Gefitinib and Methotrexate to Treat Ectopic Pregnancies with a Pre-Treatment Serum hCG 1000–10,000 IU/L: Phase II Open Label, Single Arm Multi-Centre Trial ^☆

Abstract

Background

Ectopic pregnancies are a leading cause of maternal mortality. Most are treated surgically. We evaluated the efficacy and safety of combining oral gefitinib (epidermal growth factor receptor inhibitor) with methotrexate to treat larger ectopic pregnancies.

Methods

We performed a phase II, single arm, open label study across four hospitals in Edinburgh and Melbourne. We recruited women with a stable tubal ectopic pregnancy and a pre-treatment serum hCG between 1000 and 10,000 IU/L. We administered intramuscular methotrexate (50 mg/m ²) once, and oral gefitinib (250 mg) for seven days. The primary outcome was the percentage successfully treated without needing surgery. To show the treatment is at least 70% effective, 28 participants were required, and 24 or more successfully treated without surgery. Secondary outcomes were safety, tolerability, and time to resolution. This study is registered (ACTRN12611001056987).

Findings

30 participants with stable tubal ectopic pregnancies were recruited but two withdrew, leaving 28 participants. The median (± range) pre-treatment serum hCG was 2039 (1031–8575) IU/L and nine had pre-treatment hCGs levels >3000 IU/L. The treatment successfully resolved 86% (24/28) cases with a median (±range) time to resolution of 32 (18–67) days. The treatment caused transient rash and diarrhoea, but no serious adverse events.

Interpretation

Combination gefitinib and methotrexate is at least 70% effective in resolving ectopic pregnancies with a pre-treatment serum hCG 1000–10,000 IU/L. This may be a new way to treat most stable ectopic pregnancies, but needs to be validated via a randomised clinical trial.

Highlights

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  Methotrexate and seven tablets of gefitinib resolved 86% of ectopic pregnancies with a starting hCG 1000-10,000 IU/L.

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  The treatment commonly caused a transient rash and diarrhea, but no serious adverse events

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  This could be more effective than methotrexate alone to treat ectopic pregnancies, allowing more to avoid surgery.

Evidence before this study: We searched PubMed for articles before May 31st without restriction on the start date. We included the search terms “ectopic pregnancy”, AND “treatments” AND “gefitinib”. There is already an extensive literature evaluating the use of methotrexate to treat ectopic pregnancies, and reviewing each of these trials was beyond the remit of our current study. Hence for methotrexate treatment we examined meta-analyses', reviews and international clinical guidelines on the medical management of ectopic pregnancies. We also searched for general reviews on the topic of ectopic pregnancy treatment (search terms “ectopic pregnancy” AND “review”).

Most ectopic pregnancies are treated surgically. An injection of methotrexate is now widely used clinically to treat ectopic pregnancy. However, the efficacy of methotrexate declines with increasing pre-treatment serum human chorionic gonadotrophin (hCG) levels, and declines when other clinical parameters are present suggesting the ectopic pregnancy is large (demonstrable fetal cardiac activity or a large size seen on ultrasound). One systematic meta-analysis published 10 years ago concluded that methotrexate treatment is only more cost economical than surgery if the pre-treatment serum hCG is <1500 IU/L.

A preclinical laboratory study identified the possibility that combining gefitinib (an orally available epidermal growth factor receptor inhibitor) with methotrexate may be additive in treating ectopic pregnancies, compared to either agent alone. There have also been two early phase clinical studies published. The first was a trial of 12 participants where the inclusion criteria was an ectopic pregnancy with a pre-treatment hCG <3000 IU/L. It showed the treatment appeared safe, and a comparison with a historic cohort of women treated with methotrexate alone suggested adding gefitinib may induce faster declines in serum hCG levels and resolves the ectopic pregnancy faster. The second human study was a case series that showed combination gefitinib and methotrexate resolved eight cases of extra-tubal ectopic pregnancies.

Added value of this study: This is the first study evaluating the potential of combination gefitinib and methotrexate in treating tubal ectopic pregnancies presenting with pre-treatment hCG levels between 1000 and 10,000 IU/L. This single arm clinical trial of 28 participants found combining seven tablets of gefitinib with methotrexate resolved 86% of ectopic pregnancies in a cohort that included larger ectopic pregnancies.

Implications of all the available evidence: Collectively, three single arm human trials suggest combination gefitinib and methotrexate may be a new medical treatment to resolve most ectopic pregnancies. However, the concept now needs to be tested in large randomised clinical trial before it can be used clinically.