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

BackgroundEctopic 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.MethodsWe 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/m2) 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).Findings30 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.InterpretationCombination 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.

Combination methotrexate and gefitinib: A potential medical treatment for inoperable nontubal ectopic pregnancy

“…To date, early human trials of combination gefitinib and methotrexate to treat nontubal ectopic pregnancy have been promising . However, the pretreatment and peak hCG of these interstitial ectopic cases were lower than our patient and only one had fetal cardiac activity.…”

“…During the early phase I trial, combination gefitinib and methotrexate showed a 34% reduction in median resolution time compared to methotrexate therapy alone for tubal ectopic pregnancies . Additionally, during the phase II study, an 86% success rate was found for tubal ectopic pregnancies with a pretreatment hCG between 1000 and 10 000 IU/L . Furthermore, a case series of eight women with nontubal ectopic pregnancies and pretreatment hCG between 2485 and 48 550 IU/L showed successful treatment with combination gefitinib and methotrexate without surgical intervention .…”

Clinical presentation and outcome of ectopic pregnancy

“…Cervical pregnancy responded to multiple dose methotrexate and gefitinib 250 mg twice daily for 5 days. 18,19 Among surgically managed patients, 18 patients were emergency and 25 cases of elective surgery. 13 patients were ruptured ectopic and 25 cases unruptured.…”

Evaluation of the Effect of Rosa damascena Mill. Product on Constipation During Pregnancy: A Single-Arm Clinical Trial

“…In this study, the sample size was estimated as 30 individuals considering α = 0.05, β = 0.1, and d = 1 and using the formula n = 2 (Z_(α/2) Z_β) ^ 2/d ^ 2. Given the sample loss of 20%, 35 samples were considered in this study (26).…”