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Meta-Analysis
. 2018 Oct 16;10(10):CD007927.
doi: 10.1002/14651858.CD007927.pub4.

Epidermal growth factor receptor blockers for the treatment of ovarian cancer

Jo Morrison  1 , Clemens Thoma, Richard J Goodall, Thomas J Lyons, Kezia Gaitskell, Alison J Wiggans, Andrew Bryant
Affiliations
Meta-Analysis

Epidermal growth factor receptor blockers for the treatment of ovarian cancer

Jo Morrison et al. Cochrane Database Syst Rev. .

Abstract

Background: This is an update of a previously published version of the review (Issue 10, 2011).Epithelial ovarian cancer (EOC) is the seventh most common cause of cancer death among women worldwide. Treatment consists of a combination of surgical debulking and platinum-based chemotherapy. Between 55% and 75% of women who respond to first-line therapy experience relapse within two years. Second-line chemotherapy is palliative and aims to reduce symptoms and prolong survival. Improved understanding about the molecular basis of EOC has led to the development of novel agents, such as epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors and anti-EGFR antibodies.

Objectives: To compare the effectiveness and harmful effects of interventions that target the epidermal growth factor receptor in the treatment of epithelial ovarian cancer (EOC).

Search methods: We searched the Cochrane Gynaecological Cancer Group Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL; 2010, Issue 4), MEDLINE, and Embase up to October 2010. We also searched registers of clinical trials, abstracts of scientific meetings, and reference lists of included studies, and we contacted experts in the field. This update includes further searches up to September 2017.

Selection criteria: Randomised controlled trials (RCTs) comparing anti-EGFR agents with or without conventional chemotherapy versus conventional chemotherapy alone or no treatment in women with histologically proven EOC.

Data collection and analysis: Two review authors independently abstracted data, assessed risk of bias, and performed GRADE assessment.

Main results: From 6105 references obtained through the literature search and an additional 15 references derived from grey literature searches, we identified seven RCTs that met our inclusion criteria and included 1725 participants. Trial results show that after first-line chemotherapy is provided, maintenance treatment with erlotinib (EGFR tyrosine kinase inhibitor (TKI)) probably makes little or no difference in overall survival (hazard ratio (HR) 0.99, 95% confidence interval (CI) 0.81 to 1.20; one study; 835 participants; low-certainty evidence) and may make little or no difference in progression-free survival (HR 1.05, 95% CI 0.90 to 1.23; one study; 835 participants; very low-certainty evidence). Less than 50% of participants provided quality of life data, and study authors reported these results incompletely. The certainty of evidence is very low, but treatment may reduce quality of life compared to observation.Treatment with an EGFR TKI (vandetanib) for women with relapsed EOC may make little or no difference in overall survival (HR 1.25, 95% CI 0.80 to 1.95; one study; 129 participants; low-certainty evidence) and may make little or no difference in progression-free survival (HR 0.99, 95% CI 0.69 to 1.42; one study; 129 participants; very low-certainty evidence). In treating patients with relapse, giving EGFR TKI may slightly increase some toxicities, such as severe rash (risk ratio (RR) 13.63, 95% CI 0.78 to 236.87; one study; 125 participants; very low-certainty evidence). Quality of life data were not available for meta-analysis.Anti-EGFR antibody treatment in relapsed EOC may or may not make a difference to overall survival (HR 0.93, 95% CI 0.74 to 1.18; four studies; 658 participants; moderate-certainty evidence) and may or may not have any effect on progression-free survival (HR 0.90, 95% CI 0.70 to 1.16; four studies; 658 participants; low-certainty evidence). Anti-EGFR antibody treatment may or may not increase side effects, including severe nausea and/or vomiting (RR 1.27, 95% CI 0.56 to 2.89; three studies; 503 participants; low-certainty evidence), severe fatigue (RR 1.06, 95% CI 0.66 to 1.73; I² = 0%; four studies; 652 participants; low-certainty evidence), and hypokalaemia (RR 2.01, 95% CI 0.80 to 5.06; I² = 0%; three studies; 522 participants; low-certainty evidence). Severe diarrhoea rates were heterogeneous across studies (RR 2.87, 95% CI 0.59 to 13.89; four studies; 652 participants; low-certainty evidence), and subgroup analysis revealed that severe diarrhoea was more likely with pertuzumab (RR 6.37, 95% CI 1.89 to 21.45; I² = 0%; three studies; 432 participants; low-certainty evidence) than with seribantumab treatment (RR 0.38, 95% CI 0.07 to 2.23; I² = 0%; one study; 220 participants; very low-certainty evidence). Quality of life data were incompletely reported, and we were unable to combine them in a meta-analysis.

Authors' conclusions: Current evidence suggests that an anti-EGFR single-agent biological treatment (EGFR TKI or anti-EGFR antibody) makes little or no difference to survival, either as maintenance treatment after first-line chemotherapy or in association with chemotherapy in recurrent cancer. Anti-EGFR therapy may increase some side effects and may or may not reduce quality of life.

PubMed Disclaimer

Conflict of interest statement

Jo Morrison: I have no financial conflict of interest in the results of this review. Clemens Thoma: None known. Richard J Goodall: None known. Thomas J Lyons: None known. Kezia Gaitskell: None known. Alison J Wiggans: None known. Andrew Bryant: None known.

Figures

1
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.
2
2
Study flow diagram.
3
3
Methodological quality summary: review authors' judgements about each methodological quality item for each included study.
1.1
1.1. Analysis
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.
1.2
1.2. Analysis
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.
2.1
2.1. Analysis
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.
2.2
2.2. Analysis
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.
2.3
2.3. Analysis
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.
2.4
2.4. Analysis
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.
2.5
2.5. Analysis
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.
2.6
2.6. Analysis
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.
2.7
2.7. Analysis
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.
2.8
2.8. Analysis
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.
2.9
2.9. Analysis
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.
2.10
2.10. Analysis
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.
2.11
2.11. Analysis
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.
2.12
2.12. Analysis
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.
2.13
2.13. Analysis
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).
2.14
2.14. Analysis
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.
2.15
2.15. Analysis
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).
2.16
2.16. Analysis
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.
2.17
2.17. Analysis
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.
2.18
2.18. Analysis
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.
2.19
2.19. Analysis
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.
2.20
2.20. Analysis
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.
2.21
2.21. Analysis
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.
2.22
2.22. Analysis
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.
3.1
3.1. Analysis
Comparison 3 Anti‐EGFR antibody plus chemotherapy compared to chemotherapy alone for treatment of relapsed epithelial ovarian cancer, Outcome 1 Overall survival.
3.2
3.2. Analysis
Comparison 3 Anti‐EGFR antibody plus chemotherapy compared to chemotherapy alone for treatment of relapsed epithelial ovarian cancer, Outcome 2 Progression‐free survival.
3.3
3.3. Analysis
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.
3.4
3.4. Analysis
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.
3.5
3.5. Analysis
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.
3.6
3.6. Analysis
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.
3.7
3.7. Analysis
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.
3.8
3.8. Analysis
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.
3.9
3.9. Analysis
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.
3.10
3.10. Analysis
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.
3.11
3.11. Analysis
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.
3.12
3.12. Analysis
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.
3.13
3.13. Analysis
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.
3.14
3.14. Analysis
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).
3.15
3.15. Analysis
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.
3.16
3.16. Analysis
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).
3.17
3.17. Analysis
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.
3.18
3.18. Analysis
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.
See this image and copyright information in PMC

Update of

References

References to studies included in this review

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Vergote 2014 {published data only}
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References to studies excluded from this review

Annunziata 2010 {published data only}
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Bauman 2012 {published data only}
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Blank 2010 {published data only}
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Gordon 2005 {published data only}
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Gordon 2006 {published data only}
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Guastalla 2007 {published data only}
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Hariprasad 2006 {published data only}
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Hariprasad 2009 {published data only}
    1. Hariprasad R, Kumar L, Kumar S, Bhatla N, Thulkar S, Das P. Advanced epithelial ovarian cancer (EOC): is there a place for maintenance therapy in patients with sub‐optimal debulking?. Journal of Clinical Oncology 2009;27(Suppl):abstr e14580.
Harter 2013 {published data only}
    1. Harter P, Sehouli J, Kimmig R, Rau J, Hilpert F, Kurzeder C, et al. Addition of vandetanib to pegylated liposomal doxorubicin (PLD) in patients with recurrent ovarian cancer. A randomized phase I/II study of the AGO Study Group (AGO‐OVAR 2.13). Investigational New Drugs 2013;31(6):1499‐504. [DOI] - PubMed
Hirte 2010 {published data only}
    1. Hirte H, Oza A, Hoskins P, Ellard S, Grimshaw R, Dubuc‐Lissoir J, et al. Phase II study of OSI‐774 given in combination with carboplatin in patients (pts) with recurrent epithelial ovarian cancer (EOC): NCIC CTG IND.149. European Journal of Cancer 2003;1(5 Suppl: ECCO 12 Abstract Book):A‐159, S51.
    1. Hirte H, Oza A, Swenerton K, Ellard SL, Grimshaw R, Fisher B, et al. A phase II study of erlotinib (OSI‐774) given in combination with carboplatin in patients with recurrent epithelial ovarian cancer. Gynecologic Oncology 2010;118(3):308‐12. - PubMed
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Jhaveri 2012 {published data only}
    1. Jhaveri K, Miller K, Rosen L, Schneider B, Chap L, Hannah A, et al. A phase I dose‐escalation trial of trastuzumab and alvespimycin hydrochloride (KOS‐1022; 17 DMAG) in the treatment of advanced solid tumors. Clinical Cancer Research 2012; Vol. 18, issue 18:5090‐8. - PubMed
Joly 2009 {published data only}
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Kimball 2008 {published data only}
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References to other published versions of this review

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