**4. The comparison of etoposide and methotrexate efficacies on tubal pregnancy treatment**

Etoposide, an antineoplastic agent, can produce cytotoxic effects by damaging DNA, thereby inhibiting or altering DNA synthesis. The drug appears to be cell-cycle dependent and cyclephase specific, inducing G2 phase arrest and killing cells in the G2 and late S phases. In 2002, Chen et al. successfully used a ultrasound-guided direct injection of etoposide to treat an interstitial pregnancy (C. L. Chen, et al., 2002). Based on the finding that etoposide was more effective and had fewer side effects in the management of low-risk gestational trophoblastic tumor, compared to methotrexate treatment (Matsui, et al., 2005), direct injection of etoposide for ectopic pregnancy is considered. Local administration of methotrexate was described in several cases (Hung, et al., 1996; Monteagudo, Minior, Stephenson, Monda, & Timor-Tritsch, 2005; Timor-Tritsch, et al., 1994). On the other aspect, the use of etoposide in ectopic pregnancy is relatively new. The standardized protocol is not yet available, although there were few cases used ultrasound-guided direct injection of etoposide to treat ectopic pregnancy (C. H. Chen, et al., 2009; C. L. Chen, et al., 2002; Juan, et al., 2008).

From 1993 through 2009, 28 patients of tubal pregnancy received local injection of methotrexate or etoposide were documented. In all cases, age, body weight, hemoglobin level and the operation time were recorded. The gestational age, cardiac activity of the conceptus, β-hCG levels before and after the treatment, and the occurrence and outcomes of subsequent pregnancies were evaluated. Among the enrolled patients, methotrexate has been administered locally to 11 patients and etoposide to 17 patients. In group (I), 50 mg of etoposide was injected into the ectopic sites by laparoscopy. In group (II), 50 mg of methotrexate was applied. All patients were followed up with serial β-hCG level monitoring. None of the patients had significant side effects of systemic treatment of the agents. More than 50% of the patients had a gestational size of greater than 30 mm.

The administration of methotrexate locally was chosen to avoid the adverse effect of systemic administration of methotrexate. Hung et al. observed that methotrexate alone or combined with procedures such as curettage or cervical tamponade is effective in ectopic pregnancies of up to 12 weeks (Hung, et al., 1996). In this survey, the median (range) of the time it took to decline to the non-pregnant β-hCG level (undetectable or below 5 mIU/mL) of methotrexate injection group was longer than the etoposide injection group, though not significant difference is observed (Table 1).

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Table 1. Baseline characteristics of the enrolled women

There is still no consensus about the most appropriate treatment for ectopic pregnancy. Therefore, large prospective randomized trials are still needed to establish common selection criteria, dosage, and length of follow up of the therapies. Furthermore, to increase the success rate, experiences in invasive ultrasound-guided procedures is indeed crucial for the success of this treatment option, but careful selection of patients and their compliance is also important. In this study, local injection of 50 mg etoposide to treat ectopic pregnancy was evaluated and compared with local injection of methotrexate. In women who desire future pregnancy, these two types of conservative treatment may be an acceptable and promising alternative in the management of ectopic pregnancy. Taken together, a local injection of etoposide might be a good choice for ectopic pregnancy.
