||
2011 | Fan [14] | ★★★★ | ★★ | ★★ | 8 | |||
2011 | Jung [24] | ★★★ | ★★ | ★ | 6 | |||
2012 | Wu [25] | ★★★★ | ★★ | ★★ | 8 | |||
2012 | Suzumura [27] | ★★★ | ★★ | ★★★ | 8 | |||
2013 | Yoshida [28] | ★★★★ | ★★ | ★★ | 8 | |||
2013 | Shao [29] | ★★★★ | ★★ | ★★★ | 9 | |||
2013 | Lee [30] | ★★★★ | ★★ | ★★ | 8 | |||
2013 | Yu [31] | ★★★★ | ★★ | ★★ | 8 | |||
2014 | Lim [32] | ★★★★ | ★★ | ★★★ | 9 | |||
2014 | Sato [13] | ★★★★ | ★★ | ★★ | 8 | |||
2014 | Lin [33] | ★★★ | ★★ | ★★ | 7 | |||
2014 | Ren [34] | ★★★★ | ★★ | ★★ | 8 | |||
2014 | Li [35] | ★★★ | ★★ | ★★★ | 8 | |||
2014 | Takeda [36] | ★★★ | ★★ | ★ | 6 | |||
2015 | Otsuka [37] | ★★★★ | ★★ | ★★★ | 9 | |||
2015 | Song [38] | ★★★ | ★★ | ★★ | 7 | |||
2015 | Koo [39] | ★★★★ | ★★ | ★ | 7 | |||
2016 | Ruan [40] | ★★★ | ★★ | ★★★ | 8 | |||
2016 | Hirano [41] | ★★★ | ★★ | ★★★ | 8 | |||
2016 | Suh [42] | ★★★ | ★★ | ★★ | 7 | |||
2016 | Kashima [43] | ★★★ | ★★ | ★★★ | 8 | |||
2017 | Kuan [15] | ★★★★ | ★★ | ★★ | 8 |
Study | Country | Groups | Patients (n) | Median age (year) | Stage | Treatment line | EGFRmutations | Adenocarcinoma (%) | Design | Quality (score) | |
---|---|---|---|---|---|---|---|---|---|---|---|
2010 | Kim [19] | Korea | G vs. E | 171/171 | 58/59 | IIIb, IV | 2, 3 | – | 86 | RS | 7 |
2010 | Hotta [20] | Japan | G vs. E | 330/209 | 68/68 | II-IV or recurrent | 2, 3 | – | 76 | RS | 9 |
2010 | Hong [21] | Keroa | G vs. E | 20/17 | 61/67 | IIIb, IV | 2, 3 | – | 75 | RS | 7 |
2011 | Wu [22] | Taiwan | G vs. E | 440/276 | 67/67 | IIIb, IV | 1 or later | Partial | 85 | RS | 9 |
2011 | Shin [12] | Keroa | G vs. E | 100/82 | 65/65 | III, IV | 2 | Partial | 0 | RS | 7 |
2011 | Togashi [23] | Japan | G vs. E | 85/69 | 65/68 | IIIb, IV | 1 or later | Partial | 82 | RS | 8 |
2011 | Fan [14] | Taiwan | G vs. E | 715/407 | – | IIIb, IV | 1 or later | Partial | 77 | RS | 8 |
2011 | Jung [24] | Korea | G vs. E | 72/51 | 55/55 | IIIb, IV | 1 or later | Partial | 59 | RS | 6 |
2012 | Wu [25] | Taiwan | G vs. E | 124/100 | – | IIIb, IV | 1 or later | Partial | 100 | RS | 8 |
2012 | Kim [26] | Keroa | G vs. E | 48/48 | 59/60 | IIIb, IV | 2 | Partial | 91 | RCT | 4 |
2012 | Suzumura [27] | Japan | G vs. E | 232/86 | 67/66 | IIIb, IV | – | Partial | 95 | RS | 8 |
2013 | Yoshida [28] | Japan | G vs. E | 107/35 | 64/67 | III, IV or recurrent | 1 or later | Partial | 84 | RS | 8 |
2013 | Shao [29] | Taiwan | G vs. E | 655/329 | 61/63 | IIIb, IV or recurrent | 3 | – | 80 | RS | 9 |
2013 | Lee [30] | Korea | G vs. E | 11/14 | 49/58 | IV | 1 or later | Partial | 92 | RS | 8 |
2013 | Yu [31] | China | G vs. E | 16/22 | 54/52 | – | 3 | Partial | 100 | RS | 8 |
2014 | Lim [32] | Korea | G vs. E | 121/121 | 58/58 | IIIb, IV | 1 or later | All | 98 | RS | 9 |
2014 | Sato [13] | Japan | G vs. E | 213/69 | 66/66 | IIIb, IV or recurrent | – | Partial | 86 | RS | 8 |
2014 | Lin [33] | China | G vs. E | 57/24 | – | IIIb, IV | 1 | All | 59 | RS | 7 |
2014 | Ren [34] | China | G vs. E | 60/142 | 59/59 | IV | 1 or later | Partial | 66 | RS | 8 |
2014 | Li [35] | China | G vs. E | 53/97 | 59/59 | IIIb, IV | 2 | Partial | 67 | RS | 8 |
2014 | Takeda [36] | Japan | G vs. E | 57/11 | 69/69 | III, IV or recurrent | 1 or later | All | 99 | RS | 6 |
2015 | Otsuka [37] | Japan | G vs. E | 35/9 | 70/62 | IIIb, IV | 1 or later | All | 91 | RS | 9 |
2015 | Song [38] | China | G vs. E | 37/65 | 75/75 | IIIb, IV | 2 or later | Partial | 83 | RS | 7 |
2015 | Koo [39] | Korea | G vs. E | 166/56 | – | IV | 1, 2, 3 | All | 87 | RS | 7 |
2016 | Ruan [40] | China | G vs. E | 63/134 | 59/60 | III, IV | – | All | – | RS | 8 |
2016 | Hirano [41] | Japan | G vs. E | 10/16 | 71/71 | IB-IV or recurrent | – | All | 81 | RS | 8 |
2016 | Urata [10] | Japan | G vs. E | 279/280 | 68/67 | IIIb, IV or recurrent | 2, 3 | Partial | 100 | RCT | 5 |
2016 | Suh [42] | Korea | G vs. E | 146/5 | 65/65 | IIIb, IV | 1 | All | 97 | RS | 7 |
2016 | Kashima [43] | Japan | G vs. E | 52/11 | 68/68 | IV | – | All | – | RS | 8 |
2017 | Yang [11] | China | G vs. E | 128/128 | – | IIIb, IV | 1, 2 | All | 96 | RCT | 5 |
2017 | Kuan [15] | Taiwan | G vs. E | 304/63 | 65/67 | IIIb, IV | 1 | All | – | RS | 8 |
Anti-tumor efficacy
Toxicity
Adverse effects | Gefitinib group (event/total) | Erlotinib group (event/total) | RR (95% CI) | P value | Heterogeneity | |
---|---|---|---|---|---|---|
I2 (%) | P value | |||||
Skin rash | 673/1099 | 650/944 | 0.83 (0.74–0.94) | 0.003 | 68 | 0.0009 |
Diarrhea | 298/999 | 273/745 | 0.83 (0.73–0.95) | 0.005 | 47 | 0.06 |
Nausea/Vomiting | 107/639 | 139/531 | 0.71 (0.32–1.57) | 0.4 | 74 | 0.002 |
Fatigue | 124/639 | 149/531 | 0.47 (0.23–0.95) | 0.04 | 81 | < 0.0001 |
Anorexia | 53/403 | 40/310 | 0.98 (0.40–2.42) | 0.97 | 78 | 0.001 |
Interstitial lung disease | 35/949 | 19/723 | 1.38 (0.78–2.44) | 0.26 | 0 | 0.65 |
Stomatitis | 12/260 | 29/169 | 0.29 (0.15–0.54) | 0.0001 | 24 | 0.27 |
Elevated liver enzymes | 366/931 | 264/680 | 1.16 (0.85–0.1.56) | 0.35 | 61 | 0.04 |
Infection | 45/686 | 23/466 | 1.53 (0.93–2.51) | 0.1 | 23 | 0.27 |
Neutropenia | 61/399 | 51/379 | 1.19 (0.85–1.66) | 0.32 | 0 | 0.55 |
Grade 3–5 Adverse effects | Gefitinib group (event/total) | Erlotinib group (event/total) | RR (95% CI) | P value | Heterogeneity | |
---|---|---|---|---|---|---|
I2 (%) | P value | |||||
Skin rash | 72/999 | 163/745 | 0.22 (0.12–0.41) | < 0.00001 | 73 | 0.0006 |
Diarrhea | 31/892 | 38/710 | 0.46 (0.29–0.74) | 0.001 | 0 | 0.46 |
Nausea/Vomiting | 8/639 | 27/531 | 0.23 (0.11–0.49) | 0.0001 | 20 | 0.29 |
Fatigue | 18/639 | 40/531 | 0.28 (0.09–0.87) | 0.03 | 74 | 0.02 |
Anorexia | 3/403 | 4/310 | 0.25 (0.06–1.04) | 0.06 | NA | NA |
Interstitial lung disease | 7/619 | 3/514 | 1.05 (0.27–4.06) | 0.95 | 17 | 0.3 |
Stomatitis | 3/260 | 8/169 | 0.28 (0.08–0.99) | 0.05 | 24 | 0.27 |
Elevated liver enzymes | 80/652 | 23/400 | 1.50 (0.97–2.31) | 0.07 | 0 | 0.64 |
Infection | 9/454 | 7/380 | 1.12 (0.46–2.69) | 0.8 | 20 | 0.28 |
Neutropenia | 2/399 | 3/379 | 0.67 (0.11–3.97) | 0.66 | NA | NA |
Subgroup analysis
Group | PFS | OS | ORR | |||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
No.of studies | HR (95% CI) |
P
| I2 (%) | No.of studies | RR (95% CI) |
P
| I2 (%) | No.of studies | RR (95% CI) |
P
| I2 (%) | |
Total | 24 | 1.04 (0.97–1.10) | 0.26 | 38 | 21 | 1.04 (0.89–1.21) | 0.61 | 58 | 13 | 1.08 (1.00–1.18) | 0.06 | 20 |
Nation | ||||||||||||
Keroa | 8 | 0.89 (0.78–1.02) | 0.09 | 18 | 8 | 1.03 (0.85–1.23) | 0.79 | 0 | 5 | 1.18 (0.94–1.49) | 0.16 | 0 |
China | 6 | 1.05 (0.88–1.25) | 0.63 | 20 | 5 | 0.92 (0.62–1.36) | 0.67 | 67 | 2 | 0.87 (0.70–1.08) | 0.21 | 0 |
Japan | 6 | 1.15 (0.98–1.36) | 0.09 | 20 | 4 | 1.04 (0.84–1.27) | 0.74 | 0 | 3 | 1.18 (0.98–1.41) | 0.08 | 0 |
Taiwan | 4 | 1.09 (0.77–1.54) | 0.62 | 74 | 4 | 1.12 (0.75–1.67) | 0.59 | 90 | 3 | 1.07 (0.86–1.35) | 0.54 | 71 |
Tumor stage | ||||||||||||
IIIb-IV | 22 | 1.04 (0.98–1.10) | 0.23 | 40 | 18 | 1.08 (0.92–1.26) | 0.34 | 53 | 12 | 1.09 (1.00–1.18) | 0.05 | 24 |
I-IV | 2 | 0.77 (0.39–1.51) | 0.45 | 25 | 3 | 0.54 (0.18–1.63) | 0.27 | 80 | 1 | 0.46 (0.05–4.01) | 0.48 | NA |
History | ||||||||||||
Non-squamous | 13 | 1.04 (0.96–1.14) | 0.88 | 51 | 11 | 1.06 (0.86–1.31) | 0.58 | 68 | 9 | 1.08 (0.99–1.17) | 0.09 | 42 |
Squamous included | 10 | 1.02 (0.94–1.12) | 0.6 | 11 | 9 | 0.98(0.86–1.13) | 0.81 | 48 | 4 | 1.19 (0.81–1.77) | 0.38 | 0 |
Unclear | 1 | 3.05 (0.84–11.09) | 0.09 | NA | 1 | 1.34 (0.49–3.67) | 0.57 | NA | ||||
Treatment line | ||||||||||||
First line included | 14 | 1.09 (0.98–1.20) | 0.11 | 46 | 11 | 0.97 (0.72–1.30) | 0.82 | 77 | 7 | 1.06 (0.90–1.25) | 0.52 | 52 |
Second line or later | 8 | 1.01 (0.93–1.08) | 0.89 | 22 | 8 | 1.02 (0.91–1.14) | 0.78 | 0 | 6 | 1.15 (0.98–1.35) | 0.08 | 0 |
First line only | 3 | 0.89 (0.32–2.49) | 0.82 | 66 | 2 | 0.24 (0.04–1.43) | 0.12 | 75 | ||||
Second line only | 3 | 0.93 (0.76–1.14) | 0.5 | 0 | 2 | 1.25 (0.90–1.73) | 0.19 | 0 | 2 | 1.18 (0.76–1.82) | 0.47 | 0 |
Third line only | 1 | 0.88 (0.43–1.79) | 0.72 | NA | 2 | 0.96 (0.81–1.14) | 0.47 | 0 | 1 | 0.46 (0.05–4.01) | 0.48 | NA |
Unclear | 2 | 1.48 (0.72–3.08) | 0.29 | 43 | 2 | 1.22 (0.62–2.39) | 0.56 | 0 | ||||
EGFR mutation | ||||||||||||
Partial mutation | 11 | 1.02 (0.91–1.15) | 0.68 | 21 | 11 | 1.15 (0.91–1.45) | 0.24 | 68 | 9 | 1.10 (1.00–1.21) | 0.05 | 21 |
All mutation | 9 | 1.11 (0.90–1.36) | 0.33 | 50 | 7 | 0.82 (0.54–1.25) | 0.36 | 59 | 2 | 0.88 (0.71–1.09) | 0.24 | 0 |
Unclear | 4 | 0.98 (0.76–1.26) | 0.88 | 57 | 3 | 0.97 (0.84–1.13) | 0.67 | 0 | 2 | 1.22 (0.92–1.62) | 0.18 | 2 |
Study design | ||||||||||||
Retrospective study | 21 | 1.02 (0.95–1.09) | 0.37 | 40 | 18 | 1.01 (0.84–1.21) | 0.92 | 63 | 10 | 1.10 (1.00–1.22) | 0.06 | 19 |
RCT | 3 | 1.11 (0.96–1.27) | 0.15 | 32 | 3 | 1.11 (0.93–1.32) | 0.25 | 0 | 3 | 1.04 (0.90–1.20) | 0.62 | 36 |