Epidermal growth factor receptor blockers for the treatment of ovarian cancer

Jo Morrison; Clemens Thoma; Richard J Goodall; Thomas J Lyons; Kezia Gaitskell; Alison J Wiggans; Andrew Bryant

doi:10.1002/14651858.CD007927.pub4

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Figure 1

(A) The EGFR is a transmembrane protein. (B) Following binding to its ligand, EGF, the EGFR is stimulated and develops tyrosine kinase activity. (C) Tyrosine kinase activity sets off a sequence of downstream events that lead to stimulation of cell growth. (D) EGFR activity can be blocked by antibodies that prevent EGF binding to the receptor or by use of chemicals that inhibit tyrosine kinase enzyme activity.

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Figure 2

Study flow diagram.

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Figure 3

Methodological quality summary: review authors' judgements about each methodological quality item for each included study.

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Analysis 1.1

Comparison 1 EGFR tyrosine kinase inhibitor (TKI) compared to observation alone for maintenance treatment of epithelial ovarian cancer after first‐line chemotherapy, Outcome 1 Overall survival.

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Analysis 1.2

Comparison 1 EGFR tyrosine kinase inhibitor (TKI) compared to observation alone for maintenance treatment of epithelial ovarian cancer after first‐line chemotherapy, Outcome 2 Progression‐free survival.

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Analysis 2.1

Comparison 2 EGFR tyrosine kinase inhibitor (TKI) plus chemotherapy compared to chemotherapy alone for the treatment of relapsed epithelial ovarian cancer, Outcome 1 Overall survival.

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Analysis 2.2

Comparison 2 EGFR tyrosine kinase inhibitor (TKI) plus chemotherapy compared to chemotherapy alone for the treatment of relapsed epithelial ovarian cancer, Outcome 2 Progression‐free survival.

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Analysis 2.3

Comparison 2 EGFR tyrosine kinase inhibitor (TKI) plus chemotherapy compared to chemotherapy alone for the treatment of relapsed epithelial ovarian cancer, Outcome 3 Toxicity: grade 3 or 4 neutropaenia.

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Analysis 2.4

Comparison 2 EGFR tyrosine kinase inhibitor (TKI) plus chemotherapy compared to chemotherapy alone for the treatment of relapsed epithelial ovarian cancer, Outcome 4 Toxicity: grade 3 or 4 febrile neutropaenia.

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Analysis 2.5

Comparison 2 EGFR tyrosine kinase inhibitor (TKI) plus chemotherapy compared to chemotherapy alone for the treatment of relapsed epithelial ovarian cancer, Outcome 5 Toxicity: grade 3 or 4 leucopaenia.

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Analysis 2.6

Comparison 2 EGFR tyrosine kinase inhibitor (TKI) plus chemotherapy compared to chemotherapy alone for the treatment of relapsed epithelial ovarian cancer, Outcome 6 Toxicity: grade 3 or 4 leucocytosis.

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Analysis 2.7

Comparison 2 EGFR tyrosine kinase inhibitor (TKI) plus chemotherapy compared to chemotherapy alone for the treatment of relapsed epithelial ovarian cancer, Outcome 7 Toxicity: grade 3 or 4 thrombocytopaenia.

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Analysis 2.8

Comparison 2 EGFR tyrosine kinase inhibitor (TKI) plus chemotherapy compared to chemotherapy alone for the treatment of relapsed epithelial ovarian cancer, Outcome 8 Toxicity: grade 3 or 4 anaemia.

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Analysis 2.9

Comparison 2 EGFR tyrosine kinase inhibitor (TKI) plus chemotherapy compared to chemotherapy alone for the treatment of relapsed epithelial ovarian cancer, Outcome 9 Toxicity: grade 3 or 4 nausea ± vomiting.

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Analysis 2.10

Comparison 2 EGFR tyrosine kinase inhibitor (TKI) plus chemotherapy compared to chemotherapy alone for the treatment of relapsed epithelial ovarian cancer, Outcome 10 Toxicity: grade 3 or 4 constipation.

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Analysis 2.11

Comparison 2 EGFR tyrosine kinase inhibitor (TKI) plus chemotherapy compared to chemotherapy alone for the treatment of relapsed epithelial ovarian cancer, Outcome 11 Toxicity: grade 3 or 4 rash.

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Analysis 2.12

Comparison 2 EGFR tyrosine kinase inhibitor (TKI) plus chemotherapy compared to chemotherapy alone for the treatment of relapsed epithelial ovarian cancer, Outcome 12 Toxicity: grade 3 or 4 allergic reaction/drug hypersensitivity.

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Analysis 2.13

Comparison 2 EGFR tyrosine kinase inhibitor (TKI) plus chemotherapy compared to chemotherapy alone for the treatment of relapsed epithelial ovarian cancer, Outcome 13 Toxicity: grade 3 or 4 skin toxicity (other).

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Analysis 2.14

Comparison 2 EGFR tyrosine kinase inhibitor (TKI) plus chemotherapy compared to chemotherapy alone for the treatment of relapsed epithelial ovarian cancer, Outcome 14 Toxicity: grade 3 or 4 fatigue.

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Analysis 2.15

Comparison 2 EGFR tyrosine kinase inhibitor (TKI) plus chemotherapy compared to chemotherapy alone for the treatment of relapsed epithelial ovarian cancer, Outcome 15 Toxicity: cardiac toxicity (any grade).

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Analysis 2.16

Comparison 2 EGFR tyrosine kinase inhibitor (TKI) plus chemotherapy compared to chemotherapy alone for the treatment of relapsed epithelial ovarian cancer, Outcome 16 Toxicity: grade 3 or 4 hypokalaemia.

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Analysis 2.17

Comparison 2 EGFR tyrosine kinase inhibitor (TKI) plus chemotherapy compared to chemotherapy alone for the treatment of relapsed epithelial ovarian cancer, Outcome 17 Toxicity: grade 3 or 4 hypocalcaemia.

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Analysis 2.18

Comparison 2 EGFR tyrosine kinase inhibitor (TKI) plus chemotherapy compared to chemotherapy alone for the treatment of relapsed epithelial ovarian cancer, Outcome 18 Toxicity: grade 3 or 4 hypomagnesaemia.

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Analysis 2.19

Comparison 2 EGFR tyrosine kinase inhibitor (TKI) plus chemotherapy compared to chemotherapy alone for the treatment of relapsed epithelial ovarian cancer, Outcome 19 Toxicity: grade 3 or 4 anorexia.

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Analysis 2.20

Comparison 2 EGFR tyrosine kinase inhibitor (TKI) plus chemotherapy compared to chemotherapy alone for the treatment of relapsed epithelial ovarian cancer, Outcome 20 Toxicity: grade 3 or 4 neuropathy.

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Analysis 2.21

Comparison 2 EGFR tyrosine kinase inhibitor (TKI) plus chemotherapy compared to chemotherapy alone for the treatment of relapsed epithelial ovarian cancer, Outcome 21 Toxicity: grade 3 or 4 oedema.

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Analysis 2.22

Comparison 2 EGFR tyrosine kinase inhibitor (TKI) plus chemotherapy compared to chemotherapy alone for the treatment of relapsed epithelial ovarian cancer, Outcome 22 Toxicity: treatment‐related secondary malignancy.

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Analysis 3.1

Comparison 3 Anti‐EGFR antibody plus chemotherapy compared to chemotherapy alone for treatment of relapsed epithelial ovarian cancer, Outcome 1 Overall survival.

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Analysis 3.2

Comparison 3 Anti‐EGFR antibody plus chemotherapy compared to chemotherapy alone for treatment of relapsed epithelial ovarian cancer, Outcome 2 Progression‐free survival.

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Analysis 3.3

Comparison 3 Anti‐EGFR antibody plus chemotherapy compared to chemotherapy alone for treatment of relapsed epithelial ovarian cancer, Outcome 3 Toxicity: grade 3 or 4 neutropaenia.

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Analysis 3.4

Comparison 3 Anti‐EGFR antibody plus chemotherapy compared to chemotherapy alone for treatment of relapsed epithelial ovarian cancer, Outcome 4 Toxicity: grade 3 or 4 febrile neutropaenia.

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Analysis 3.5

Comparison 3 Anti‐EGFR antibody plus chemotherapy compared to chemotherapy alone for treatment of relapsed epithelial ovarian cancer, Outcome 5 Toxicity: grade 3 or 4 leucopaenia.

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Analysis 3.6

Comparison 3 Anti‐EGFR antibody plus chemotherapy compared to chemotherapy alone for treatment of relapsed epithelial ovarian cancer, Outcome 6 Toxicity: grade 3 or 4 thrombocytopaenia.

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Analysis 3.7

Comparison 3 Anti‐EGFR antibody plus chemotherapy compared to chemotherapy alone for treatment of relapsed epithelial ovarian cancer, Outcome 7 Toxicity: grade 3 or 4 anaemia.

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Analysis 3.8

Comparison 3 Anti‐EGFR antibody plus chemotherapy compared to chemotherapy alone for treatment of relapsed epithelial ovarian cancer, Outcome 8 Toxicity: grade 3 or 4 diarrhoea.

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Analysis 3.9

Comparison 3 Anti‐EGFR antibody plus chemotherapy compared to chemotherapy alone for treatment of relapsed epithelial ovarian cancer, Outcome 9 Toxicity: grade 3 or 4 nausea ± vomiting.

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Analysis 3.10

Comparison 3 Anti‐EGFR antibody plus chemotherapy compared to chemotherapy alone for treatment of relapsed epithelial ovarian cancer, Outcome 10 Toxicity: grade 3 or 4 dyspepsia.

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Analysis 3.11

Comparison 3 Anti‐EGFR antibody plus chemotherapy compared to chemotherapy alone for treatment of relapsed epithelial ovarian cancer, Outcome 11 Toxicity: grade 3 or 4 abdominal pain.

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Analysis 3.12

Comparison 3 Anti‐EGFR antibody plus chemotherapy compared to chemotherapy alone for treatment of relapsed epithelial ovarian cancer, Outcome 12 Toxicity: grade 3 or 4 rash.

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Analysis 3.13

Comparison 3 Anti‐EGFR antibody plus chemotherapy compared to chemotherapy alone for treatment of relapsed epithelial ovarian cancer, Outcome 13 Toxicity: grade 3 or 4 allergic reaction/drug hypersensitivity.

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Analysis 3.14

Comparison 3 Anti‐EGFR antibody plus chemotherapy compared to chemotherapy alone for treatment of relapsed epithelial ovarian cancer, Outcome 14 Toxicity: grade 3 or 4 skin toxicity (other).

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Analysis 3.15

Comparison 3 Anti‐EGFR antibody plus chemotherapy compared to chemotherapy alone for treatment of relapsed epithelial ovarian cancer, Outcome 15 Toxicity: grade 3 or 4 fatigue.

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Analysis 3.16

Comparison 3 Anti‐EGFR antibody plus chemotherapy compared to chemotherapy alone for treatment of relapsed epithelial ovarian cancer, Outcome 16 Toxicity: cardiac toxicity (any grade).

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Analysis 3.17

Comparison 3 Anti‐EGFR antibody plus chemotherapy compared to chemotherapy alone for treatment of relapsed epithelial ovarian cancer, Outcome 17 Toxicity: grade 3 or 4 hypokalaemia.

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Analysis 3.18

Comparison 3 Anti‐EGFR antibody plus chemotherapy compared to chemotherapy alone for treatment of relapsed epithelial ovarian cancer, Outcome 18 Toxicity: grade 3 or 4 back pain.

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Summary of findings for the main comparison. EGFR tyrosine kinase inhibitor (TKI) compared to observation alone for maintenance treatment of epithelial ovarian cancer after first‐line chemotherapy

EGFR tyrosine kinase inhibitor (TKI) compared to observation alone for maintenance treatment of epithelial ovarian cancer after first‐line chemotherapy
Patient or population: maintenance treatment of epithelial ovarian cancer after first‐line chemotherapy Setting: hospital outpatient treatment of women with ovarian/fallopian tube/primary peritoneal cancer after response to first‐line chemotherapy Intervention: EGFR tyrosine kinase inhibitor (TKI) Comparison: observation alone
Outcomes	*Anticipated absolute effects (95% CI)**		Relative effect (95% CI)	No. of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with observation alone	Risk with EGFR tyrosine kinase inhibitor (TKI)
Overall survival	Median 50.8 months in the EGFR TKI group vs 59.1 months in the observation arm See comment		HR 0.99 (0.81 to 1.20)	835 (1 RCT)	⊕⊕⊝⊝ LOW^a	Outcome unlikely to be affected by blinding. due to the way HRs are calculated, the assumed and corresponding risks were not estimated.
Progression‐free survival	Median PFS of 12.7 months in the EGFR TKI group vs 12.4 months in the observation arm See comment		HR 1.05 (0.90 to 1.23)	835 (1 RCT)	⊕⊝⊝⊝ VERY LOW^b	due to the way HRs are calculated, the assumed and corresponding risks were not estimated.
Quality of life assessed with EORTC QLQ‐C30 and OV28 (Ovarian Cancer Module) questionnaires	"Global health/QOL scores showed a significant overall difference between the two treatment arms during the first year (P 0.0102) in favour of the observation arm. In addition, the QLQ‐C30 found statistically significant differences at the 5% level in symptom levels for diarrhoea, loss of appetite, nausea/vomiting, and fatigue, with worse symptom scores for the erlotinib arm. None of the scales, however,reported differences of 10 points except for the diarrhoea [sic] scale in which differences of more than 20 points were observed at most assessments during the first year. Sensitivity analyses by means of imputation revealed similar results".		‐	835 (1 RCT)	⊕⊝⊝⊝ VERY LOW^c	Analysable data were not provided in the published paper or after communication with the study author, and so we were unable to analyse or exclude selective reporting bias.
*The risk in the intervention group (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; EGFR: epidermal growth factor receptor; HR: hazard ratio; RR: risk ratio; OR: odds ratio; PFS: progression‐free survival; QOL: quality of life; QLQ‐C30: Quality of Life Questionnaire C30; RCT: randomised controlled trial; TKI: tyrosine kinase inhibitor.
GRADE Working Group grades of evidence High‐certainty: we are very confident that the true effect lies close to that of the estimate of the effect Moderate‐certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low‐certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect Very low‐certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect
^aDowngraded by two levels for imprecision (confidence intervals that cross zero and single study) and inability to assess inconsistency, as results were based on a single study. ^bDowngraded by three levels due to risk of bias (unblinded study); imprecision (confidence intervals that cross zero and single study); and inability to assess inconsistency, as results were based on a single study. ^cDowngraded by three levels due to the possibility of selective reporting bias (incompletely reported predefined outcome, so possibility of selective outcome reporting); imprecision; and risk of bias (unblinded), as no data were available to analyse effect and outcome was highly likely to be affected by lack of blinding.

Summary of findings for the main comparison. EGFR tyrosine kinase inhibitor (TKI) compared to observation alone for maintenance treatment of epithelial ovarian cancer after first‐line chemotherapy

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Summary of findings 2. EGFR tyrosine kinase inhibitor (TKI) plus chemotherapy compared to chemotherapy alone for the treatment of relapsed epithelial ovarian cancer

EGFR tyrosine kinase inhibitor (TKI) plus chemotherapy compared to chemotherapy alone for the treatment of relapsed epithelial ovarian cancer
Patient or population: treatment of relapsed epithelial ovarian cancer Setting: hospital outpatient treatment of women with relapsed ovarian/fallopian tube/primary peritoneal cancer Intervention: EGFR tyrosine kinase inhibitor (TKI) plus chemotherapy Comparison: chemotherapy alone
Outcomes	*Anticipated absolute effects (95% CI)**		Relative effect (95% CI)	No. of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with chemotherapy alone	Risk with EGFR tyrosine kinase inhibitor (TKI) plus chemotherapy
Overall survival	Median OS for chemotherapy alone was 18 months compared to 14 months in the chemotherapy plus EGFR TKI arm.		HR 1.25 (0.80 to 1.95)	129 (1 RCT)	⊕⊕⊝⊝ LOW^a,b	Outcome unlikely to be affected by blinding. due to the way HRs are calculated, the assumed and corresponding risks were not estimated.
Progression‐free survival	Median PFS for chemotherapy only was 3.5 months compared to a median PFS of 3.0 months in the chemotherapy plus EGFR TKI arm.		HR 0.99 (0.69 to 1.42)	129 (1 RCT)	⊕⊝⊝⊝ VERY LOW^c	due to the way HRs are calculated, the assumed and corresponding risks were not estimated.
Toxicity: grade 3 or 4 rash Assessed with National Cancer Institute Common Toxicity Criteria version 3 (CTCv3.0) or CommonTerminology Criteria for Adverse Events (CTCAE)	Study population		RR 13.63 (0.78 to 236.87)	125 (1 RCT)	⊕⊝⊝⊝ VERY LOW^c
	1 per 100	11 per 100 (1 to 100)
Toxicity: grade 3 or 4 nausea ± vomiting Assessed with National Cancer Institute Common Toxicity Criteria version 3 (CTCv3.0) or Common Terminology Criteria for Adverse Events (CTCAE)	Study population		RR 0.63 (0.16 to 2.52)	125 (1 RCT)	⊕⊝⊝⊝ VERY LOW^c
	8 per 100	5 per 100 (1 to 20)
Toxicity: grade 3 or 4 fatigue Assessed with National Cancer Institute Common Toxicity Criteria version 3 (CTCv3.0) or Common Terminology Criteria for Adverse Events (CTCAE)	Study population		RR 0.87 (0.28 to 2.72)	125 (1 RCT)	⊕⊝⊝⊝ VERY LOW^c
	9 per 100	8 per 100 (3 to 26)
Toxicity: cardiac toxicity (any grade)	Study population		RR 5.24 (0.26 to 107.02)	125 (1 RCT)	⊕⊕⊝⊝ LOW^b
	16 per 1000	82 per 1000 (4 to 1000)
Quality of life: not measured	‐	‐	‐	‐	‐	No QoL data included in the publication
*The risk in the intervention group (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; CTCAE: Common Terminology Criteria for Adverse Events; EGFR: epidermal growth factor receptor; HR: hazard ratio; PFS: progression‐free survival; QoL: quality of life; RCT: randomised controlled trial; RR: risk ratio; TKI: tyrosine kinase inhibitor
GRADE Working Group grades of evidence High‐certainty: we are very confident that the true effect lies close to that of the estimate of the effect Moderate‐certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low‐certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect Very low‐certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect
^aOutcome unlikely to be affected by lack of blinding. ^bDowngraded by two levels due to imprecision (one small study, wide confidence intervals that cross zero, and too few events for adequate power). ^cDowngraded by three levels due to risk of bias (blinding absent or unclear); imprecision; and inability to assess inconsistency (one small study, wide confidence intervals that cross zero, and too few events for adequate power).

Summary of findings 2. EGFR tyrosine kinase inhibitor (TKI) plus chemotherapy compared to chemotherapy alone for the treatment of relapsed epithelial ovarian cancer

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Summary of findings 3. Anti‐EGFR antibody plus chemotherapy compared to chemotherapy alone for treatment of relapsed epithelial ovarian cancer

Anti‐EGFR antibody plus chemotherapy compared to chemotherapy alone for treatment of relapsed epithelial ovarian cancer
Patient or population: treatment of relapsed epithelial ovarian cancer Setting: hospital outpatient treatment of women with ovarian/fallopian tube/primary peritoneal cancer after response to first‐line chemotherapy Intervention: anti‐EGFR antibody plus chemotherapy Comparison: chemotherapy alone
Outcomes	*Anticipated absolute effects (95% CI)**		Relative effect (95% CI)	No. of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with chemotherapy alone	Risk with anti‐EGFR antibody plus chemotherapy
Overall survival	Median OS by study in intervention and placebo groups, respectively Chekerov 2017: "overall survival are not yet evaluable" Kaye 2013: 28.2 months vs median overall survival not reached Kurzeder 2016: median OS 10.2 months vs 8.4 months Lui 2016: median OS 13.7 months vs 10.12 months Makhija 2010: median OS 13 months and 13.1 months		HR 0.93 (0.74 to 1.18)	658 (4 RCTs)	⊕⊕⊕⊝ MODERATE^a	Outcome unlikely to be affected by blinding. due to the way HRs are calculated, the assumed and corresponding risks were not estimated.
Progression‐free survival	Median progression‐free survival (PFS) by study in intervention and placebo groups, respectively Chekerov 2017: median PFS 9.5 months vs 10.7 months Kaye 2013: median PFS 34.1 weeks vs 40.0 weeks Kurzeder 2016: median PFS 4.3 months vs 2.6 months Lui 2016: median PFS 3.75 months vs 3.68 months Makhija 2010: median PFS 2.9 months and 2.6 months		HR 0.90 (0.70 to 1.16)	658 (4 RCTs)	⊕⊕⊝⊝ LOW^b	due to the way HRs are calculated, the assumed and corresponding risks were not estimated.

Toxicity: grade 3 to 4 anaemia Assessed with National Cancer Institute Common Toxicity Criteria version 3 (CTCv3.0) or Common Terminology Criteria for Adverse Events (CTCAE)	Study population		RR 0.84 (0.47 to 1.49)	652 (4 RCTs)	⊕⊕⊝⊝ LOW^b
	78 per 1000	65 per 1000 (37 to 116)
Toxicity: grade 3 or 4 diarrhoea Assessed with National Cancer Institute Common Toxicity Criteria version 3 (CTCv3.0) or Common Terminology Criteria for Adverse Events (CTCAE)	Study population		RR 2.87 (0.59 to 13.89)	652 (4 RCTs)	⊕⊝⊝⊝ VERY LOW^c	Diarrhoea differential side effect dependent upon type of anti‐EGFR antibody
	20 per 1000	58 per 1000 (12 to 283)
Toxicity: grade 3 or 4 diarrhoea ‐ pertuzumab Assessed with National Cancer Institute Common Toxicity Criteria version 3 (CTCv3.0) or Common Terminology Criteria for Adverse Events (CTCAE)	Study population		RR 6.37 (1.89 to 21.45)	432 (3 RCTs)	⊕⊕⊝⊝ LOW^b	Diarrhoea was a more consistent side effect with pertuzumab when separated from trials of other anti‐EGFR inhibitors
	14 per 1000	89 per 1000 (26 to 299)
Toxicity: grade 3 or 4 diarrhoea ‐ seribantumab Assessed with National Cancer Institute Common Toxicity Criteria version 3 (CTCv3.0) or Common Terminology Criteria for Adverse Events (CTCAE)	Study population		RR 0.38 (0.07 to 2.23)	220 (1 RCT)	⊕⊝⊝⊝ VERY LOW^d
	38 per 1000	14 per 1000 (3 to 84)
Toxicity: grade 3 or 4 nausea ± vomiting Assessed with National Cancer Institute Common Toxicity Criteria version 3 (CTCv3.0) or Common Terminology Criteria for Adverse Events (CTCAE)	Study population		RR 1.27 (0.56 to 2.89)	503 (3 RCTs)	⊕⊕⊝⊝ LOW^b
	41 per 1000	52 per 1000 (23 to 118)
Toxicity: grade 3 or 4 fatigue Assessed with National Cancer Institute Common Toxicity Criteria version 3 (CTCv3.0) or Common Terminology Criteria for Adverse Events (CTCAE)	Study population		RR 1.06 (0.66 to 1.73)	652 (4 RCTs)	⊕⊕⊝⊝ LOW^b
	95 per 1000	101 per 1000 (63 to 164)
Toxicity: grade 3 or 4 hypokalaemia Assessed with National Cancer Institute Common Toxicity Criteria version 3 (CTCv3.0) or Common Terminology Criteria for Adverse Events (CTCAE)	Study population		RR 2.01 (0.80 to 5.06)	522 (3 RCTs)	⊕⊕⊝⊝ LOW^b
	26 per 1000	52 per 1000 (21 to 132)
Quality of life	Quality of life (QoL) (Hilpert data 2016 ‐ see additional references for Kurzeder 2016 study): abdominal/gastrointestinal QoL (QLQ‐OV28) score 3.9 (95% CI ‐3.3 to 11.2); diarrhoeal symptoms QoL score worse on pertuzumab; score difference 21.2 (95% CI 10.1 to 32.3; P = 0.0003). Makhija 2010 (reported only in conference abstract form ‐ see Lalla 2008 in subsidiary references for Makhija 2010): "The median time to symptom deterioration was 1.7 months in the gemcitabine+placebo arm vs. 3.8 months in the gemcitabine+pertuzumab arm (HR = 0.62, 95% CI: 0.36‐1.05). Symptom improvement (≥ 3 point increase in FOSI) occurred in 28 women (43%) given gemcitabine+pertuzumab, compared to 18 (28%) in those receiving gemcitabine+placebo". ClinicalTrials.gov identifier: NCT00096993 This outcome was included in the original version of this review; no new results have been identified.	‐	(1 RCT)	⊕⊝⊝⊝ VERY LOW^e	Quality of life was not reported consistently; narrative description of data is provided in review text, as data could not be added to meta‐analysis.
*The risk in the intervention group (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; CTCAE: Common Terminology Criteria for Adverse Events; EGFR: epidermal growth factor receptor; HR: hazard ratio; OS: overall survival; PFS: progression‐free survival; QLQ‐OV28: European Organization for Research and Treatment of Cancer module for ovarian cancer; QoL: quality of life; RCT: randomised controlled trial; RR: risk ratio
GRADE Working Group grades of evidence High‐certainty: we are very confident that the true effect lies close to that of the estimate of the effect Moderate‐certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low‐certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect Very low‐certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect
^aOutcome unlikely to be affected by lack of blinding. Downgraded by one level due to imprecision (wide confidence intervals that cross zero). ^bDowngraded by two levels due to lack of blinding in studies or unclear method of randomisation in studies and imprecision. ^cDowngraded by three levels for inconsistency between studies of different anti‐EGFR antibodies; imprecision; and lack of blinding or unclear method of randomisation in studies. ^dDowngraded by three levels due to imprecision (wide confidence intervals that cross zero and too few events for adequate power); lack of blinding or unclear method of randomisation in studies; and inconsistency (one study). ^eDowngraded by 3+ levels due to risk of bias (lack of blinding); inability to gauge inconsistency (only one study); minimal data presented and inability to assess adequately but wide confidence intervals; selective reporting bias as data collected but not presented in final publication; and risk of indirectness as symptom may be due to progression of disease rather than to treatment.

Summary of findings 3. Anti‐EGFR antibody plus chemotherapy compared to chemotherapy alone for treatment of relapsed epithelial ovarian cancer

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Comparison 1. EGFR tyrosine kinase inhibitor (TKI) compared to observation alone for maintenance treatment of epithelial ovarian cancer after first‐line chemotherapy

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Overall survival Show forest plot	1		Hazard Ratio (Random, 95% CI)	Subtotals only

2 Progression‐free survival Show forest plot	1		Hazard Ratio (Random, 95% CI)	Subtotals only

Comparison 1. EGFR tyrosine kinase inhibitor (TKI) compared to observation alone for maintenance treatment of epithelial ovarian cancer after first‐line chemotherapy

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Comparison 2. EGFR tyrosine kinase inhibitor (TKI) plus chemotherapy compared to chemotherapy alone for the treatment of relapsed epithelial ovarian cancer

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Overall survival Show forest plot	1		Hazard Ratio (Random, 95% CI)	Subtotals only

2 Progression‐free survival Show forest plot	1		Hazard Ratio (Random, 95% CI)	Subtotals only

3 Toxicity: grade 3 or 4 neutropaenia Show forest plot	1		Risk Ratio (IV, Random, 95% CI)	Subtotals only

4 Toxicity: grade 3 or 4 febrile neutropaenia Show forest plot	1		Risk Ratio (IV, Random, 95% CI)	Subtotals only

5 Toxicity: grade 3 or 4 leucopaenia Show forest plot	1		Risk Ratio (IV, Random, 95% CI)	Subtotals only

6 Toxicity: grade 3 or 4 leucocytosis Show forest plot	1		Risk Ratio (IV, Random, 95% CI)	Subtotals only

7 Toxicity: grade 3 or 4 thrombocytopaenia Show forest plot	1		Risk Ratio (IV, Random, 95% CI)	Subtotals only

8 Toxicity: grade 3 or 4 anaemia Show forest plot	1		Risk Ratio (IV, Random, 95% CI)	Subtotals only

9 Toxicity: grade 3 or 4 nausea ± vomiting Show forest plot	1		Risk Ratio (IV, Random, 95% CI)	Subtotals only

10 Toxicity: grade 3 or 4 constipation Show forest plot	1		Risk Ratio (IV, Random, 95% CI)	Subtotals only

11 Toxicity: grade 3 or 4 rash Show forest plot	1		Risk Ratio (IV, Random, 95% CI)	Subtotals only

12 Toxicity: grade 3 or 4 allergic reaction/drug hypersensitivity Show forest plot	1		Risk Ratio (IV, Random, 95% CI)	Subtotals only

13 Toxicity: grade 3 or 4 skin toxicity (other) Show forest plot	1		Risk Ratio (IV, Random, 95% CI)	Subtotals only

14 Toxicity: grade 3 or 4 fatigue Show forest plot	1		Risk Ratio (IV, Random, 95% CI)	Subtotals only

15 Toxicity: cardiac toxicity (any grade) Show forest plot	1		Risk Ratio (IV, Random, 95% CI)	Subtotals only

16 Toxicity: grade 3 or 4 hypokalaemia Show forest plot	1		Risk Ratio (IV, Random, 95% CI)	Subtotals only

17 Toxicity: grade 3 or 4 hypocalcaemia Show forest plot	1		Risk Ratio (IV, Random, 95% CI)	Subtotals only

18 Toxicity: grade 3 or 4 hypomagnesaemia Show forest plot	1		Risk Ratio (IV, Random, 95% CI)	Subtotals only

19 Toxicity: grade 3 or 4 anorexia Show forest plot	1		Risk Ratio (IV, Random, 95% CI)	Subtotals only

20 Toxicity: grade 3 or 4 neuropathy Show forest plot	1		Risk Ratio (IV, Random, 95% CI)	Subtotals only

21 Toxicity: grade 3 or 4 oedema Show forest plot	1		Risk Ratio (IV, Random, 95% CI)	Subtotals only

22 Toxicity: treatment‐related secondary malignancy Show forest plot	1		Risk Ratio (IV, Random, 95% CI)	Subtotals only

Comparison 2. EGFR tyrosine kinase inhibitor (TKI) plus chemotherapy compared to chemotherapy alone for the treatment of relapsed epithelial ovarian cancer

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Comparison 3. Anti‐EGFR antibody plus chemotherapy compared to chemotherapy alone for treatment of relapsed epithelial ovarian cancer

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Overall survival Show forest plot	4	658	Hazard Ratio (Random, 95% CI)	0.93 [0.74, 1.18]

1.1 Platinum‐sensitive	1	149	Hazard Ratio (Random, 95% CI)	1.02 [0.63, 1.67]
1.2 Platinum‐resistant or refractory	3	509	Hazard Ratio (Random, 95% CI)	0.91 [0.70, 1.18]
2 Progression‐free survival Show forest plot	4	658	Hazard Ratio (Random, 95% CI)	0.90 [0.70, 1.16]

2.1 Platinum‐sensitive	1	149	Hazard Ratio (Random, 95% CI)	1.17 [0.81, 1.70]
2.2 Platinum‐resistant or refractory	3	509	Hazard Ratio (Random, 95% CI)	0.83 [0.63, 1.09]
3 Toxicity: grade 3 or 4 neutropaenia Show forest plot	4	652	Risk Ratio (IV, Random, 95% CI)	1.05 [0.64, 1.71]

3.1 Pertuzumab	3	432	Risk Ratio (IV, Random, 95% CI)	1.16 [0.66, 2.05]
3.2 Seribantumab	1	220	Risk Ratio (IV, Random, 95% CI)	0.64 [0.26, 1.60]
4 Toxicity: grade 3 or 4 febrile neutropaenia Show forest plot	2	302	Risk Ratio (IV, Random, 95% CI)	0.38 [0.10, 1.43]

5 Toxicity: grade 3 or 4 leucopaenia Show forest plot	2	302	Risk Ratio (IV, Random, 95% CI)	0.66 [0.28, 1.57]

6 Toxicity: grade 3 or 4 thrombocytopaenia Show forest plot	3	432	Risk Ratio (IV, Random, 95% CI)	0.99 [0.42, 2.34]

7 Toxicity: grade 3 or 4 anaemia Show forest plot	4	652	Risk Ratio (IV, Random, 95% CI)	0.84 [0.47, 1.49]

7.1 Pertuzumab	3	432	Risk Ratio (IV, Random, 95% CI)	0.71 [0.33, 1.51]
7.2 Seribantumab	1	220	Risk Ratio (IV, Random, 95% CI)	1.06 [0.44, 2.55]
8 Toxicity: grade 3 or 4 diarrhoea Show forest plot	4	652	Risk Ratio (IV, Random, 95% CI)	2.87 [0.59, 13.89]

8.1 Pertuzumab	3	432	Risk Ratio (IV, Random, 95% CI)	6.37 [1.89, 21.45]
8.2 Seribantumab	1	220	Risk Ratio (IV, Random, 95% CI)	0.38 [0.07, 2.23]
9 Toxicity: grade 3 or 4 nausea ± vomiting Show forest plot	3	503	Risk Ratio (IV, Random, 95% CI)	1.27 [0.56, 2.89]

9.1 Pertuzumab	2	283	Risk Ratio (IV, Random, 95% CI)	1.48 [0.54, 4.06]
9.2 Seribantumab	1	220	Risk Ratio (IV, Random, 95% CI)	0.95 [0.23, 3.88]
10 Toxicity: grade 3 or 4 dyspepsia Show forest plot	1		Risk Ratio (IV, Random, 95% CI)	Subtotals only

11 Toxicity: grade 3 or 4 abdominal pain Show forest plot	2	373	Risk Ratio (IV, Random, 95% CI)	1.30 [0.49, 3.44]

11.1 Pertuzumab	1	153	Risk Ratio (IV, Random, 95% CI)	0.99 [0.14, 6.83]
11.2 Seribantumab	1	220	Risk Ratio (IV, Random, 95% CI)	1.43 [0.46, 4.41]
12 Toxicity: grade 3 or 4 rash Show forest plot	1	130	Risk Ratio (IV, Random, 95% CI)	0.0 [0.0, 0.0]

13 Toxicity: grade 3 or 4 allergic reaction/drug hypersensitivity Show forest plot	1		Risk Ratio (IV, Random, 95% CI)	Subtotals only

14 Toxicity: grade 3 or 4 skin toxicity (other) Show forest plot	1	130	Risk Ratio (IV, Random, 95% CI)	0.0 [0.0, 0.0]

15 Toxicity: grade 3 or 4 fatigue Show forest plot	4	652	Risk Ratio (IV, Random, 95% CI)	1.06 [0.66, 1.73]

15.1 Pertuzumab	3	432	Risk Ratio (IV, Random, 95% CI)	0.97 [0.57, 1.66]
15.2 Seribantumab	1	220	Risk Ratio (IV, Random, 95% CI)	1.57 [0.52, 4.77]
16 Toxicity: cardiac toxicity (any grade) Show forest plot	3	421	Risk Ratio (IV, Random, 95% CI)	0.96 [0.54, 1.72]

16.1 Pertuzumab	3	421	Risk Ratio (IV, Random, 95% CI)	0.96 [0.54, 1.72]
17 Toxicity: grade 3 or 4 hypokalaemia Show forest plot	3	522	Risk Ratio (IV, Random, 95% CI)	2.01 [0.80, 5.06]

17.1 Pertuzumab	2	302	Risk Ratio (IV, Random, 95% CI)	1.52 [0.47, 4.93]
17.2 Seribantumab	1	220	Risk Ratio (IV, Random, 95% CI)	3.14 [0.71, 13.83]
18 Toxicity: grade 3 or 4 back pain Show forest plot	1		Risk Ratio (IV, Random, 95% CI)	Subtotals only

Comparison 3. Anti‐EGFR antibody plus chemotherapy compared to chemotherapy alone for treatment of relapsed epithelial ovarian cancer

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