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Combination gefitinib and methotrexate treatment for non-tubal ectopic pregnancies: a case series.

ABSTRACT: Non-tubal ectopic pregnancies are a rare subgroup of ectopic pregnancies implanted at sites other than the Fallopian tube. Mortality from non-tubal ectopic pregnancies is higher compared with that for tubal ectopic pregnancies, and they are becoming more common, partly due to the rising incidence of Caesarean sections and use of assisted reproductive technologies. Non-tubal ectopic pregnancies can be especially difficult to treat. Surgical treatment is complex, and follow-up after medical treatment is usually protracted. There is therefore a need for more effective medical therapies to resolve non-tubal ectopic pregnancies and reduce operative intervention. We have recently reported successful use of combination gefitinib (an orally available epidermal growth factor receptor inhibitor) and methotrexate for treatment of tubal pregnancies. To our knowledge, this combination has not been used to treat non-tubal pregnancies. Here we report the use of combination gefitinib and methotrexate to treat eight women with stable, non-tubal ectopic pregnancies at two tertiary academic teaching hospitals (Edinburgh, UK and Melbourne, Australia); five interstitial and three Caesarean section scar ectopic pregnancies. Pretreatment serum hCG levels ranged from 2458 to 48 550 IU/l, and six women had pretreatment hCG levels >5000 IU/l. The women were co-administered 1-2 doses of i.m. methotrexate (50 mg/m² on Day 1, ± Day 4 or Day 7) with seven once daily doses of oral gefitinib (250 mg). The women were monitored until complete resolution of the ectopic pregnancy, defined as a serum hCG <15 IU/l. Time to resolution (days from first methotrexate dose until serum hCG <15 IU/l), safety and tolerability, complication rates and subsequent fertility outcomes were also recorded. All eight women were successfully treated with combination gefitinib and methotrexate. The most common side effects were transient acne/rash and diarrhoea, known side effects of gefitinib. All women promptly resumed menstruation and importantly, three women subsequently conceived spontaneously. Two have delivered a healthy infant at term and the third is currently in her second trimester of pregnancy. Hence, our case series supports a future clinical trial to determine the efficacy of combination gefitinib and methotrexate to treat non-tubal ectopic pregnancies.

SUBMITTER: Horne AW

PROVIDER: S-EPMC4059335 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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Combination gefitinib and methotrexate treatment for non-tubal ectopic pregnancies: a case series.

Horne A W AW Skubisz M M MM Tong S S Duncan W C WC Neil P P Wallace E M EM Johns T G TG

Human reproduction (Oxford, England) 20140507 7

Non-tubal ectopic pregnancies are a rare subgroup of ectopic pregnancies implanted at sites other than the Fallopian tube. Mortality from non-tubal ectopic pregnancies is higher compared with that for tubal ectopic pregnancies, and they are becoming more common, partly due to the rising incidence of Caesarean sections and use of assisted reproductive technologies. Non-tubal ectopic pregnancies can be especially difficult to treat. Surgical treatment is complex, and follow-up after medical treatm ...[more]

PMID: 24812320

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Project description:BackgroundTubal ectopic pregnancy (tEP) is the most common life-threatening condition in gynaecology. Treatment options include surgery and medical management. Stable women with tEPs with pre-treatment serum human chorionic gonadotrophin (hCG) levels <?1000 IU/L respond well to outpatient medical treatment with intramuscular methotrexate. However, tEPs with hCG >?1000 IU/L can take significant time to resolve with methotrexate and require multiple outpatient monitoring visits. In pre-clinical studies, we found that tEP implantation sites express high levels of epidermal growth factor receptor. In early-phase trials, we found that combination therapy with gefitinib, an orally active epidermal growth factor receptor antagonist, and methotrexate resolved tEPs without the need for surgery in over 70% of cases, did not cause significant toxicities, and was well tolerated. We describe the protocol of a randomised trial to assess the efficacy of combination gefitinib and methotrexate, versus methotrexate alone, in reducing the need for surgical intervention for tEPs.Methods and analysisWe propose to undertake a multi-centre, double-blind, placebo-controlled, randomised trial (around 70 sites across the UK) and recruit 328 women with tEPs (with pre-treatment serum hCG of 1000-5000 IU/L). Women will be randomised in a 1:1 ratio by a secure online system to receive a single dose of intramuscular methotrexate (50 mg/m2) and either oral gefitinib or matched placebo (250 mg) daily for 7 days. Participants and healthcare providers will remain blinded to treatment allocation throughout the trial. The primary outcome is the need for surgical intervention for tEP. Secondary outcomes are the need for further methotrexate treatment, time to resolution of the tEP (serum hCG ??15 IU/L), number of hospital visits associated with treatment (until resolution or scheduled/emergency surgery), and the return of menses by 3 months after resolution. We will also assess adverse events and reactions until day of resolution or surgery, and participant-reported acceptability at 3 months.DiscussionA medical intervention that reduces the need for surgery and resolves tEP faster would be a favourable treatment alternative. If effective, we believe that gefitinib and methotrexate could become standard care for stable tEPs.Trial registrationISRCTN Registry ISRCTN67795930 . Registered 15 September 2016.

Project description:IntroductionTubal ectopic pregnancy (tEP) is the most common life-threatening condition in gynaecology. tEPs with pretreatment serum human chorionic gonadotrophin (hCG) levels <1000 IU/L respond well to outpatient medical treatment with intramuscular methotrexate (MTX). TEPs with hCG >1000 IU/L take a significant time to resolve with MTX and require multiple outpatient monitoring visits. Gefitinib is an orally active epidermal growth factor receptor (EGFR) antagonist. In preclinical studies, we found that EP implantation sites express high levels of EGFR and that gefitinib augments MTX-induced regression of pregnancy-like tissue. We performed a phase I toxicity study administering oral gefitinib and intramuscular MTX to 12 women with tEPs. The combination therapy did not cause significant toxicities and was well tolerated. We noted that combination therapy resolved the tEPs faster than MTX alone. We now describe the protocol of a larger single arm trial to estimate the efficacy and side effects of combination gefitinib and MTX to treat stable tEPs with hCG 1000-10 000 IU/L METHODS AND ANALYSIS: We propose to undertake a single-arm multicentre open label trial (in Edinburgh and Melbourne) and recruit 28 women with tEPs (pretreatment serum hCG 1000-10 000 IU/L). We intend to give a single dose of intramuscular MTX (50 mg/m(2)) and oral gefitinib (250 mg) daily for 7 days. Our primary outcome is the resolution of EP to non-pregnant hCG levels <15 IU/L without requirement of surgery. Our secondary outcomes are comparison of time to resolution against historical controls given MTX only, and safety and tolerability as determined by clinical/biochemical assessment.Ethics and disseminationEthical approval has been obtained from Scotland A Research Ethics Committee (MREC 11/AL/0350), Southern Health Human Research Ethics Committee B (HREC 11180B) and the Mercy Health Human Research Ethics Committee (R12/25). Data will be presented at international conferences and published in peer-reviewed journals.Trial registration numberACTRN12611001056987.

Project description:BackgroundTo evaluate the ophthalmic manifestations and radiographic features of ectopic orbital meningioma to improve diagnostic accuracy.MethodsPatient data from patients admitted to our institution during a 217-month period from August 1999 to September 2017 were included. Patient ophthalmic manifestations, radiographic features (CT and MRI), diagnosis, pathology, therapeutic regimens, and prognosis were retrospectively reviewed.ResultsSix patients with ectopic orbital meningioma were identified. The mean age at the first visit was 33.2 years (range, 7-56 years). All six patients displayed manifestations of exophthalmos, upper eyelid oedema, and motility impairment with a mean history of illness of 20.3 months (range 3-72 months). Optical lesions were located in the superonasal extraconal compartment (3/6, 50%), bitemporal extraconal compartment (1/6, 16.7%) and orbital intraconal compartment (2/6, 33%). Radiographic features were ill-defined, heterogeneous, enhancing soft tissue masses with extraocular muscular adhesion (6/6, 100%) and calcification (1/6, 16.7%), not adjacent to the optic nerve and not extending along the dura. Six cases were treated intraoperatively with complete surgical resection, indicating that all lesions were independent of the optic nerve and sphenoid ridge. The histopathologic classification was mostly of meningothelial cells (5/6, 83%). Immunohistochemistry revealed EMA and vimentin to have positive expression in all six cases, while two cases were calponin-positive and strongly expressed in the olfactory bulb. Postoperatively, lesions caused no visual impairment, and there were no cases of recurrence.ConclusionsEctopic orbital meningiomas are rare tumours that are not easily diagnosed without postoperative histopathology. This report highlights some of the distinguishing features of isolated orbital lesions, especially around the location of frontoethmoidal suture. Accompanying upper eyelid oedema and eye mobility restriction were observed to be dissimilar to other orbital tumours. In these cases, a diagnosis of ectopic orbital meningioma should be considered.

Dataset Information

Combination gefitinib and methotrexate treatment for non-tubal ectopic pregnancies: a case series.

Publications

Combination gefitinib and methotrexate treatment for non-tubal ectopic pregnancies: a case series.

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