Approximately 95 % of patients with post-molar GTN have low- risk scores (0–6) and can anticipate a complete cure usually with single agents with preservation of reproductive function, if desired. Patients with stage I (non-metastatic) GTN who desire sterilization can opt for hysterectomy, although chemotherapy should still be administered to prevent persistent active disease due to occult metastases. A second D&C does not appear to have substantial therapeutic value, but may be necessary if the patient develops heavy bleeding due to retained products of conception [41, 42].

For most low-risk patients, monotherapy with methotrexate (MTX) or actinomycin D (ActD) is the preferred treatment [43]. A number of different regimens are currently in use which have been reported to achieve 50–90 % remissions (Table 21.3) [32, 43]. The wide variability results from differences in dose, frequency, route of administration, and patient selection [43, 44]. MTX with folinic acid (also called calcium leucovorin) rescue (MTXFA) is the initial choice at the New England Trophoblastic Disease Center because it is effective, well tolerated, convenient for the patient, and cost effective. There is no hair loss and only about 5 % of patients experience mouth ulcers, sore eyes, or rarely pleuritic or peritoneal pains from serositis [45]. ActD should be substituted for MTX if there is evidence of abnormal liver function tests. Courses are repeated every 2 weeks until the hCG level becomes undetectable. Patients with low-risk disease should receive three courses after remission is achieved to eliminate any residual tumor and reduce the chance of relapse [46]. Patients who develop resistance to MTXFA as determined by an inadequate response, plateau, or re-elevation of the hCG level, should be switched to ActD or multidrug therapy. The multidrug regimen we recommend for patients resistant to monotherapy consists of MTX, ActD, etoposide, cyclophosphamide and Vincristin (EMACO) (Table 21.4) [3]. Because survival in patients with low-risk disease is 100 %, the least toxic regimens should always be employed initially. Only 30 % of patients with a WHO score of 5–6 can be cured with monotherapy and should receive multidrug regimens initially. Characteristically these patients have hCG levels >100,000 mIU/ml and doppler ultrasound evidence of large tumor burden [47]. Remission is achieved when the hCG level becomes undetectable for three consecutive weeks. At this point the patient should be followed with monthly hCG levels for 12 months to detect relapse before becoming pregnant. During this time effective contraception is mandatory. The use of birth control pills has been shown to be safe [29]. However, we do not recommend insertion of intrauterine devices until the hCG level becomes undetectable because of the risk of uterine perforation, bleeding and infection if residual tumor is present. Pregnancy may be undertaken after 1 year of normal hCG values.

The primary treatment of patients with PSTT and ETT is surgical because of their relative resistance to chemotherapy. Lymph node sampling is recommended at the time of hysterectomy if there is evidence of deep myometrial invasion. Cures have been reported in patients with metastatic disease with a multidrug regimen consisting of etoposide, methotrexate, actinomycin D, and cisplatin (EMA/EP) particularly when the time interval from the antecedent pregnancy is <4 years (Table 21.6) 48–52]. Although not generally applicable, the efficacy of fertility-sparing surgery in select cases has been reported [53, 54].

Patients with FIGO stage IV and stages II-III whose scores are >6 are at high risk of developing drug resistance and should be treated initially with multiagent regimens. EMACO (Table 21.4), which consists of etoposide, MTX, ActD, Cytoxan and Oncovin, is the most widely used initial regimen for high-risk GTN since it is effective with cure rates ranging from 70 % to 90 %, and has predictable and easily managed short-term toxic effects [55–59]. A similar regimen, EMA/EP (Table 21.5), substituting cisplatin for Oncovin and Cytoxan, can be utilized as salvage therapy when resistance to EMACO occurs [60, 61]. Treatment should be dose-intensive every 2–3 weeks, toxicity permitting. Alopecia is universal as is myelosuppression, although the use of recombinant hematopoietic growth factors such as Granulocyte Colony Stimulating Factor (G-CSF) and, when absolutely necessary, platelet transfusions allow for continued treatment intensity and avoidance of neutropenic febrile episodes. Treatment should be continued until the hCG level becomes undetectable and remains undetectable for three consecutive weeks. Three to four courses of consolidation therapy is strongly recommended because the relapse rate in patients with high-risk disease can approach 10 % [62, 63]. Seckl and co-authors have reported that the cumulative 5-year survival rate of patients with high-risk disease treated with EMACO is between 75 % and 90 %. Long –term survival was only 27 % when liver metastases were present, 70 % with brain metastases, and 10 % with involvement of both sites. Deaths occurred in patients who presented with widespread disease frequently due to delayed diagnosis, from life-threatening complications such as respiratory failure and central nervous system hemorrhage, from the development of drug resistance, or from inadequate treatment [64]. The Charing Cross group has utilized 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 to almost completely eliminate early mortality which may result from respiratory compromise and hemorrhage [65].

The use of radiation therapy in patients with GTN is limited to the treatment of brain metastases where whole head or localized radiation therapy in conjunction with chemotherapy can prevent a life-threatening or debilitating hemorrhage and should be initiated promptly [66]. Solitary superficial cerebral lesions are best treated surgically [67].

Surgery should also be considered as an important adjunct in the management of high risk patients [68]. 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. Removal of tumor masses in the bowel should also be performed because of the risk of hemorrhage. Unresponsive masses in the liver and kidneys should be removed, although embolization has been used with some success in controlling liver metastases. Splenectomy should always be performed when that organ is involved. After completion of chemotherapy, patients with high- risk disease should be followed for 12–24 months before pregnancy is attempted.

Although late sequelae from chemotherapy are very rare, an increase incidence of risk of another cancer, most commonly leukemia, has been reported in association with etoposide making long-term surveillance in these patients warranted [69]. Recent data from the same institution indicates lower second cancer rates than previously reported, although patients may experience earlier menopause [70].

Chemoresistant or recurrent disease, usually encountered in patients with high-risk disease, poses a significant treatment challenge [32]. This group is characterized by multi-organ involvement. When resistance or relapse occurs, re-imaging should be performed to determine the feasibility of surgery. PET scanning can help to identify the site of active disease [37]. The half-life for hCG is 48 h or less after surgery if the disease has been completely removed. However, when surgery or radiation is not possible or successful, several salvage regimens can be utilized. Table 21.6 contains a list of the various salvage regimens that have been utilized successfully in the management of resistant/recurrent GTN. Although anecdotal successes have been reported with high-dose chemotherapy with peripheral stem-cell transplantation, this technique does not appear to cure many patients with refractory disease [71, 72].