High-Risk Gestational Trophoblastic Neoplasia (FIGO Score ≥7) Treatment
Multiagent 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.[3-5]Table 2. Specifics of the EMA/CO Regimena,b,c
|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)|
|IV = intravenously; PO = orally.|
|aAdapted from Bower et al.|
|bAdapted from Escobar et al.|
|cAdapted from Lurain et al.|
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, and these results 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] Moreover, routinely when the addition of cisplatin plus etoposide was added to EMA/CO, a 9% improvement was reported in the survival results of these high-risk patients. Among the women who had an intact uterus, about 50% 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 intravenously [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.
Examples of other regimens that have been used include the following:
- MAC: Methotrexate, folinic acid, dactinomycin, and cyclophosphamide.
- Another MAC: Methotrexate, dactinomycin, and chlorambucil.
- EMA: Etoposide, methotrexate, folinic acid, and dactinomycin (EMA/CO without the CO).
- CHAMOCA: Methotrexate, dactinomycin, cyclophosphamide, doxorubicin, melphalan, hydroxyurea, and vincristine.
- CHAMOMA: Methotrexate, folinic acid, hydroxyurea, dactinomycin, vincristine, melphalan, and doxorubicin.
Brain metastases are associated with poor prognosis, particularly when liver metastases are also present.[7-9] However, even patients with brain metastases may achieve long-term remission in 50% to 80% of cases.[3,4,9] Patients with central nervous system (CNS) metastases receive additional therapy simultaneously with the initiation of systemic chemotherapy. Some centers utilize whole-brain irradiation (30 Gy in 2 Gy fractions) with or without intrathecal methotrexate. However, some investigators omit the cranial radiation, relying on replacement of the standard dose of methotrexate in the EMA/CO regimen with the higher dose of 1,000 mg/m2 IV for 24 hours on the first day, as noted above, to achieve therapeutic CNS levels.Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with high risk metastatic gestational trophoblastic tumor. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.References
- Deng L, Yan X, Zhang J, et al.: Combination chemotherapy for high-risk gestational trophoblastic tumour. Cochrane Database Syst Rev (2): CD005196, 2009. [PUBMED Abstract]
- Curry SL, Blessing JA, DiSaia PJ, et al.: A prospective randomized comparison of methotrexate, dactinomycin, and chlorambucil versus methotrexate, dactinomycin, cyclophosphamide, doxorubicin, melphalan, hydroxyurea, and vincristine in "poor prognosis" metastatic gestational trophoblastic disease: a Gynecologic Oncology Group study. Obstet Gynecol 73 (3 Pt 1): 357-62, 1989. [PUBMED Abstract]
- Bower M, Newlands ES, Holden L, et al.: EMA/CO for high-risk gestational trophoblastic tumors: results from a cohort of 272 patients. J Clin Oncol 15 (7): 2636-43, 1997. [PUBMED Abstract]
- Escobar PF, Lurain JR, Singh DK, et al.: Treatment of high-risk gestational trophoblastic neoplasia with etoposide, methotrexate, actinomycin D, cyclophosphamide, and vincristine chemotherapy. Gynecol Oncol 91 (3): 552-7, 2003. [PUBMED Abstract]
- Lurain JR, Singh DK, Schink JC: Management of metastatic high-risk gestational trophoblastic neoplasia: FIGO stages II-IV: risk factor score > or = 7. J Reprod Med 55 (5-6): 199-207, 2010 May-Jun. [PUBMED Abstract]
- Alifrangis C, Agarwal R, Short D, et al.: EMA/CO for high-risk gestational trophoblastic neoplasia: good outcomes with induction low-dose etoposide-cisplatin and genetic analysis. J Clin Oncol 31 (2): 280-6, 2013. [PUBMED Abstract]
- Small W Jr, Lurain JR, Shetty RM, et al.: Gestational trophoblastic disease metastatic to the brain. Radiology 200 (1): 277-80, 1996. [PUBMED Abstract]
- Crawford RA, Newlands E, Rustin GJ, et al.: Gestational trophoblastic disease with liver metastases: the Charing Cross experience. Br J Obstet Gynaecol 104 (1): 105-9, 1997. [PUBMED Abstract]
- Newlands ES, Holden L, Seckl MJ, et al.: Management of brain metastases in patients with high-risk gestational trophoblastic tumors. J Reprod Med 47 (6): 465-71, 2002. [PUBMED Abstract]