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

化疗与西妥昔单抗以及化疗单独用于化疗初治的晚期非小细胞肺癌

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Referencias

References to studies included in this review

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estudios excluidos
estudios en curso
otras referencias

Butts CA, Bodkin D, Middleman EL, Englund CW, Ellison D, Alam Y, et al. Randomized phase II study of gemcitabine plus cisplatin or carboplatin [corrected], with or without cetuximab, as first‐line therapy for patients with advanced or metastatic non small‐cell lung cancer. Journal of Clinical Oncology 2007;25:5777‐84.

Lynch TJ, Patel T, Dreisbach L, McCleod M, Heim WJ, Hermann RC, et al. Cetuximab and first‐line taxane/carboplatin chemotherapy in advanced non‐small‐cell lung cancer: results of the randomized multicenter phase III trial BMS099. Journal of Clinical Oncology 2010;28(6):911‐7.

Pirker R, Pereira JR, Szczesna A, von Pawel J, Krzakowski M, Ramlau R, et al. Cetuximab plus chemotherapy in patients with advanced non‐small‐cell lung cancer (FLEX): an open‐label randomised phase III trial. The Lancet 2009;373(9674):1525‐31.

Rosell R, Robinet G, Szczesna A, Ramlau R, Constenla M, Mennecier BC, et al. Randomized phase II study of cetuximab plus cisplatin/vinorelbine compared with cisplatin/vinorelbine alone as first‐line therapy in EGFR‐expressing advanced non‐small‐cell lung cancer. Annals of Oncology 2008;19(2):362‐9.

References to studies excluded from this review

Ir a:

estudios incluidos
estudios en curso
otras referencias

Baselga J, Pfister D, Cooper MR, Cohen R, Burtness B, Bos M, et al. Phase I studies of anti‐epidermal growth factor receptor chimeric antibody C225 alone and in combination with cisplatin. Journal of Clinical Oncology 2000;18(4):904‐14.

Belani CP, Schreeder MT, Steis RG, Guidice RA, Marsland TA, Butler EH, et al. Cetuximab in combination with carboplatin and docetaxel for patients with metastatic or advanced‐stage nonsmall cell lung cancer: a multicenter phase 2 study. Cancer 2008;113(9):2512‐7.

Borghaei H, Langer CJ, Millenson M, Ruth KJ, Litwin S, Tuttle H, et al. Phase II study of paclitaxel, carboplatin, and cetuximab as first line treatment, for patients with advanced non‐small cell lung cancer (NSCLC): results of OPN‐017. Journal of Thoracic Oncology 2008;3(11):1286‐92.

Maione P, Mencoboni M, Carrozza F, Vigano MG, Gebbia V, Verusio C, et al. Addition of cetuximab (C) to gemcitabine (G) in elderly or performance status 2 (PS) patients (pts) with advanced non small‐cell lung cancer (NSCLC): The calc1 randomised phase 2 trials. Annals of Oncology. 2008; Vol. 19:ix24‐ix32.

Google Scholar

Gridelli C, Morabito A, Gebbia V, Mencoboni M, Carrozza F, Viganò MG, et al. Cetuximab and gemcitabine in elderly or adult PS2 patients with advanced non‐small‐cell lung cancer: The cetuximab in advanced lung cancer (CALC1‐E and CALC1‐PS2) randomized phase II trials. Lung Cancer 2010;67(1):86‐92.

NCT00085501. S0342: Paclitaxel, carboplatin, and cetuximab in treating patients with stage IIIB or stage IV non‐small cell lung cancer. www.clinicaltrials.gov/show/NCT00085501.

NCT00097214. Carboplatin plus cetuximab for treatment of stage IIIB/IV non‐small cell lung cancer (NSCLC). www.clinicaltrials.gov/show/NCT00097214.

NCT00103207. Cetuximab in treating patients with recurrent or stage IIIB or stage IV lung cancer. www.clinicaltrials.gov/show/NCT00103207.

NCT00112294. Study of taxane/carboplatin +/‐ cetuximab as first‐line treatment for patients with advanced/metastatic non‐small cell lung cancer. www.clinicaltrials.gov/show/NCT00112294.

NCT00118118. Cetuximab in treating patients with recurrent or progressive metastatic non‐small cell lung cancer. www.clinicaltrials.gov/show/NCT00118118.

NCT00148798. Study of cisplatin/vinorelbine +/‐ cetuximab as first‐line treatment of advanced non small cell lung cancer (FLEX). www.clinicaltrials.gov/show/NCT00148798.

NCT00165334. Cetuximab and vinorelbine in elderly subjects with lung cancer. www.clinicaltrials.gov/show/NCT00165334.

NCT00193453. Gemcitabine, docetaxel, and cetuximab in patients with unresectable advanced non‐small cell lung cancer. www.clinicaltrials.gov/show/NCT00193453.

NCT00216203. Pemetrexed plus cetuximab in patients with recurrent non small cell lung cancer. www.clinicaltrials.gov/show/NCT00216203.

NCT00828841. Phase 2b study of cetuximab with platinum‐based chemo as first line treatment of recurrent or advanced NSCLC. www.clinicaltrials.gov/show/NCT00828841.

NCT01004731. Study of anti‐epidermal growth factor receptor (EGFr) antibody, cetuximab, in combination with gemcitabine/carboplatin in patients with stage IV lung cancer. www.clinicaltrials.gov/show/NCT01004731.

Pirker R, Szczesna A, Von Pawel J, Krzakowski M, Ramlau R, Park K, et al. FLEX: A randomized, multicenter, phase III study of cetuximab in combination with cisplatin/vinorelbine (CV) versus CV alone in the first‐line treatment of patients with advanced non‐small cell lung cancer (NSCLC) [Abstract No. 3]. Journal of Clinical Oncology: ASCO annual meeting proceedings. 2008.

Google Scholar

Robert F, Blumenschein G, Herbst RS, Fossella FV, Tseng J, Saleh MN, et al. Phase I/IIa study of cetuximab with gemcitabine plus carboplatin in patients with chemotherapy‐naive advanced non‐small‐cell lung cancer. Journal of Clinical Oncology 2005;23(36):9089‐96.

Rosell R, Ramlau R, Szczesna A, Daniel C, Bertrand M, Garcia AR, et al. Randomized phase II clinical trial of cetuximab in combination with cisplatin (C) and cinorelbine (V) or CV alone in patients with advanced epidermal growth factor receptor (EGFR)‐expressing non‐small‐cell lung cancer (NSCLC) [abstract]. European Journal of Cancer: ECCO III European Cancer Conference; 2003 Sept 21‐25; Copenhagen, Denmark. 2003.

Google Scholar

Spigel DR, Greco FA, Thompson DS, Webb C, Rubinsak J, Inhorn RC, et al. Phase II study of cetuximab, docetaxel, and gemcitabine in patients with previously untreated advanced non‐small‐cell lung cancer. Clinical Lung Cancer 2010;11(3):198‐203.

Stinchcombe TE, Bradford DS, Hensing TA, LaRocca RV, Saleh M, Evans T, et al. A multicenter phase II trial of carboplatin and cetuximab for treatment of advanced nonsmall cell lung cancer. Cancer Investigation 2010;28(2):208‐15.

Thienelt CD, Bunn PA, Hanna N, Rosenberg A, Needle MN, Long ME, et al. Multicenter phase I/II study of cetuximab with paclitaxel and carboplatin in untreated patients with stage IV non‐small‐cell lung cancer. Journal of Clinical Oncology 2005;23(34):8786‐93.

Von Pawel J, Park K, et al. Phase III study comparing cisplatin/vinorelbine plus cetuximab versus cisplatin/vinorelbine as first‐line treatment for patients with epidermal growth factor (EGFR)‐expressing advanced non‐small cell lung cancer (NSCLC) (FLEX). Journal of Clinical Oncology: ASCO annual meeting proceedings. 42nd Annual Meeting of the American Society of Clinical Oncology; 2006 June 2‐6; Atlanta, GA. 2006.

Google Scholar

References to ongoing studies

Ir a:

estudios incluidos
estudios excluidos
otras referencias

NCT00946712. S0819: Carboplatin/paclitaxel with or without bevacizumab and/or cetuximab in stage IV or recurrent non‐small cell lung cancer. www.clinicaltrials.gov/show/NCT00946712.

Additional references

Ir a:

estudios incluidos
estudios excluidos
estudios en curso

Blumenschein GR, Paulus R, Curran WJ, Robert F, Fossella F, Werner‐Wasik M, et al. Phase II study of cetuximab in combination with chemoradiation in patients with stage IIIA/B non‐small‐cell lung cancer: RTOG 0324. Journal of Clinical Oncology 2011;29(17):2312‐8.

Butts. Study of Gemcitabine/Platinum +/‐ Cetuximab as First‐Line Treatment for Patients With Advanced/Metastatic Non‐Small Cell Lung Cancer. http://clinicaltrials.gov/ct2/show/study/NCT001123462005.

Google Scholar

Dahabreh IJ, Terasawa T, Castaldi PJ, Trikalinos TA. Systematic review: anti‐epidermal growth factor receptor treatment effect modification by KRAS mutations in advanced colorectal cancer. Annals of Internal Medicine 2011;154(1):37‐49.

Eberhard DA, Johnson BE, Amler LC, Goddard AD, Heldens SL, Herbst RS, et al. Mutations in the epidermal growth factor receptor and in KRAS are predictive and prognostic indicators in patients with non‐small‐cell lung cancer treated with chemotherapy alone and in combination with erlotinib. Journal of Clinical Oncology 2005;23(25):5900‐9.

FDA. Final Labeling Text (bevacizumab). www.accessdata.fda.gov/drugsatfda_docs/label/2009/125085s0169lbl.pdf (accessed 19 May 2012).

FDA. Gefitinib (marketed as Iressa) Information. www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm110473.htm (accessed 19 May 2012).

FDA 2010. Highlights for Prescribing Information (Tarceva). www.accessdata.fda.gov/drugsatfda_docs/label/2010/021743s14s16lbl.pdf (accessed 19 May 2012).

FDA. FDA Approves Erbitux to Treat Late‐Stage Head and Neck Cancer. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm278894.htm (accessed 23 May 2012).

Govindan R, Page N, Morgensztern D, Read W, Tierney R, Vlahiotis A, et al. Changing epidemiology of small‐cell lung cancer in the United States over the last 30 years: analysis of the surveillance, epidemiologic, and end results database. Journal of Clinical Oncology 2006;24(28):4539‐44.

McMaster University. GRADEpro 3.6. McMaster University, 2014.

Gridelli C, Ardizzoni A, Le Chevalier T, Manegold C, Perrone F, Thatcher N, et al. Treatment of advanced non‐small‐cell lung cancer patients with ECOG performance status 2: results of an European Experts Panel. Annals of Oncology 2004;15(3):419‐26.

Guyatt GH, Oxman AD, Kunz R, Vist GE, Falck‐Ytter Y, Schünemann HJ, GRADE Working Group. Rating quality of evidence and strength of recommendations: What is "quality of evidence" and why is it important to clinicians?. British Medical Journal 2008;336(7651):995‐8.

Herbst RS, Kelly K, Chansky K, Mack PC, Franklin WA, Hirsch FR, et al. Phase II selection design trial of concurrent chemotherapy and cetuximab versus chemotherapy followed by cetuximab in advanced‐stage non‐small‐cell lung cancer: Southwest Oncology Group study S0342. Journal of Clinical Oncology 2010;28(31):4747‐54.

Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions. Version 5.1 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane‐handbook.org.

International Agency for Research on Cancer. Fast stats: most frequent cancers. www.globocan.iarc.fr/factsheets/populations/factsheet.asp?uno=900 (accessed 19 May 2012).

Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA: A Cancer Journal for Clinicians 2010;60(5):277‐300.

Kim ES, Mauer AM, William WN, Tran HT, Liu D, Lee JJ, et al. A phase 2 study of cetuximab in combination with docetaxel in chemotherapy‐refractory/resistant patients with advanced nonsmall cell lung cancer. Cancer 2009;115(8):1713‐22.

Lin H, Jiang J, Liang X, Zhou X, Huang R. Chemotherapy with cetuximab or chemotherapy alone for untreated advanced non‐small‐cell lung cancer: a systematic review and meta‐analysis. Lung Cancer 2010;70(1):57‐62.

Marino P, Pampallona S, Preatoni A, Cantoni A, Invernizzi F. Chemotherapy vs supportive care in advanced non‐small‐cell lung cancer. Results of a meta‐analysis of the literature. Chest 1994;106(3):861‐5.

Miller AB HB, Staquet M, Winkler A. Reporting results of cancer treatment. Cancer 1981;47(1):207‐14.

Mitsudomi T. Erlotinib, gefitinib, or chemotherapy for EGFR mutation‐positive lung cancer?. The Lancet Oncology 2011;12(8):710‐1.

National Cancer Institute. FDA Approval for Cetuximab. www.cancer.gov/cancertopics/druginfo/fda‐cetuximab (accessed 23 May 2012).

Nieder C, Pawinski A, Dalhaug A, Andratschke N. A review of clinical trials of cetuximab combined with radiotherapy for non‐small cell lung cancer. Radiation Oncology 2012;7:3.

Pirker R, Pereira JR, von Pawel J, Krzakowski M, Ramlau R, Park K, et al. EGFR expression as a predictor of survival for first‐line chemotherapy plus cetuximab in patients with advanced non‐small‐cell lung cancer: analysis of data from the phase 3 FLEX study. The Lancet Oncology 2012;13(1):33‐42.

Reeves TD, Hill EG, Armeson KE, Gillespie MB. Cetuximab therapy for head and neck squamous cell carcinoma: a systematic review of the data. Otolaryngology‐Head and Neck Surgery 2011;144(5):676‐84.

The Nordic Cochrane Centre, The Cochrane Collaboration. Review Manager (RevMan). Version 5.3. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014.

Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, et al. Comparison of four chemotherapy regimens for advanced non‐small‐cell lung cancer. The New England Journal of Medicine 2002;346(2):92‐8.

Stinchcombe TE, Socinski MA. Current treatments for advanced stage non‐small cell lung cancer. Proceedings of the American Thoracic Society 2009;6(2):233‐41.

Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. Journal of the National Cancer Institute 2000;92(3):205‐16.

Tol J, Punt CJ. Monoclonal antibodies in the treatment of metastatic colorectal cancer: a review. Clinical Therapeutics 2010;32(3):437‐53.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

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estudios excluidos
estudios en curso

Butts 2007

Methods	1. Design: A multicentre, open‐label, parallel group, randomised phase II trial 2. Centres: 32 US and 9 Canadian sites 3. Randomisation: Patients were assigned to treatment arms in a 1:1 ratio. Randomisation was stratiﬁed by site, ECOG PS (0 or 1), and on‐study platinum (cisplatin, carboplatin)
Participants	Inclusion criteria: chemotherapy‐naive patients at least 18 years of age and with an ECOG PS less than 2, with histologically or cytologically documented advanced NSCLC (stage IIIB with pleural effusion or stage IV) of all histologic subtypes 1. Female, n (%): 73 (55.7) 2. Age in years, median (range): 66 (35‐84) 3. White people, n (%): 109 (83.2) 4. ECOG PS 0‐1, n (%): 129 (98.5) 5. Tumour stage IIIB/IV: 123 (93.9) 6. Adenocarcinoma, n (%): 61 (46.6) 7. Never smoked, n (%): 19 (14.5) 8. EGFR expression, n (%): NA 9. KRAS mutations, n (%): NA 10. EGFR mutations, n (%): NA
Interventions	1. Arm A (n = 65): gemcitabine + cisplatin + cetuximab, or gemcitabine + carboplatin + cetuximab (21.5% received poststudy chemotherapy) 2. Arm B (n = 66): gemcitabine + cisplatin, or gemcitabine + carboplatin (37.9% received poststudy cetuximab) Cross‐over between treatment arms was not allowed
Outcomes	1. Primary: Objective response rate 2. Secondary: Progression‐free survival, overall survival (including data on one‐year survival rate), safety, disease control rate, duration of response, time to response
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	No details on the procedure were provided
Allocation concealment (selection bias)	Unclear risk	There was no mention of allocation concealment
Blinding of participants and personnel (performance bias) overall survival and one‐year survival rate	Low risk	No blinding. However, the results on the two outcomes were mainly determined by the biological, objective effect of treatments and unlikely to be affected by the participants' and personnels' knowledge of the assignment status
Blinding of participants and personnel (performance bias) progression‐free survival, objective response rate, quality of life, and serious adverse events	High risk	No blinding. Progression‐free survival, objective response rate, and serious adverse events are not objective outcomes and could be affected by participants' and/or personnels' knowledge of the assignment status. The study did not use quality of life as an outcome
Blinding of outcome assessment (detection bias) overall survival and one‐year survival rate	Low risk	Quote: "The sponsor conducted centralized reviews to confirm investigator measurements and to determine best response. These reviews were blinded, as the sponsor reviewer did not receive information as to which treatment the patients were receiving"
Blinding of outcome assessment (detection bias) progression‐free survival, objective response rate, quality of life, and serious adverse events	Low risk	Quote: "The sponsor conducted centralized reviews to confirm investigator measurements and to determine best response. These reviews were blinded, as the sponsor reviewer did not receive information as to which treatment the patients were receiving"
Incomplete outcome data (attrition bias) All outcomes	Low risk	Quote: "Efﬁcacy analyses were performed on an intent‐to‐treat basis. Analyses of safety and dosing data were restricted to treated patients." In effect, the information on safety were available for almost all (130, 99.2%) patients
Selective reporting (reporting bias)	Low risk	Data on all outcomes concerned in this review, except quality of life, were reported in the original paper. Examination of the protocol of the trial showed that quality of life was not a pre‐specified outcome (see: http://clinicaltrials.gov/ct2/show/study/NCT00112346)
Other bias	Low risk	No evidence about other bias was found

Lynch 2010

Methods	1. Design: A multicentre, open‐label, parallel group, randomised phase III trial 2. Centres: 96 US centres 3. Randomisation: Patients were randomly assigned 1:1 to cetuximab plus TC or TC alone. Choice of taxane was at the investigator’s discretion on an individual‐patient basis. The random assignment was stratiﬁed by study site, ECOG PS (0 or 1), and intended taxane (paclitaxel or docetaxel)
Participants	Inclusion criteria: patients who had histologically or cytologically conﬁrmed stage IV, stage IIIB (with malignant pleural effusion), or recurrent (after radiotherapy or surgery) NSCLC with bidimensionally measurable disease, were ≥ 18 years of age, and had an ECOG PS less than 2 1. Female, n (%): 280 (41.4) 2. Age in years, median (range): 65 (34‐87) 3. White people, n (%): 596 (88.1) 4. ECOG PS 0‐1, n (%): 665 (98.4) 5. Tumour stage IIIB/IV: 646 (95.6) 6. Adenocarcinoma, n (%): 354 (52.4) 7. Never smoked, n (%): 53 (7.8) 8. EGFR expression, n (%): NA 9. KRAS mutations, n (%): NA 10. EGFR mutations, n (%): NA
Interventions	1. Arm A (n = 338): taxane (paclitaxel or docetaxel) +carboplatin + cetuximab (24.3% received poststudy chemotherapy) 2. Arm B (n = 338): taxane (paclitaxel or docetaxel) +carboplatin (26% received poststudy cetuximab) Cross over to cetuximab was not permitted
Outcomes	1. Primary: Progression‐free survival 2. Secondary: Objective response rate, overall survival (including data on one‐year survival rate), quality of life, safety
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	No details on the procedure were provided
Allocation concealment (selection bias)	Unclear risk	There was no mention of allocation concealment
Blinding of participants and personnel (performance bias) overall survival and one‐year survival rate	Low risk	No blinding. However, the results on the two outcomes were mainly determined by the biological, objective effect of treatments and unlikely to be affected by the participants' and personnels' knowledge of the assignment status
Blinding of participants and personnel (performance bias) progression‐free survival, objective response rate, quality of life, and serious adverse events	High risk	No blinding. The four outcomes are not objective in nature and could be affected by participants' and/or personnels' knowledge of the assignment status
Blinding of outcome assessment (detection bias) overall survival and one‐year survival rate	Low risk	The outcomes were assessed by an independent radiologic review committee consisting of two primary radiologist reviewers and a third for adjudication. Final review was conducted by an oncologist, integrating radiologic assessment with clinical information
Blinding of outcome assessment (detection bias) progression‐free survival, objective response rate, quality of life, and serious adverse events	Low risk	The outcomes were assessed by an independent radiologic review committee consisting of two primary radiologist reviewers and a third for adjudication. Final review was conducted by an oncologist, integrating radiologic assessment with clinical information
Incomplete outcome data (attrition bias) All outcomes	Low risk	Quote: "Baseline characteristics and efﬁcacy were analyzed in all randomly assigned patients. Analyses of safety and dosing included only treated patients (patients receiving at least one dose of any study therapy)." Almost all (645, 95.4%) patients were available for safety analysis
Selective reporting (reporting bias)	Low risk	Data on all six outcomes concerned in this review were reported in the original paper
Other bias	Low risk	No evidence about other bias was found

Pirker 2009

Methods	1. Design: A multicentre, open‐label, parallel group, randomised phase III trial 2. Centres: 155 centres across the world 3. Randomisation: Patients were randomised centrally using an interactive voice response system. The random allocation schedule was generated using a computer. Randomisation was stratiﬁed by the ECOG PS (0–1 vs 2) and tumour stage (IIIB with malignant pleural effusion [wet IIIB] vs IV). Permutated blocks were assigned to each of four randomisation strata
Participants	Inclusion criteria: Chemotherapy‐naive patients with histologically or cytologically proven stage wet IIIB or stage IV NSCLC and immunohistochemical evidence of EGFR expression in at least one positively stained tumour cell 1. Female, n (%): 335 (29.8) 2. Age in years, median (range): 60 (18‐83) 3. White people, n (%): 946 (84.1) 4. ECOG PS 0‐1, n (%): 929 (82.6) 5. Tumour stage IIIB/IV: 1125 (100.0) 6. Adenocarcinoma, n (%): 532 (47.3) 7. Never smoked, n (%): 244 (21.7) 8. EGFR expression, n (%): 1125 (100.0) 9. KRAS mutations, n (%): NA 10. EGFR mutations, n (%): NA
Interventions	1. Arm A (n = 557): cisplatin + vinorelbine + cetuximab (17% received poststudy chemotherapy) 2. Arm B (n = 568): cisplatin + vinorelbine (27% received poststudy cetuximab)
Outcomes	1. Primary: Overall survival (including data on one‐year survival rate) 2. Secondary: Progression‐free survival, best overall response, quality of life, safety
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Patients were randomised centrally using an interactive voice response system. The random allocation schedule was generated using a computer
Allocation concealment (selection bias)	Low risk	Quote: "......generated the random allocation schedule using a computer; physicians and study monitors did not have access to the code"
Blinding of participants and personnel (performance bias) overall survival and one‐year survival rate	Low risk	No blinding. However, the results on the two outcomes were mainly determined by the biological, objective effect of treatments and unlikely to be affected by the participants' and personnels' knowledge of the assignment status
Blinding of participants and personnel (performance bias) progression‐free survival, objective response rate, quality of life, and serious adverse events	High risk	No blinding. The four outcomes are not objective in nature and could be affected by participants' and/or personnels' knowledge of the assignment status
Blinding of outcome assessment (detection bias) overall survival and one‐year survival rate	Low risk	No blinding. However, overall survival and one‐year survival rate were objective, "hard" outcomes and were unlikely to have been affected by the subjective judgement of assessors
Blinding of outcome assessment (detection bias) progression‐free survival, objective response rate, quality of life, and serious adverse events	High risk	No blinding. The assessments of these outcomes involved subjective judgements and were vulnerable to the performance of assessors who were aware of the assignment status
Incomplete outcome data (attrition bias) All outcomes	Low risk	Quote: "Eﬃcacy analysis was by intention to treat". Almost all (1110, 98.7%) patients were available for safety analysis
Selective reporting (reporting bias)	Low risk	Data on all six outcomes concerned in this review were reported in the original paper
Other bias	Low risk	No evidence about other bias was found

Rosell 2008

Methods	1. Design: A multicentre, open‐label, parallel group, randomised phase II trial 2. Centres: 16 centres in 6 European countries 3. Randomisation: No details were provided
Participants	Inclusion criteria: Chemotherapy‐naive patients with histologically or cytologically proven NSCLC, stage IV or stage IIIB with documented malignant pleural effusion, according to American Joint Committee on Cancer criteria, and immunohistochemical evidence of EGFR expression in the primary tumour and/or metastases 1. Female, n (%): 22 (25.6) 2. Age in years, median (range): 58 (33‐74) 3. White people, n (%): 86 (100.0) 4. ECOG PS 0‐1, n (%): NA (Karnofsky performance status 80‐100: 78 (92.9) 5. Tumour stage IIIB/IV: 86 (100.0) 6. Adenocarcinoma, n (%): 37 (43.0) 7. Never smoked, n (%): NA 8. EGFR expression, n (%): 86 (100.0) 9. KRAS mutations, n (%): NA 10. EGFR mutations, n (%): NA
Interventions	1. Arm A (n = 43): cisplatin + vinorelbine + cetuximab 2. Arm B (n = 43): cisplatin + vinorelbine
Outcomes	1. Primary: Overall response rate 2. Secondary: Overall survival (including data on one‐year survival rate), progression‐free survival, time to treatment failure, duration of response, safety
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	No details on the procedure were provided
Allocation concealment (selection bias)	Unclear risk	There was no mention of allocation concealment
Blinding of participants and personnel (performance bias) overall survival and one‐year survival rate	Low risk	No blinding. However, the results on the two outcomes were mainly determined by the biological, objective effect of treatments and unlikely to be affected by the participants' and personnels' knowledge of the assignment status
Blinding of participants and personnel (performance bias) progression‐free survival, objective response rate, quality of life, and serious adverse events	High risk	No blinding. Progression‐free survival, objective response rate, and serious adverse events are not objective outcomes and could be affected by participants' and/or personnels' knowledge of the assignment status. The study did not use quality of life as an outcome
Blinding of outcome assessment (detection bias) overall survival and one‐year survival rate	Low risk	No blinding. However, overall survival and one‐year survival rate were objective, "hard" outcomes and unlikely to have been affected by the subjective judgement of assessors
Blinding of outcome assessment (detection bias) progression‐free survival, objective response rate, quality of life, and serious adverse events	High risk	No blinding. The assessments of these outcomes involved subjective judgements and were vulnerable to the performance of assessors who were aware of the assignment status
Incomplete outcome data (attrition bias) All outcomes	Low risk	Quote: "The efﬁcacy analysis was based on the intent to treat population deﬁned as all randomized patients. The safety analysis was based on all patients who had received any dose of study treatment." Almost all (85, 98.8%) patients were available for safety analysis
Selective reporting (reporting bias)	Unclear risk	Data on quality of life was not reported in the paper. As no protocol or registration can be found for this trial, it is difficult to say whether quality of life was a pre‐specified outcome. Thus, the risk for selective reporting bias was considered unclear
Other bias	Low risk	No evidence about other bias was found

ECOG PS ‐ Eastern Cooperative Oncology Group performance status
EGFR ‐ epidermal growth factor receptor

NA ‐ not available

NSCLC ‐ non‐small cell lung cancer

Characteristics of excluded studies [ordered by study ID]

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estudios incluidos
estudios en curso

Study	Reason for exclusion
Baselga 2000	Not comparing cetuximab plus chemotherapy with chemotherapy alone
Belani 2008	Single‐arm, non‐randomised study
Borghaei 2008	Single‐arm, non‐randomised study
Gridelli 2008	Not comparing cetuximab plus chemotherapy with chemotherapy alone
Gridelli 2010	Not comparing cetuximab plus chemotherapy with chemotherapy alone
NCT00085501	The drugs used in different arms were the same (treatment schedules were different)
NCT00097214	Single‐arm, non‐randomised study
NCT00103207	Single‐arm, non‐randomised study
NCT00112294	Duplicate of an included study (Lynch 2010)
NCT00118118	Single‐arm, non‐randomised study
NCT00148798	Duplicate of an included study (Pirker 2009)
NCT00165334	Single‐arm, non‐randomised study
NCT00193453	Single‐arm, non‐randomised study
NCT00216203	Single‐arm, non‐randomised study
NCT00828841	Not comparing cetuximab plus chemotherapy with chemotherapy alone
NCT01004731	Single‐arm, non‐randomised study
Pirker 2008	Duplicate of an included study (Pirker 2009)
Robert 2005	Single‐arm, non‐randomised study
Rosell 2003	Duplicate of an included study (Rosell 2008)
Spigel 2010	Single‐arm, non‐randomised study
Stinchcombe 2010	Single‐arm, non‐randomised study
Thienelt 2005	Single‐arm, non‐randomised study
Von Pawel 2006	Duplicate of an included study (Pirker 2009)

Characteristics of ongoing studies [ordered by study ID]

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estudios incluidos
estudios excluidos

NCT00946712

Trial name or title
Methods	Randomised, phase III study
Participants	1546 patients with advanced non‐small cell lung cancer
Interventions	Active Comparator: Arm I Patients receive carboplatin IV over 30 minutes and paclitaxel IV over 3 hours with or without bevacizumab IV over 30‐90 minutes on day 1. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. After completion of 6 courses, patients receiving bevacizumab may continue to receive bevacizumab (as above) in the absence of disease progression or unacceptable toxicity Experimental: Arm II Patients receive carboplatin and paclitaxel with or without bevacizumab as in arm I. Patients also receive cetuximab IV over 1‐2 hours on days 1, 8, and 15. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. After completion of 6 courses, patients may continue to receive cetuximab with or without bevacizumab (as above) in the absence of disease progression or unacceptable toxicity
Outcomes	Primary Outcome Measures: overall survival; progression‐free survival of EGFR FISH‐positive patients by institutional review Secondary Outcome Measures: overall survival and progression‐free survival of EGFR FISH‐positive patients by centralised review; progression‐free survival of the entire study population by centralised review and by institutional review; response; toxicity as assessed by NCI CTCAE version 4.0; comparison of other purported EGFR‐related biomarkers with EGFR IHC, EGFR FISH, and patient outcomes; Correlation of KRAS mutations with response and outcome
Starting date
Contact information
Notes

EGFR ‐ epidermal growth factor receptor

Data and analyses

Open in table viewer

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]
Open in figure viewer Analysis 1.1 Comparison 1 chemotherapy plus cetuximab versus chemotherapy alone, Outcome 1 Overall survival.
2 Progression‐free survival Show forest plot	4		Hazard Ratio (Random, 95% CI)	0.91 [0.83, 1.00]
Open in figure viewer Analysis 1.2 Comparison 1 chemotherapy plus cetuximab versus chemotherapy alone, Outcome 2 Progression‐free survival.
3 Objective response rate Show forest plot	4	2018	Risk Ratio (M‐H, Random, 95% CI)	1.31 [1.14, 1.51]
Open in figure viewer Analysis 1.3 Comparison 1 chemotherapy plus cetuximab versus chemotherapy alone, Outcome 3 Objective response rate.
4 One‐year survival rate Show forest plot	4	2018	Risk Ratio (M‐H, Random, 95% CI)	1.13 [1.02, 1.25]
Open in figure viewer Analysis 1.4 Comparison 1 chemotherapy plus cetuximab versus chemotherapy alone, Outcome 4 One‐year survival rate.
5 Abdominal pain Show forest plot	1	130	Risk Ratio (M‐H, Random, 95% CI)	3.09 [0.13, 74.54]
Open in figure viewer Analysis 1.5 Comparison 1 chemotherapy plus cetuximab versus chemotherapy alone, Outcome 5 Abdominal pain.
6 Acneiform rash Show forest plot	4	1970	Risk Ratio (M‐H, Random, 95% CI)	37.36 [10.66, 130.95]
Open in figure viewer Analysis 1.6 Comparison 1 chemotherapy plus cetuximab versus chemotherapy alone, Outcome 6 Acneiform rash.
7 Anorexia Show forest plot	1	130	Risk Ratio (M‐H, Random, 95% CI)	9.28 [0.51, 168.90]
Open in figure viewer Analysis 1.7 Comparison 1 chemotherapy plus cetuximab versus chemotherapy alone, Outcome 7 Anorexia.
8 Anxiety Show forest plot	1	130	Risk Ratio (M‐H, Random, 95% CI)	1.03 [0.07, 16.14]
Open in figure viewer Analysis 1.8 Comparison 1 chemotherapy plus cetuximab versus chemotherapy alone, Outcome 8 Anxiety.
9 Asthenia Show forest plot	2	215	Risk Ratio (M‐H, Random, 95% CI)	2.51 [0.10, 62.68]
Open in figure viewer Analysis 1.9 Comparison 1 chemotherapy plus cetuximab versus chemotherapy alone, Outcome 9 Asthenia.
10 Back pain Show forest plot	1	130	Risk Ratio (M‐H, Random, 95% CI)	5.15 [0.25, 105.31]
Open in figure viewer Analysis 1.10 Comparison 1 chemotherapy plus cetuximab versus chemotherapy alone, Outcome 10 Back pain.
11 Bleeding events Show forest plot	1	1110	Risk Ratio (M‐H, Random, 95% CI)	0.68 [0.31, 1.51]
Open in figure viewer Analysis 1.11 Comparison 1 chemotherapy plus cetuximab versus chemotherapy alone, Outcome 11 Bleeding events.
12 Cardiac events Show forest plot	1	1110	Risk Ratio (M‐H, Random, 95% CI)	1.14 [0.69, 1.87]
Open in figure viewer Analysis 1.12 Comparison 1 chemotherapy plus cetuximab versus chemotherapy alone, Outcome 12 Cardiac events.
13 Constipation Show forest plot	1	130	Risk Ratio (M‐H, Random, 95% CI)	2.06 [0.19, 22.19]
Open in figure viewer Analysis 1.13 Comparison 1 chemotherapy plus cetuximab versus chemotherapy alone, Outcome 13 Constipation.
14 Dehydration Show forest plot	2	775	Risk Ratio (M‐H, Random, 95% CI)	2.20 [0.80, 6.01]
Open in figure viewer Analysis 1.14 Comparison 1 chemotherapy plus cetuximab versus chemotherapy alone, Outcome 14 Dehydration.
15 Diarrhoea Show forest plot	3	1885	Risk Ratio (M‐H, Random, 95% CI)	2.10 [1.26, 3.48]
Open in figure viewer Analysis 1.15 Comparison 1 chemotherapy plus cetuximab versus chemotherapy alone, Outcome 15 Diarrhoea.
16 Dysphasia Show forest plot	1	130	Risk Ratio (M‐H, Random, 95% CI)	3.09 [0.13, 74.54]
Open in figure viewer Analysis 1.16 Comparison 1 chemotherapy plus cetuximab versus chemotherapy alone, Outcome 16 Dysphasia.
17 Dyspnea Show forest plot	3	1325	Risk Ratio (M‐H, Random, 95% CI)	2.62 [0.53, 12.96]
Open in figure viewer Analysis 1.17 Comparison 1 chemotherapy plus cetuximab versus chemotherapy alone, Outcome 17 Dyspnea.
18 Epistaxis Show forest plot	1	130	Risk Ratio (M‐H, Random, 95% CI)	3.09 [0.33, 28.97]
Open in figure viewer Analysis 1.18 Comparison 1 chemotherapy plus cetuximab versus chemotherapy alone, Outcome 18 Epistaxis.
19 Fatigue Show forest plot	3	1885	Risk Ratio (M‐H, Random, 95% CI)	1.29 [0.86, 1.95]
Open in figure viewer Analysis 1.19 Comparison 1 chemotherapy plus cetuximab versus chemotherapy alone, Outcome 19 Fatigue.
20 Hypokalaemia Show forest plot	1	1110	Risk Ratio (M‐H, Random, 95% CI)	1.74 [1.02, 2.99]
Open in figure viewer Analysis 1.20 Comparison 1 chemotherapy plus cetuximab versus chemotherapy alone, Outcome 20 Hypokalaemia.
21 Hypomagnesemia Show forest plot	2	775	Risk Ratio (M‐H, Random, 95% CI)	6.57 [1.13, 38.12]
Open in figure viewer Analysis 1.21 Comparison 1 chemotherapy plus cetuximab versus chemotherapy alone, Outcome 21 Hypomagnesemia.
22 Hypotension Show forest plot	1	130	Risk Ratio (M‐H, Random, 95% CI)	0.34 [0.01, 8.28]
Open in figure viewer Analysis 1.22 Comparison 1 chemotherapy plus cetuximab versus chemotherapy alone, Outcome 22 Hypotension.
23 Infection Show forest plot	1	85	Risk Ratio (M‐H, Random, 95% CI)	3.58 [0.79, 16.27]
Open in figure viewer Analysis 1.23 Comparison 1 chemotherapy plus cetuximab versus chemotherapy alone, Outcome 23 Infection.
24 Infusion reaction Show forest plot	3	1885	Risk Ratio (M‐H, Random, 95% CI)	3.50 [1.76, 6.94]
Open in figure viewer Analysis 1.24 Comparison 1 chemotherapy plus cetuximab versus chemotherapy alone, Outcome 24 Infusion reaction.
25 Mucosal inﬂammation Show forest plot	1	130	Risk Ratio (M‐H, Random, 95% CI)	0.34 [0.01, 8.28]
Open in figure viewer Analysis 1.25 Comparison 1 chemotherapy plus cetuximab versus chemotherapy alone, Outcome 25 Mucosal inﬂammation.
26 Nausea Show forest plot	3	860	Risk Ratio (M‐H, Random, 95% CI)	1.24 [0.75, 2.05]
Open in figure viewer Analysis 1.26 Comparison 1 chemotherapy plus cetuximab versus chemotherapy alone, Outcome 26 Nausea.
27 Pneumonia Show forest plot	1	130	Risk Ratio (M‐H, Random, 95% CI)	3.09 [0.13, 74.54]
Open in figure viewer Analysis 1.27 Comparison 1 chemotherapy plus cetuximab versus chemotherapy alone, Outcome 27 Pneumonia.
28 Pulmonary embolism Show forest plot	1	1110	Risk Ratio (M‐H, Random, 95% CI)	1.47 [0.79, 2.76]
Open in figure viewer Analysis 1.28 Comparison 1 chemotherapy plus cetuximab versus chemotherapy alone, Outcome 28 Pulmonary embolism.
29 Pyrexia Show forest plot	2	215	Risk Ratio (M‐H, Random, 95% CI)	2.24 [0.88, 5.71]
Open in figure viewer Analysis 1.29 Comparison 1 chemotherapy plus cetuximab versus chemotherapy alone, Outcome 29 Pyrexia.
30 Respiratory failure Show forest plot	1	1110	Risk Ratio (M‐H, Random, 95% CI)	1.92 [0.82, 4.50]
Open in figure viewer Analysis 1.30 Comparison 1 chemotherapy plus cetuximab versus chemotherapy alone, Outcome 30 Respiratory failure.
31 Sepsis Show forest plot	1	1110	Risk Ratio (M‐H, Random, 95% CI)	3.42 [0.95, 12.35]
Open in figure viewer Analysis 1.31 Comparison 1 chemotherapy plus cetuximab versus chemotherapy alone, Outcome 31 Sepsis.
32 Stomatitis Show forest plot	1	130	Risk Ratio (M‐H, Random, 95% CI)	3.09 [0.13, 74.54]
Open in figure viewer Analysis 1.32 Comparison 1 chemotherapy plus cetuximab versus chemotherapy alone, Outcome 32 Stomatitis.
33 Syncope Show forest plot	1	85	Risk Ratio (M‐H, Random, 95% CI)	3.58 [0.79, 16.27]
Open in figure viewer Analysis 1.33 Comparison 1 chemotherapy plus cetuximab versus chemotherapy alone, Outcome 33 Syncope.
34 Vomiting Show forest plot	3	1325	Risk Ratio (M‐H, Random, 95% CI)	0.98 [0.69, 1.40]
Open in figure viewer Analysis 1.34 Comparison 1 chemotherapy plus cetuximab versus chemotherapy alone, Outcome 34 Vomiting.
35 Anaemia Show forest plot	4	1970	Risk Ratio (M‐H, Random, 95% CI)	0.93 [0.75, 1.17]
Open in figure viewer Analysis 1.35 Comparison 1 chemotherapy plus cetuximab versus chemotherapy alone, Outcome 35 Anaemia.
36 Febrile neutropenia Show forest plot	2	1755	Risk Ratio (M‐H, Random, 95% CI)	1.40 [1.10, 1.77]
Open in figure viewer Analysis 1.36 Comparison 1 chemotherapy plus cetuximab versus chemotherapy alone, Outcome 36 Febrile neutropenia.
37 Leukopenia Show forest plot	2	1755	Risk Ratio (M‐H, Random, 95% CI)	1.36 [1.17, 1.58]
Open in figure viewer Analysis 1.37 Comparison 1 chemotherapy plus cetuximab versus chemotherapy alone, Outcome 37 Leukopenia.
38 Thrombocytopenia Show forest plot	3	860	Risk Ratio (M‐H, Random, 95% CI)	1.26 [0.96, 1.66]
Open in figure viewer Analysis 1.38 Comparison 1 chemotherapy plus cetuximab versus chemotherapy alone, Outcome 38 Thrombocytopenia.
39 Neutropenia Show forest plot	3	1885	Risk Ratio (M‐H, Random, 95% CI)	1.05 [0.97, 1.15]
Open in figure viewer Analysis 1.39 Comparison 1 chemotherapy plus cetuximab versus chemotherapy alone, Outcome 39 Neutropenia.

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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Referencias

References to studies included in this review

Butts 2007 {published data only}

Lynch 2010 {published data only}

Pirker 2009 {published data only}

Rosell 2008 {published data only}

References to studies excluded from this review

Baselga 2000 {published data only}

Belani 2008 {published data only}

Borghaei 2008 {published data only}

Gridelli 2008 {published data only}

Gridelli 2010 {published data only}

NCT00085501 {unpublished data only}

NCT00097214 {unpublished data only}

NCT00103207 {unpublished data only}

NCT00112294 {unpublished data only}

NCT00118118 {unpublished data only}

NCT00148798 {unpublished data only}

NCT00165334 {unpublished data only}

NCT00193453 {unpublished data only}

NCT00216203 {unpublished data only}

NCT00828841 {unpublished data only}

NCT01004731 {unpublished data only}

Pirker 2008 {published data only}

Robert 2005 {published data only}

Rosell 2003 {published data only}

Spigel 2010 {published data only}

Stinchcombe 2010 {published data only}

Thienelt 2005 {published data only}

Von Pawel 2006 {published data only}

References to ongoing studies

NCT00946712 {unpublished data only}

Additional references

Blumenschein 2011

Butts 2005

Dahabreh 2011

Eberhard 2005

FDA 2004

FDA 2005

FDA 2010

FDA 2011

Govindan 2006

GRADEpro 2014 [Computer program]

Gridelli 2004

Guyatt 2008

Herbst 2010

Higgins 2011

IARC 2010

Jemal 2010

Kim 2009

Lin 2010

Marino 1994

Miller 1981

Mitsudomi 2011

National Cancer Institute 2011

Nieder 2012

Pirker 2012

Reeves 2011

RevMan 2014 [Computer program]

Schiller 2002

Stinchcombe 2009

Therasse 2000

Tol 2010

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Characteristics of excluded studies [ordered by study ID]

Characteristics of ongoing studies [ordered by study ID]

Data and analyses

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