Chemotherapy with cetuximab versus chemotherapy alone for chemotherapy‐naive advanced non‐small cell lung cancer

Zu‐Yao Yang; Li Liu; Chen Mao; Xin‐Yin Wu; Ya‐Fang Huang; Xue‐Feng Hu; Jin‐Ling Tang

doi:10.1002/14651858.CD009948.pub2

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Figure 1

Figure 1. The flow chart of study selection

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Figure 2

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

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Figure 3

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

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Figure 4

Forest plot of comparison: 1 chemotherapy plus cetuximab versus chemotherapy alone, outcome: 1.1 Overall survival.

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Figure 5

Forest plot of comparison: 1 chemotherapy plus cetuximab versus chemotherapy alone, outcome: 1.2 Progression‐free survival.

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Figure 6

Forest plot of comparison: 1 chemotherapy plus cetuximab versus chemotherapy alone, outcome: 1.3 Objective response rate.

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Analysis 1.1

Comparison 1 chemotherapy plus cetuximab versus chemotherapy alone, Outcome 1 Overall survival.

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Analysis 1.2

Comparison 1 chemotherapy plus cetuximab versus chemotherapy alone, Outcome 2 Progression‐free survival.

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Analysis 1.3

Comparison 1 chemotherapy plus cetuximab versus chemotherapy alone, Outcome 3 Objective response rate.

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Analysis 1.4

Comparison 1 chemotherapy plus cetuximab versus chemotherapy alone, Outcome 4 One‐year survival rate.

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Analysis 1.5

Comparison 1 chemotherapy plus cetuximab versus chemotherapy alone, Outcome 5 Abdominal pain.

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Analysis 1.6

Comparison 1 chemotherapy plus cetuximab versus chemotherapy alone, Outcome 6 Acneiform rash.

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Analysis 1.7

Comparison 1 chemotherapy plus cetuximab versus chemotherapy alone, Outcome 7 Anorexia.

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Analysis 1.8

Comparison 1 chemotherapy plus cetuximab versus chemotherapy alone, Outcome 8 Anxiety.

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Analysis 1.9

Comparison 1 chemotherapy plus cetuximab versus chemotherapy alone, Outcome 9 Asthenia.

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Analysis 1.10

Comparison 1 chemotherapy plus cetuximab versus chemotherapy alone, Outcome 10 Back pain.

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Analysis 1.11

Comparison 1 chemotherapy plus cetuximab versus chemotherapy alone, Outcome 11 Bleeding events.

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Analysis 1.12

Comparison 1 chemotherapy plus cetuximab versus chemotherapy alone, Outcome 12 Cardiac events.

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Analysis 1.13

Comparison 1 chemotherapy plus cetuximab versus chemotherapy alone, Outcome 13 Constipation.

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Analysis 1.14

Comparison 1 chemotherapy plus cetuximab versus chemotherapy alone, Outcome 14 Dehydration.

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Analysis 1.15

Comparison 1 chemotherapy plus cetuximab versus chemotherapy alone, Outcome 15 Diarrhoea.

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Analysis 1.16

Comparison 1 chemotherapy plus cetuximab versus chemotherapy alone, Outcome 16 Dysphasia.

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Analysis 1.17

Comparison 1 chemotherapy plus cetuximab versus chemotherapy alone, Outcome 17 Dyspnea.

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Analysis 1.18

Comparison 1 chemotherapy plus cetuximab versus chemotherapy alone, Outcome 18 Epistaxis.

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Analysis 1.19

Comparison 1 chemotherapy plus cetuximab versus chemotherapy alone, Outcome 19 Fatigue.

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Analysis 1.20

Comparison 1 chemotherapy plus cetuximab versus chemotherapy alone, Outcome 20 Hypokalaemia.

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Analysis 1.21

Comparison 1 chemotherapy plus cetuximab versus chemotherapy alone, Outcome 21 Hypomagnesemia.

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Analysis 1.22

Comparison 1 chemotherapy plus cetuximab versus chemotherapy alone, Outcome 22 Hypotension.

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Analysis 1.23

Comparison 1 chemotherapy plus cetuximab versus chemotherapy alone, Outcome 23 Infection.

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Analysis 1.24

Comparison 1 chemotherapy plus cetuximab versus chemotherapy alone, Outcome 24 Infusion reaction.

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Analysis 1.25

Comparison 1 chemotherapy plus cetuximab versus chemotherapy alone, Outcome 25 Mucosal inﬂammation.

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Analysis 1.26

Comparison 1 chemotherapy plus cetuximab versus chemotherapy alone, Outcome 26 Nausea.

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Analysis 1.27

Comparison 1 chemotherapy plus cetuximab versus chemotherapy alone, Outcome 27 Pneumonia.

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Analysis 1.28

Comparison 1 chemotherapy plus cetuximab versus chemotherapy alone, Outcome 28 Pulmonary embolism.

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Analysis 1.29

Comparison 1 chemotherapy plus cetuximab versus chemotherapy alone, Outcome 29 Pyrexia.

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Analysis 1.30

Comparison 1 chemotherapy plus cetuximab versus chemotherapy alone, Outcome 30 Respiratory failure.

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Analysis 1.31

Comparison 1 chemotherapy plus cetuximab versus chemotherapy alone, Outcome 31 Sepsis.

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Analysis 1.32

Comparison 1 chemotherapy plus cetuximab versus chemotherapy alone, Outcome 32 Stomatitis.

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Analysis 1.33

Comparison 1 chemotherapy plus cetuximab versus chemotherapy alone, Outcome 33 Syncope.

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Analysis 1.34

Comparison 1 chemotherapy plus cetuximab versus chemotherapy alone, Outcome 34 Vomiting.

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Analysis 1.35

Comparison 1 chemotherapy plus cetuximab versus chemotherapy alone, Outcome 35 Anaemia.

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Analysis 1.36

Comparison 1 chemotherapy plus cetuximab versus chemotherapy alone, Outcome 36 Febrile neutropenia.

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Analysis 1.37

Comparison 1 chemotherapy plus cetuximab versus chemotherapy alone, Outcome 37 Leukopenia.

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Analysis 1.38

Comparison 1 chemotherapy plus cetuximab versus chemotherapy alone, Outcome 38 Thrombocytopenia.

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Analysis 1.39

Comparison 1 chemotherapy plus cetuximab versus chemotherapy alone, Outcome 39 Neutropenia.

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Chemotherapy plus cetuximab compared with chemotherapy alone for chemotherapy‐naive advanced non‐small cell lung cancer
Patient or population: Patients with advanced non‐small cell lung cancer Settings: First‐line treatment Intervention: Chemotherapy plus cetuximab Comparison: Chemotherapy
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Chemotherapy alone	Chemotherapy plus cetuximab
Overall survival¹	8.9 months	10.5 months	HR 0.87 (0.79 to 0.96)	2018 (4 studies)	⊕⊕⊕⊕ high
Progression‐free survival¹	4.4 months	4.9 months	HR 0.91 (0.83 to 1.00)	2018 (4 studies)	⊕⊕⊝⊝ low⁵
One‐year survival rate²	40 per 100	45 per 100 (41 to 50)	RR 1.13 (1.02 to 1.25)	2018 (4 studies)	⊕⊕⊕⊕ high
Objective response rate²	23 per 100	30 per 100 (26 to 35)	RR 1.31 (1.14 to 1.51)	2018 (4 studies)	⊕⊕⊕⊝ low⁶
Quality of life³	See comment	See comment	Not estimable	1801 (2 studies)	⊕⊕⊝⊝ low⁵	Both studies reported that there were no significant differences in the change of quality of life between the two treatment arms, but no detailed data were reported
Serious adverse events^2,4	1. acneiform rash: 0.3 per 100 2. hypomagnesemia: 0.8 per 100 3. infusion reaction: 1.1 per 100 4. diarrhoea: 2.3 per 100 5. hypokalaemia: 3.6 per 100 6. febrile neutropenia: 7.6 per 100 7.leukopenia: 42.7 per 100	1. acneiform rash: 11.2 per 100 (3.2 to 39.3) 2. hypomagnesemia: 5.3 per 100 (0.9 to 30.5) 3. infusion reaction: 3.9 per 100 (1.9 to 7.6) 4. diarrhoea: 4.8 per 100 (2.9 to 8.0) 5. hypokalaemia: 6.3 per 100 (3.7 to 10.8) 6. febrile neutropenia: 10.6 per 100 (8.4 to 13.5) 7.leukopenia: 58.1 per 100 (50.0 to 67.5)	1. acneiform rash: RR 37.36 (10.66 to 130.95) 2. hypomagnesemia: RR 6.57 (1.13 to 38.12) 3. infusion reaction: RR 3.50 (1.76 to 6.94) 4. diarrhoea: RR 2.10 (1.26 to 3.48) 5. hypokalaemia: RR 1.74 (1.02 to 2.99) 6. febrile neutropenia: RR 1.40 (1.10 to 1.77) 7.leukopenia: RR 1.36 (1.17 to 1.58)	1. acneiform rash: 1970 (4 studies) 2. hypomagnesemia: 775 (2 studies) 3. infusion reaction: 1885 (3 studies) 4. diarrhoea: 1885 (3 studies) 5. hypokalaemia: 1110 (1 study) 6. febrile neutropenia: 1755 (2 studies) 7.leukopenia: 1755 (2 studies)	⊕⊕⊝⊝ low⁵	For other adverse events, there were no significant differences between the two treatment arms
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; HR: Hazard ratio; RR: Risk Ratio.
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
¹ For time‐to‐event outcomes, e.g. overall survival, the assumed risk was obtained by calculating the median value of the "median survival time of the control arm" reported by different studies. The corresponding risk was obtained in a similar way, i.e. by calculating the median value of the "median survival time of the intervention arm" reported by different studies. ² For dichotomous outcomes, e.g. one‐year survival rate, the assumed risk was obtained by meta‐analysis of the one‐year survival rates of control arms from all relevant studies. ³ For the assessment of quality of life: In Lynch 2010, the FACT‐LCS5 questionnaire was used; in Pirker 2009, the European Organisation for Research and Treatment of Cancer quality of life questionnaire C30 (version 3.0), EORTC lung cancer speciﬁc QLQ‐LC13, and EuroQoL (EQ‐5D) questionnaires were used. ⁴ The overall risk of serious adverse events was not available. Thus, specific adverse events that occurred with significantly different frequencies in the two arms were summarised instead. ⁵ The quality of evidence is downgraded by two factors, i.e. study limitations and imprecision, according to the guidelines of the GRADE Working Group. ⁶ The quality of evidence is downgraded by one factor, i.e. study limitations, according to the guidelines of the GRADE Working Group.

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Comparison 1. chemotherapy plus cetuximab versus chemotherapy alone

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Overall survival Show forest plot	4		Hazard Ratio (Random, 95% CI)	0.87 [0.79, 0.96]

2 Progression‐free survival Show forest plot	4		Hazard Ratio (Random, 95% CI)	0.91 [0.83, 1.00]

3 Objective response rate Show forest plot	4	2018	Risk Ratio (M‐H, Random, 95% CI)	1.31 [1.14, 1.51]

4 One‐year survival rate Show forest plot	4	2018	Risk Ratio (M‐H, Random, 95% CI)	1.13 [1.02, 1.25]

5 Abdominal pain Show forest plot	1	130	Risk Ratio (M‐H, Random, 95% CI)	3.09 [0.13, 74.54]

6 Acneiform rash Show forest plot	4	1970	Risk Ratio (M‐H, Random, 95% CI)	37.36 [10.66, 130.95]

7 Anorexia Show forest plot	1	130	Risk Ratio (M‐H, Random, 95% CI)	9.28 [0.51, 168.90]

8 Anxiety Show forest plot	1	130	Risk Ratio (M‐H, Random, 95% CI)	1.03 [0.07, 16.14]

9 Asthenia Show forest plot	2	215	Risk Ratio (M‐H, Random, 95% CI)	2.51 [0.10, 62.68]

10 Back pain Show forest plot	1	130	Risk Ratio (M‐H, Random, 95% CI)	5.15 [0.25, 105.31]

11 Bleeding events Show forest plot	1	1110	Risk Ratio (M‐H, Random, 95% CI)	0.68 [0.31, 1.51]

12 Cardiac events Show forest plot	1	1110	Risk Ratio (M‐H, Random, 95% CI)	1.14 [0.69, 1.87]

13 Constipation Show forest plot	1	130	Risk Ratio (M‐H, Random, 95% CI)	2.06 [0.19, 22.19]

14 Dehydration Show forest plot	2	775	Risk Ratio (M‐H, Random, 95% CI)	2.20 [0.80, 6.01]

15 Diarrhoea Show forest plot	3	1885	Risk Ratio (M‐H, Random, 95% CI)	2.10 [1.26, 3.48]

16 Dysphasia Show forest plot	1	130	Risk Ratio (M‐H, Random, 95% CI)	3.09 [0.13, 74.54]

17 Dyspnea Show forest plot	3	1325	Risk Ratio (M‐H, Random, 95% CI)	2.62 [0.53, 12.96]

18 Epistaxis Show forest plot	1	130	Risk Ratio (M‐H, Random, 95% CI)	3.09 [0.33, 28.97]

19 Fatigue Show forest plot	3	1885	Risk Ratio (M‐H, Random, 95% CI)	1.29 [0.86, 1.95]

20 Hypokalaemia Show forest plot	1	1110	Risk Ratio (M‐H, Random, 95% CI)	1.74 [1.02, 2.99]

21 Hypomagnesemia Show forest plot	2	775	Risk Ratio (M‐H, Random, 95% CI)	6.57 [1.13, 38.12]

22 Hypotension Show forest plot	1	130	Risk Ratio (M‐H, Random, 95% CI)	0.34 [0.01, 8.28]

23 Infection Show forest plot	1	85	Risk Ratio (M‐H, Random, 95% CI)	3.58 [0.79, 16.27]

24 Infusion reaction Show forest plot	3	1885	Risk Ratio (M‐H, Random, 95% CI)	3.50 [1.76, 6.94]

25 Mucosal inﬂammation Show forest plot	1	130	Risk Ratio (M‐H, Random, 95% CI)	0.34 [0.01, 8.28]

26 Nausea Show forest plot	3	860	Risk Ratio (M‐H, Random, 95% CI)	1.24 [0.75, 2.05]

27 Pneumonia Show forest plot	1	130	Risk Ratio (M‐H, Random, 95% CI)	3.09 [0.13, 74.54]

28 Pulmonary embolism Show forest plot	1	1110	Risk Ratio (M‐H, Random, 95% CI)	1.47 [0.79, 2.76]

29 Pyrexia Show forest plot	2	215	Risk Ratio (M‐H, Random, 95% CI)	2.24 [0.88, 5.71]

30 Respiratory failure Show forest plot	1	1110	Risk Ratio (M‐H, Random, 95% CI)	1.92 [0.82, 4.50]

31 Sepsis Show forest plot	1	1110	Risk Ratio (M‐H, Random, 95% CI)	3.42 [0.95, 12.35]

32 Stomatitis Show forest plot	1	130	Risk Ratio (M‐H, Random, 95% CI)	3.09 [0.13, 74.54]

33 Syncope Show forest plot	1	85	Risk Ratio (M‐H, Random, 95% CI)	3.58 [0.79, 16.27]

34 Vomiting Show forest plot	3	1325	Risk Ratio (M‐H, Random, 95% CI)	0.98 [0.69, 1.40]

35 Anaemia Show forest plot	4	1970	Risk Ratio (M‐H, Random, 95% CI)	0.93 [0.75, 1.17]

36 Febrile neutropenia Show forest plot	2	1755	Risk Ratio (M‐H, Random, 95% CI)	1.40 [1.10, 1.77]

37 Leukopenia Show forest plot	2	1755	Risk Ratio (M‐H, Random, 95% CI)	1.36 [1.17, 1.58]

38 Thrombocytopenia Show forest plot	3	860	Risk Ratio (M‐H, Random, 95% CI)	1.26 [0.96, 1.66]

39 Neutropenia Show forest plot	3	1885	Risk Ratio (M‐H, Random, 95% CI)	1.05 [0.97, 1.15]

Comparison 1. chemotherapy plus cetuximab versus chemotherapy alone

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