Chemotherapy is highly effective in most patients with GTN. Cure rates of 100% in low-risk disease and 80% to 90% in high-risk cases are reported from a number of treatment centers.29 Despite the success of chemotherapy, the role of other modalities such as surgery and radiation therapy should not be overlooked. The best results are achieved when patients are treated under the auspices of a multidisciplinary team.
Low-Risk Disease
Most patients with low-risk GTN (risk score <7) including all cases of nonmetastatic disease and most cases of postmolar metastatic disease have survival rates that approach 100% when treated with monotherapy with either methotrexate (MTX) or actinomycin D (actD).29 A number of different regimens are currently in use (Table 75.2). A recently reported study compared biweekly intravenous actD and weekly intramuscular MTX regimens, and showed that the biweekly actD regimen was associated with a statistically significantly higher complete response rate.28 Overall, the weekly intramuscular or intermittent continuous intravenous infusion MTX regimens are thought to be less effective than the daily (for 5 days) MTX or the 8-day alternating MTX/leucovorin regimens.30 Lurain et al.31 analyzed their experience using secondary actD in patients with MTX resistance and found a 75% complete response rate. The patients who were resistant to both MTX and actD ultimately achieved complete response with multiagent salvage therapy.31 Maesta et al.,32 using multivariate analysis, studied prognostic factors that affect time to remission in low-risk GTN and concluded that complete molar histology, metastases, the use of multiagent therapy, and higher FIGO score were the main factors associated with longer time to remission. Chapman-Davis et al.33 stressed the importance of dose-intensive treatment in patients with low-risk GTN treated initially with 5-day MTX. Shah et al.34 performed a cost analysis of single-agent chemotherapy in low-risk GTN and concluded that 8-day MTX-folinic acid was consistently less expensive than actD.
MTX with folinic acid is the initial choice at the New England Trophoblastic Disease Center for low-risk GTN because it has the least toxicity and a high rate of response.35 Courses are administered at 2-week intervals until the serum beta-hCG level becomes undetectable. The results of a recent study from the Netherlands and United Kingdom suggest that three rather than two additional courses of consolidation therapy should be administered after patients achieve remission to reduce the likelihood of relapse.36 ActD is used when the patient develops resistance to MTX or if there is evidence of MTX-induced abnormal liver function tests. Patients with low-risk GTN who develop resistance to sequential monotherapy should be switched to a multidrug regimen such as MTX, actD, and cyclophosphamide in lower-volume disease (Table 75.3); or etoposide, MTX, actD, cyclophosphamide, and vincristine (EMA/CO) for large-volume disease (Table 75.4).37 Remission is defined as an undetectable hCG level for 3 consecutive weeks. Hysterectomy with ovarian preservation should also be considered as primary therapy for patients with stage I disease who have completed their family. It is advisable to administer adjunctive chemotherapy at the time of surgery because of the risk of occult disease.38
After attaining undetectable hCG levels, patients should be followed with monthly hCG levels for 12 months. During this time, effective contraception is mandatory and also serves the useful purpose of suppressing pituitary hCG which can falsely suggest residual disease.39 Pregnancy may be undertaken after 1 year of normal hCG titers.
High-Risk Disease
Dose-intensive multiple-agent chemotherapy should be used initially in all patients with stage II and III disease whose prognostic scores are >6 and all patients with stage IV disease.40 Table 75.4 summarizes the most widely used regimens including EMA/CO and etoposide, MTX, actD, and cisplatin (EMA/EP), which are associated with cure rates ranging from 70% to 90%. Cagayan41 reported a remission rate of 72% with the primary use of EMA/CO and an overall survival rate of 86%. Despite the success of EMA/CO, roughly 30% to 40% of women with high-risk disease will have an incomplete response to first-line multiagent therapy or will relapse from remission and will need additional multiagent chemotherapy with potentially other multimodality treatment. An alternative regimen containing cisplatin (EMA/EP) should be used as salvage therapy for patients who develop resistance to EMA/CO.42 A recent Cochrane Database review of chemotherapy for resistant or recurrent GTN recognizes the efficacy of a number of platinum/etoposide combinations.43 5-Fluorouracil has also been shown to be an active agent in the management of this disease in both low-risk and high-risk patients.44 The Charing Cross group has reported that the use of induction low-dose etoposide 100 mg/m2, and cisplatin 20 mg/m2 (days 1 and 2 every 7 days) in selected patients with high tumor burden may almost completely eliminate early mortality that may result from respiratory compromise and hemorrhage.45 They also report a 94% remission rate with EMA/CO by carefully excluding nongestational tumors in patients with atypical presentation using genetic analysis. Treatment should be dose-intensive every 2 to 3 weeks, toxicity permitting. The use of granulocyte colony-stimulating factor and, when absolutely necessary, platelet transfusions are important to maintain adequate dose-intensity and to prevent unnecessary dose reduction. Treatment should be continued until the hCG level becomes undetectable and remains undetectable for 3 consecutive weeks. The administration of four courses of the remission regimen after the patient achieves remission is recommended to reduce relapse.46
Role of Radiation Therapy
Radiation therapy has little application in patients with GTN except in selected patients with cerebral metastases. The use of whole brain or localized radiation therapy in conjunction with chemotherapy can prevent a life-threatening or debilitating hemorrhage and should be initiated promptly.47 An alternative to the use of radiation for cerebral metastases is the use of intrathecal MTX in combination with multiagent chemotherapy, particularly in the presence of meningeal involvement.48
Role of Surgery
Surgery also plays an important role in the management of high-risk patients.49 Hysterectomy in patients with heavy bleeding, large bulky intrauterine disease, or in the presence of significant pelvic sepsis should be performed regardless of the patient’s parity.38 Removal of tumor masses in the bowel should also be performed because of the risk of hemorrhage. Unresponsive masses in the liver, kidneys, and spleen should be removed, although embolization has been used with some success in controlling liver metastases.
Although pulmonary disease is usually chemosensitive, resection of persistent lung nodules can be curative and should be considered when the metastasis is solitary, limited to one lung, and the beta-hCG <1,000.50 Normalization of beta-hCG within 1 to 2 weeks after resection of a pulmonary lesion is a good indication of a positive outcome. Alifrangis et al.51
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