Methods
Institutional human research ethics approval was sought and obtained at both participating sites (Southern Health Human Research Ethics Committee B, 11180B, and Scotland A Research Ethics Committee, 11/AL/0350) to allow administration of combination gefitinib and methotrexate to eight women with non-tubal EPs, and written informed consent was obtained from each participant. The diagnosis of non-tubal EP was made according to set ultrasound diagnostic criteria (Jurkovic et al., 2003; Jurkovic, 2007) in combination with quantitative serum hCG measurement. Inclusion criteria required the women to be assessed as haemodynamically stable (with no pallor, postural change in blood pressure, syncope or pre-syncope, severe abdominal pain or signs of abdominal peritonism, as well as requiring a normal serum haemoglobin and haematocrit) and to have normal baseline white cell count, renal and hepatic indices. Exclusion criteria included severe dermatological, gastrointestinal and pulmonary comorbidities (systems most likely to be affected by combination treatment), allergy to gefitinib and/or methotrexate and Japanese ethnicity (the latter being an increased risk factor for gefitinib-associated interstitial lung disease).
Participants were treated with daily oral gefitinib 250 mg for 7 days in addition to 50 mg/m of i.m. methotrexate on Day 1. Quantitative serum hCG measurement was repeated on Day 4 and Day 7 of treatment, and initial treatment success was defined as a ≥15% fall in serum hCG between these two measurements. Additional doses of methotrexate at 50 mg/m were administered where this did not occur, or where there was a significant rise in the serum hCG between Day 1 and Day 4. Serum hCG was then measured weekly until there was complete resolution of the EP, defined as a serum hCG of ≤15 IU/l. Haematological, renal and hepatic blood indices were monitored at each visit.
Treatment outcome parameters recorded included time to resolution (days from first methotrexate dose until serum hCG <15 IU/l), safety, tolerability and complication rates. Side effects and symptoms were classified according to the Common Terminology and Criteria for Adverse Events (CTCAE) version 4.03 (National Cancer Institute, National Institutes of Health, U.S. Department of Health and Human Services, June 14, 2010). Participants were contacted at 3, 6 and 12 months post-treatment to document return of menstrual cycles and any subsequent fertility outcomes.