Are EGFR inhibitors, alone or in combination with conventional chemotherapy, likely to improve outcome in women with ovarian cancer?

Approximately a quarter of gynaecological cancers are of ovarian origin while ovarian cancers account for half of the deaths related to gynaecological cancers. The annual incidence world-wide is about 6.6 cases per 100,000 women, with an annual mortality rate of four deaths per 100,000 women. Nine out of ten ovarian cancers arise from the surface layer of the ovary and three-quarters of these are diagnosed at an advanced stage, when they have spread throughout the abdominal cavity. Treatment is usually a combination of surgery, to remove as much of the visible cancer as possible (debulking surgery), followed by platinum-based chemotherapy to shrink remaining disease. The majority of ovarian cancers (70 to 80%) respond to chemotherapy. Unfortunately, most women will relapse and ultimately die because ovarian cancer cells become resistant to multiple types of chemotherapy.

Since ovarian cancer is able to develop resistance to chemotherapy, it is important to search for agents that target different cellular mechanisms in cancer cells. The epidermal growth factor receptor (EGFR or ErbB1) is a cell surface molecule normally involved in controlling cell growth. Uncontrolled EGFR activation is found in ovarian cancer and is linked to a poor outcome. EGFR is a key promoter of cell growth and has a role in the development of cancer. Preventing EGFR activity is therefore an attractive target for novel therapeutic agents. Anti-EGFR agents have been developed to act on different steps of EGFR activation.

Several EGFR inhibitors have been tried in different trials against ovarian, fallopian tube and primary peritoneal cancers with minimal to moderate success. Some of these agents have the advantage that they can be given in tablet form, but can cause significant side effects. They have been tried in combination with chemotherapy; following initial diagnosis or relapse; or on their own following conventional chemotherapy to try to prevent or delay cancer recurrence (consolidation treatment).

This review found evidence from only one study, which looked at the effect of adding pertuzumab to conventional chemotherapy in women whose ovarian cancer had come back after initial treatment. This study found that, when all of the women were looked at together, there was no significant benefit to adding pertuzumab (an antibody blocking the EGFR pathway) to conventional chemotherapy (gemcitabine), in terms of survival time, although there was a suggestion that it might slow the growth of the cancer (increased progression-free survival), but this result was only an indication and was not statistically significant. In a small group of women who had an aggressive type of ovarian cancer that responded poorly to chemotherapy, there may have been a benefit to adding pertuzumab, but the numbers of these women were too small to be certain of any real effect and the differences seen may be due to chance rather than a real finding. The trial did show that there were worse side effects in women who received pertuzumab in addition to gemcitabine, although due to the relatively small number of side effects recorded (because the trial was done on a relatively small number of women), this result was also not statistically significant, although is fairly likely to be a real effect. Because of how the study was performed, some of these results may be due to bias (inaccuracies that produce a false pattern of differences between observed and true values) in the study. We found three other ongoing studies but the results are not yet available.

Authors' conclusions: 

EGFR inhibitors, including pertuzumab, may add activity to conventional chemotherapy for treatment of platinum-resistant ovarian cancer. Certain subsets of women with particularly aggressive tumours resistant to conventional chemotherapy may benefit from EGFR inhibitor treatment. Further RCTs are necessary before EGFR inhibitors are introduced as first- or second-line treatment of ovarian cancer.

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Background: 

Ovarian cancer is the seventh most common cause of cancer death in women world-wide. Treatment consists of a combination of surgical debulking and platinum-based chemotherapy, alone or in combination with paclitaxel. Between 55% and 75% of women who respond to first-line therapy relapse within two years of completing treatment. Second-line chemotherapy is palliative and aims to reduce symptoms and prolong survival. Increased understanding about the molecular basis of ovarian cancer has led to the development of novel agents, such as epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors, and their effectiveness and toxicities in women with advanced ovarian cancer needs to be assessed.

Objectives: 

To compare the effectiveness and toxicities of epidermal growth factor receptor (EGFR) inhibitors alone or in combination with standard chemotherapy in the treatment of ovarian cancer.

Search strategy: 

We searched the Cochrane Gynaecological Cancer Group Trials Register, The Cochrane Central Register of Controlled Trials (CENTRAL) Issue 4, 2010, 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 contacted experts in the field.

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 ovarian cancer.

Data collection and analysis: 

Two review authors independently abstracted data and assessed risk of bias. We reported adjusted hazard ratios (HRs) for overall and progression-free survival and risk ratios (RRs) comparing adverse events in women who received gemcitabine plus pertuzumab and gemcitabine plus placebo.

Main results: 

We found only one completed and three ongoing RCTs that met our inclusion criteria. The completed trial randomised 131 women with relapsed ovarian cancer to receive gemcitabine and pertuzumab or placebo and gemcitabine (control). There was no statistically significant difference in overall survival (OS), progression-free survival (PFS) and response between women who received gemcitabine and pertuzumab and those who received control, although PFS approached borderline significance (adjusted HR = 0.66, 95% CI 0.43 to 1.03; P = 0.06). The trial reported a higher rate of adverse events in the gemcitabine and pertuzumab arm for most outcomes, but most were not statistically significant (although many approached borderline significance) because the trial lacked statistical power due to its relatively small size and the low number of observed events. The trial was at moderate risk of bias.

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