英国爱丁堡大学Andrew W Horne团队研究了吉非替尼联合甲氨蝶呤治疗输卵管异位妊娠的疗效与安全性。该项研究成果发表在2023年2月1日出版的《柳叶刀》杂志上。

输卵管异位妊娠可导致严重的发病率甚至死亡。目前的治疗方法是甲氨蝶呤或手术。约有30%的女性接受甲氨蝶呤治疗失败，随后需要进行抢救性手术。表皮生长因子受体抑制剂吉非替尼可能会改善甲氨蝶呤的疗效。研究组评估了口服吉非替尼联合甲氨蝶呤治疗与单独甲氨蝶呤治疗输卵管异位妊娠的疗效。

研究组在英国50家医院进行了一项多中心、随机、双盲、安慰剂对照试验。被诊断为输卵管异位妊娠的参与者接受单剂量肌肉注射甲氨蝶呤（50 mg/m²），并随机（1：1比例）7天额外口服吉非替尼（每日250 mg）或安慰剂。通过意向治疗分析，主要结局是手术干预以解决异位妊娠。次要结局包括异位妊娠和严重不良事件的解决时间。

2016年11月2日至2021年10月6日，328名参与者被分配使用甲氨蝶呤和吉非替尼（n=165）或甲氨蝶啶和安慰剂（n=163）治疗。安慰剂组中有3名参与者退出。吉非替尼组165名参与者中有50名（30%）进行了手术干预，安慰剂组160名参与者中有47名（29%），调整后风险比为1.15。在没有手术干预的情况下，吉非替尼组和安慰剂组的中位缓解时间分别为28.0天和28.0天。吉非替尼组165名参与者中有5名（3%）发生严重不良事件，安慰剂组162名参与者中有6名（4%）。吉非替尼组腹泻和皮疹更常见。

研究结果表明，对于输卵管异位妊娠的女性，口服吉非替尼与胃肠外甲氨蝶呤相比没有临床益处，并增加了轻微的不良反应。

附：英文原文

Title: Combination of gefitinib and methotrexate to treat tubal ectopic pregnancy (GEM3): a multicentre, randomised, double-blind, placebo-controlled trial

Author: Andrew W Horne, Stephen Tong, Catherine A Moakes, Lee J Middleton, W Colin Duncan, Ben W Mol, Lucy H R Whitaker, Davor Jurkovic, Arri Coomarasamy, Natalie Nunes, Tom Holland, Fiona Clarke, Ann M Doust, Jane P Daniels, Amna Ahmed, Hazel Alexander, Sonal Anderson, Rita Arya, Gabriel Awadzi, Miriam Baumgarten, Renee Behrens, Kelly Bingham, Cecilia Bottomley, Tom Bourne, Ying Cheong, Justin Chu, Frances Collins, Janet Cresswell, Sangeetha Devarajan, Punukollu Durgadevi, Umo Esen, Radwan Faraj, Priscilla Fernandez, Joanne Fletcher, Benjamin Galea, Ingrid Granne, Pratima Gupta, Susannah Hogg, Shahzya Huda, Sucheta Iyengar, Ngozi Izuwah-Njoku, Feras Izzat, Thangamma Katimada-Annaiah, Pinky Khatri, Kathleen King, Emma Kirk, Chitra Kumar, Geeta Kumar, Louise Linsell, Mayank Madhra, Krupa Madhvani, Rebecca McKay, Fouzia Memon, Usha Menon, Shruti Mohan, Scott Nelson, Helena Nik, Hema Nosib, Jerry Oghoetuoma, Abigail Oliver, Binita Pande, Mamta Pathak, Alexandra Peace-Gadsby, Janaki Putran, Sundararajah Raajkumar, Vinita Raheja, Malar Raja, Gautam Raje, Sandhya Rao, Penny Robshaw, Faye Rodger, Jackie Ross, Sherif Saleh, Sridevi Sankharan, Mona Sharma, Sanjay Sinha, Kate Stewart, Lauren Sutherland, Rebecca Thompson, Sakunthala Tirumuru, Nicola Watson, Sandra Watson, Ursula Winters, Catherine Wykes

Issue&Volume: 2023-02-01

Abstract:

Background

Tubal ectopic pregnancies can cause substantial morbidity or even death. Current treatment is with methotrexate or surgery. Methotrexate treatment fails in approximately 30% of women who subsequently require rescue surgery. Gefitinib, an epidermal growth factor receptor inhibitor, might improve the effects of methotrexate. We assessed the efficacy of oral gefitinib with methotrexate, versus methotrexate alone, to treat tubal ectopic pregnancy.

Methods

We performed a multicentre, randomised, double-blind, placebo-controlled trial across 50 UK hospitals. Participants diagnosed with tubal ectopic pregnancy were administered a single dose of intramuscular methotrexate (50 mg/m2) and randomised (1:1 ratio) to 7 days of additional oral gefitinib (250 mg daily) or placebo. The primary outcome, analysed by intention to treat, was surgical intervention to resolve the ectopic pregnancy. Secondary outcomes included time to resolution of ectopic pregnancy and serious adverse events. This trial is registered at the ISRCTN registry, ISCRTN 67795930.

Findings

Between Nov 2, 2016, and Oct 6, 2021, 328 participants were allocated to methotrexate and gefitinib (n=165) or methotrexate and placebo (n=163). Three participants in the placebo group withdrew. Surgical intervention occurred in 50 (30%) of 165 participants in the gefitinib group and in 47 (29%) of 160 participants in the placebo group (adjusted risk ratio 1·15, 95% CI 0·85 to 1·58; adjusted risk difference –0·01, 95% CI –0·10 to 0·09; p=0·37). Without surgical intervention, median time to resolution was 28·0 days in the gefitinib group and 28·0 days in the placebo group (subdistribution hazard ratio 1·03, 95% CI 0·75 to 1·40). Serious adverse events occurred in five (3%) of 165 participants in the gefitinib group and in six (4%) of 162 participants in the placebo group. Diarrhoea and rash were more common in the gefitinib group.

Interpretation

In women with a tubal ectopic pregnancy, adding oral gefitinib to parenteral methotrexate does not offer clinical benefit over methotrexate and increases minor adverse reactions.

DOI: 10.1016/S0140-6736(22)02478-3

Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(22)02478-3/fulltext