gynecology and obstetrics
Gestational Trophoblastic Disease
Treatment of Gestational Trophoblastic Disease
Tumor removal by suction curettage or hysterectomy (if fertility is not desired, especially if women > 40 years) Further evaluation for persistent disease and spread of tumor Chemotherapy for persistent disease Posttreatment contraception for persistent disease (See alsoNational Comprehensive Cancer Network (NCCN): NCCN Clinical Practice Guidelines in Oncology: Gestational Trophoblastic Neoplasia.) Usually, any type of gestational trophoblastic disease can be successfully diagnosed and treated and fertility can be preserved. Desire to preserve fertility should be discussed when planning treatment for gestational trophoblastic disease. Hydatidiform mole, invasive mole, placental site trophoblastic tumor, and epithelioid trophoblastic tumor are evacuated by suction curettage. Alternatively, if childbearing is not planned, hysterectomy may be done. A chest x-ray is taken. Serum beta-hCG is measured serially. Effective contraception is recommended while hCG is being monitored. If the beta-hCG level does not normalize within 10 weeks, the disease is classified as persistent. Persistent disease requires CT of the brain, chest, abdomen, and pelvis. Results dictate whether disease is classified as nonmetastatic or metastatic. Persistent disease is usually treated with chemotherapy. Treatment is considered successful if at least 3 consecutive serum beta-hCG measurements at 1-week intervals are normal. Pregnancy should be prevented for 6 months after treatment because pregnancy would increase beta-hCG levels, making it difficult to determine whether treatment has been successful. Typically, oral contraceptives are given for 6 months; alternatively, any effective contraceptive method can be used. For most types of gestational trophoblastic neoplasia, chemotherapy is the primary treatment. Low-risk metastatic disease can be cured, often with a single chemotherapy agent (eg,methotrexate, actinomycin D [dactinomycin]). Multidrug chemotherapy is an acceptable alternative. ( Treatment references ). TheNational Comprehensive Cancer Network guidelines(NCCN) recommends multidaymethotrexateormethotrexate/folate regimens. If patients have contraindications tomethotrexateregimens, actinomycin D regimens are recommended. Serum hCG levels are monitored during chemotherapy and after normalization of hCG levels. Usually, additional cycles of consolidation therapy are given. Hysterectomy shortens the duration and amount of chemotherapy needed for remission in patients with low-risk disease. After hysterectomy, patients still require chemotherapy and serum hCG monitoring. If treatment is successful, hCG levels should decrease by ≥ 10% over three cycles of treatment. An alternative treatment is needed if there is significant toxicity or if hCG levels Do not decrease as expected. Increase > 10% over two cycles For patients previously treated with multi-daymethotrexateregimens, 5-day actinomycin D is recommended. All patients with high-risk gestational trophoblastic neoplasia (WHO risk score > 6) should be referred to specialists. High-risk metastatic disease requires aggressive multidrug chemotherapy because patients are likely to develop resistance if a single drug is used. EMA-CO is the most widely used regimen. It consists ofetoposide,methotrexate, plusdactinomycin(EMA), alternating withcyclophosphamideplusvincristine(CO). Surgery and/or radiation therapy are often part of primary treatment. Survival rates in specialized centers exceed 86% ( Treatment references ). A meta-analysis included 2276 patients with high-risk gestational trophoblastic neoplasia; treatments included chemotherapy in 99.7%, surgery in 35.8%, and radiation in 4.9%. Complete response to primary chemotherapy was 79.7%, and the mortality rate was 10%. The most frequently used chemotherapy regimens were EMA/CO or EMA/EP, which were associated with lower mortality than other chemotherapy regimens (8.1% versus 12.4%, odds ratio 0.42) and higher likelihood of complete response (75.9% versus 60.7%, odds ratio 2.98). The study concluded that chemotherapy (EMA/CO or EMA/EP) was associated with improved outcomes. Mortality was higher in patients with ultra-high-risk, relapsed, and disease after a term pregnancy ( Treatment of high-risk gestational trophoblastic neoplasia resistant to initial chemotherapy is difficult. Options include EMA/EP (etoposide/methotrexate/actinomycin D/etoposide/cisplatin) Paclitaxel/etoposidealternating withcisplatin/etoposide Multi-dayetoposide/cisplatinregimens High-dose chemotherapy with stem cell support Programmed death receptor 1 (PD-1) is present in almost all gestational trophoblastic disease lesions. Some patients with drug-resistant gestational trophoblastic neoplasia have been treated with checkpoint inhibitors (pembrolizumab,avelumab) with some benefit. Cure rates are Low-risk: 90 to 95% ( Treatment references ) High-risk: 60 to 80% ( Treatment references ) Risk of disease progression and resistance to single-drug chemotherapy is determined by the FIGO staging system and the WHO risk scoring system. Gestational trophoblastic disease is considered low risk if it is one of the following: FIGO stage I (persistently elevated beta-hCG level and/or tumor confined to the uterus) FIGO stage II or III with a WHO risk score of ≤ 6 Gestational trophoblastic disease is considered high risk if it is one of the following: FIGO stages II and III with a WHO risk score of > 6 FIGO stage IV After remission of gestational trophoblastic neoplasia (normalization of hCG levels), hCG levels should be measured at 2-week intervals during the first 3 months, then at monthly intervals for at least 12 months. After 12 months, risk of recurrence is < 1%; risk is higher for patients with high-risk disease. In patients with high-risk disease, hCG levels should be measured at 6- to 12-month intervals after the first 12 months of remission. Oral contraceptives during chemotherapy and the 12 months after remission are recommended. 1.Hao J, Zhou W, Zhang M, et al: Direct comparisons of efficacy and safety between actinomycin-D andmethotrexatein women with low-risk gestational trophoblastic neoplasia: a meta-analysis of randomized and high-quality non-randomized studies.BMC Cancer21(1):1122, 2021. Published 2021 Oct 18. doi:10.1186/s12885-021-08849-7 2.Ngan HYS, Seckl MJ, Berkowitz RS, et al: Update on the diagnosis and management of gestational trophoblastic disease.Int J Gynecol Obstet143:79–85, 2018. doi: 10.1002/ijgo.12615 3.Albright BB, Ellett T, Knochenhauer HE, et al: Treatments and outcomes in high-risk gestational trophoblastic neoplasia: A systematic review and meta-analysis.BJOG130(5):443-453, 2023. doi:10.1111/1471-0528.17374 4.Goldstein DP, Berkowitz RS, Horowitz NS: Optimal management of low-risk gestational trophoblastic neoplasia.Expert Rev Anticancer Ther15(11):1293-1304, 2015. doi:10.1586/14737140.2015.1088786 5.Savage P, Kelpanides I, Tuthill M, Short D, Seckl MJ: Brain metastases in gestational trophoblast neoplasia: an update on incidence, management and outcome.Gynecol Oncol137(1):73-76, 2015. doi:10.1016/j.ygyno.2015.01.530 