Multi-agent chemotherapy is standard for the initial management of high-risk gestational trophoblastic neoplasia (GTN). A systematic literature review revealed only one randomized controlled trial (and no high-quality trials)—conducted in the 1980s—comparing multiagent chemotherapy regimens for high-risk GTN. In the trial, only 42 women were randomly assigned to either a CHAMOMA regimen (i.e., methotrexate, folinic acid, hydroxyurea, dactinomycin, vincristine, melphalan, and doxorubicin) or MAC (i.e., methotrexate, dactinomycin, and chlorambucil). There was substantially more life-threatening toxicity in the CHAMOMA arm and no evidence of higher efficacy. However, there were serious methodologic problems with this trial. It was reportedly designed as an equivalency trial, but owing to the small sample size, the trial was inadequately powered to assess equivalence. In addition, the characteristics of the patients randomly assigned to the two study arms were not reported (although the authors stated that there were no major differences in the patient populations assigned to each arm), nor was the method of randomization or allocation concealment described.
There are no randomized trials comparing regimens in common use to establish the superiority of one over another. Therefore, the literature does not permit firm conclusions about the best chemotherapeutic regimen.[Level of evidence 3iiiDii] However, since EMA/CO (i.e., etoposide, methotrexate, and dactinomycin/cyclophosphamide and vincristine) is the most commonly used regimen, the specifics are provided in Table 2 below.[3,4,5]
Table 2. Specifics of the EMA/CO Regimena,b,c
|IV = intravenously; PO = orally.|
|a Adapted from Bower et al.|
|b Adapted from Escobar et al.|
|c Adapted from Lurain et al.|
|1||Etoposide||100 mg/m2 IV for 30 min|
| ||Dactinomycin||0.5 mg IV push|
| ||Methotrexate||300 mg/m2 IV for 12 h|
|2||Etoposide||100 mg/m2 IV for 30 min|
| ||Dactinomycin||0.5 mg IV push|
| ||Folinic Acid||15 mg or PO every 12 h × 4 doses, beginning 24 h after the start of methotrexate|
|8||Cyclophosphamide||600 mg/m2 IV infusion|
| ||Vincristine||0.8–1.0 mg/m2 IV push (maximum dose 2 mg)|
Cycles are repeated every 2 weeks (on days 15, 16, and 22) until any metastases present at diagnosis disappear and serum beta-human chorionic gonadotropin (beta-hCG) has normalized, then the treatment is usually continued for an additional three to four cycles.
Results of a large, consecutive case series of 272 patients with up to 16 years of follow-up showed a complete remission rate of 78% using this regimen, results that are consistent with other case series in the literature that employed EMA/CO. More than two-thirds of the women who did not have a complete response or subsequently had disease recurrence could be salvaged with cisplatin-containing regimens (with or without resection of metastases), yielding a long-term cure rate of 86.2% (95% CI, 81.9%–90.5%).[Level of evidence: 3iiA] Among the women who had an intact uterus, about one-half of them retained their fertility. Patients with documented brain metastases received higher doses of systemic methotrexate as part of the EMA component (i.e., etoposide, methotrexate, folinic acid, and dactinomycin) of EMA/CO (1 g/m2 IV for 24 hours, followed by folinic-acid rescue, 15 mg orally every 6 hours for 12 doses starting 32 hours after methotrexate). Patients with brain metastases received an increased dose of systemic methotrexate of 1 g/m2 for 24 hours followed by folinic acid (15 mg orally every 6 hours for 12 doses starting 32 hours after methotrexate). Patients with lung metastases received cranial prophylaxis with irradiation and intrathecal methotrexate 12.5 mg every 2 weeks with the CO (i.e., cyclophosphamide and vincristine) cycles.