The Evolution of Methotrexate as a Treatment for Ectopic Pregnancy and Gestational Trophoblastic Neoplasia: A Review

Methotrexate was developed in 1949 as a synthetic folic acid analogue to compete with folic acid and thus interfere with cell replication. While initially developed as a potential treatment for acute lymphoblastic leukaemia, a serendipitous observation led to methotrexate's use to effect the dramatic cure of a case of advanced choriocarcinoma. This prompted the exploration for the potential of methotrexate to treat other conditions involving disordered trophoblastic tissue. Methotrexate has subsequently revolutionized the treatment of two pregnancy-related conditions—gestational trophoblastic neoplasia and ectopic pregnancy. This article reviews the development of modern treatment protocols that use methotrexate to medically treat these two important gynaecological conditions

Using a decline in serum hCG between days 0-4 to predict ectopic pregnancy treatment success after single-dose methotrexate:a retrospective cohort study

<p>Abstract</p> <p>Background</p> <p>The current measure of treatment efficacy of single-dose methotrexate for ectopic pregnancy, is a fall in serum hCG of ≥15% between days 4–7 of treatment, which has a positive predictive value of 93% for treatment success. Two small studies have proposed a fall in serum hCG between days 0–4 after treatment confers similar, earlier prognostic information, with positive predictive values of 100% and 88% for treatment success. We sought to validate this in a large, independent cohort because of the potentially significant clinical implications.</p> <p>Methods</p> <p>We conducted a retrospective study of women (n=206) treated with single-dose methotrexate for ectopic pregnancy (pre-treatment serum hCG levels ≤3000 IU/L) at Scottish hospitals between 2006–2011. Women were divided into two cohorts based on whether their serum hCG levels rose or fell between days 0–4 after methotrexate. Treatment outcomes of women in each cohort were compared, and the test performance characteristics calculated. This methodology was repeated for the current measure (≥15% fall in serum hCG between days 4–7 of treatment) and an alternate early measure (<20% fall in serum hCG between days 0–4 of treatment), and all three measures were compared for their ability to predict medical treatment success.</p> <p>Results</p> <p>In our cohort, the positive predictive value of the current clinical measure was 89% (95% CI 84-94%) (121/136). A falling serum hCG between days 0–4 predicted treatment success in 85% (95% CI 79-92%) of cases (94/110) and a <20% fall in serum hCG between days 0–4 predicted treatment success in 94% (95% CI 88-100%) of cases (59/63). There was no significant difference in the ability of these tests to predict medical treatment success.</p> <p>Conclusions</p> <p>We have verified that a decline in serum hCG between days 0–4 after methotrexate treatment for ectopic pregnancies, with pre-treatment serum hCG levels ≤3000 IU/L, provides an early indication of likelihood of treatment success, and performs just as well as the existing measure, which only provides prognostic information on day 7.</p

Maternal Serum Macrophage Inhibitory Cytokine-1 as a Biomarker for Ectopic Pregnancy in Women with a Pregnancy of Unknown Location

Ectopic pregnancy (EP) occurs in 1-2% of pregnancies, but is over-represented as a leading cause of maternal death in early pregnancy. It remains a challenge to diagnose early and accurately. Women often present in early pregnancy with a 'pregnancy of unknown location' (PUL) and the diagnosis and exclusion of EP is difficult due to a lack of reliable biomarkers. A serum biomarker able to clearly distinguish between EP and other pregnancy outcomes would greatly assist clinicians in diagnosing and safely managing PULs. This study evaluates the ability of maternal serum macrophage inhibitory cytokine-1 (MIC-1) levels to differentiate between EP and other pregnancy outcomes in women with a PUL.Sera were collected from 120 women with a PUL at first clinical presentation and assayed for MIC-1 by ELISA. Results were classified according to ultimate pregnancy outcome and the discriminatory ability of MIC-1 to diagnose EP was assessed.Serum MIC-1 levels were lower in women with histologically confirmed (definite) EP (dEP) (median 552 ng/mL; interquartile range (IQR) 414-693 ng/mL) compared to women with definite viable intra-uterine pregnancies (dVIUPs) (722 ng/mL; IQR 412-1122 ng/mL), and higher when compared to women with definite non-viable intra-uterine pregnancies (dNVIUPs) (465 ng/mL; IQR 341-675 ng/mL). MIC-1 levels were significantly higher in women with dEP compared to women whose PULs resolved without medical intervention (srPUL) (401 ng/mL; IQR 315-475 ng/mL) (p<0.003). There were no women with an ectopic pregnancy where serum MIC-1>1000 ng/mL.Serum MIC-1 levels in PUL were not able to categorically diagnose EP, however, MIC-1 could distinguish women with an EP that required medical intervention and those women whose PULs spontaneously resolved. A single serum MIC-1 measurement also excluded EP at levels above 1000 ng/mL. MIC-1 may play a role in the development of a combined assay of biomarkers for the diagnosis of EP

Combination gefitinib and methotrexate to treat ectopic pregnancy: early phase clinical trials

This body of work examines novel diagnostics and therapeutics for ectopic pregnancy. The incidence of ectopic pregnancy is 1-2% of pregnancies, where implantation occurs outside of the endometrial cavity. It remains a leading cause of maternal death in early pregnancy. The management of ectopic pregnancy is predominantly surgical; this is mandated when rupture has occurred, however, only 5% of women present this way. The medical treatment option, consisting of single-dose methotrexate, has limited efficacy in treating more advanced ectopic pregnancies, so that only 25-30% of diagnosed women benefit from it. The introduction of epidermal growth factor receptor inhibitors such as gefitinib into the pharmaceutical lexicon has created a potentially novel approach to the treatment of trophoblastic tissue disorders. Pre-clinical experiments have shown that combining gefitinib with methotrexate effects significant, supra-additive regression of trophoblastic cells and tissues. The main aim of this PhD is to translate these findings into clinical practice, thereby improving the medical management of ectopic pregnancy. In a phase I dose-escalation toxicity study, we established the safety of combination gefitinib and methotrexate in 12 women with ectopic pregnancies currently eligible for medical management; combination treatment effected a more rapid decline in serum human chorionic gonadotrophin (hCG) levels and shortened the time to resolution compared to controls. We then applied combination treatment to larger and more complex non-tubal ectopic pregnancies; in a case series of 8 women, all were successfully treated with no undue toxicity caused. Subsequently, in a phase II study of 28 women, we confirmed combination gefitinib and methotrexate to be safe, well tolerated and effective at treating an extended range of ectopic pregnancies. To further improve diagnosis and management of ectopic pregnancy, we identified and investigated two novel biomarkers – adrenomedullin and macrophage inhibitory cytokine-1 (MIC-1). We could not confirm altered adrenomedullin expression in ectopic pregnancy, and correspondingly, it was not a useful biomarker of the condition. MIC-1 was able to exclude ectopic pregnancy above a certain threshold, demonstrating potential to form part of a panel of biomarkers for the diagnosis of the condition. We also validated that an early falling serum hCG is predictive of medical treatment success after single-dose methotrexate for ectopic pregnancy: in two studies examining 251 women, a fall in hCG between days 1-4 of treatment was 85-88% predictive of treatment success. Finally, we examined the potential of combination gefitinib and methotrexate to improve treatment of persistent gestational trophoblastic disease (pGTD), a rare form of pregnancy with malignant progression; in a separate phase I dose-escalation toxicity study, we found the combination to again be safe and well tolerated in 6 women, despite higher doses of methotrexate administered. Collectively, this work has contributed new approaches to the diagnosis and treatment of ectopic pregnancy and pGTD. It provides proof-in-principle evidence that combination gefitinib and methotrexate may be more effective in the treatment of ectopic pregnancy, underpinning future funding and investigation. It is my hope that this work will minimise the suffering of women diagnosed with these conditions

Combination gefitinib and methotrexate to treat ectopic pregnancy: early phase clinical trials

This body of work examines novel diagnostics and therapeutics for ectopic pregnancy. The incidence of ectopic pregnancy is 1-2% of pregnancies, where implantation occurs outside of the endometrial cavity. It remains a leading cause of maternal death in early pregnancy. The management of ectopic pregnancy is predominantly surgical; this is mandated when rupture has occurred, however, only 5% of women present this way. The medical treatment option, consisting of single-dose methotrexate, has limited efficacy in treating more advanced ectopic pregnancies, so that only 25-30% of diagnosed women benefit from it. The introduction of epidermal growth factor receptor inhibitors such as gefitinib into the pharmaceutical lexicon has created a potentially novel approach to the treatment of trophoblastic tissue disorders. Pre-clinical experiments have shown that combining gefitinib with methotrexate effects significant, supra-additive regression of trophoblastic cells and tissues. The main aim of this PhD is to translate these findings into clinical practice, thereby improving the medical management of ectopic pregnancy. In a phase I dose-escalation toxicity study, we established the safety of combination gefitinib and methotrexate in 12 women with ectopic pregnancies currently eligible for medical management; combination treatment effected a more rapid decline in serum human chorionic gonadotrophin (hCG) levels and shortened the time to resolution compared to controls. We then applied combination treatment to larger and more complex non-tubal ectopic pregnancies; in a case series of 8 women, all were successfully treated with no undue toxicity caused. Subsequently, in a phase II study of 28 women, we confirmed combination gefitinib and methotrexate to be safe, well tolerated and effective at treating an extended range of ectopic pregnancies. To further improve diagnosis and management of ectopic pregnancy, we identified and investigated two novel biomarkers – adrenomedullin and macrophage inhibitory cytokine-1 (MIC-1). We could not confirm altered adrenomedullin expression in ectopic pregnancy, and correspondingly, it was not a useful biomarker of the condition. MIC-1 was able to exclude ectopic pregnancy above a certain threshold, demonstrating potential to form part of a panel of biomarkers for the diagnosis of the condition. We also validated that an early falling serum hCG is predictive of medical treatment success after single-dose methotrexate for ectopic pregnancy: in two studies examining 251 women, a fall in hCG between days 1-4 of treatment was 85-88% predictive of treatment success. Finally, we examined the potential of combination gefitinib and methotrexate to improve treatment of persistent gestational trophoblastic disease (pGTD), a rare form of pregnancy with malignant progression; in a separate phase I dose-escalation toxicity study, we found the combination to again be safe and well tolerated in 6 women, despite higher doses of methotrexate administered. Collectively, this work has contributed new approaches to the diagnosis and treatment of ectopic pregnancy and pGTD. It provides proof-in-principle evidence that combination gefitinib and methotrexate may be more effective in the treatment of ectopic pregnancy, underpinning future funding and investigation. It is my hope that this work will minimise the suffering of women diagnosed with these conditions

Molecular diagnostics and therapeutics for ectopic pregnancy

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Serum MIC-1 levels in women at first presentation with a PUL, categorised according to final pregnancy outcome.

<p>Serum MIC-1 levels &gt;1000 ng/mL exclude EP.</p

Participant categorisation and baseline characteristics according to final pregnancy outcome (median ± SEM).

<p>Participant categorisation and baseline characteristics according to final pregnancy outcome (median ± SEM).</p

Phase II single arm open label multicentre clinical trial to evaluate the efficacy and side effects of combination gefitinib and methotrexate to treat ectopic pregnancies (GEM II) : study protocol

Peer reviewedPublisher PD