Primary treatment of metastatic high-risk gestational trophoblastic neoplasia with EMA-CO chemotherapy

OBJECTIVE: To evaluate the efficacy of etoposide, methotrexate, actinomycin D, cyclophosphamide and vincristine (EMA-CO) in the primary treatment of metastatic high-risk gestational trophoblastic neoplasia. STUDY DESIGN: Thirty women with metastatic high-risk gestational trophoblastic neoplasia were treated primarily with EMA-CO between 1986 and 2005. Patients who had incomplete responses or developed resistance to EMA-CO were treated with drug combinations employing etoposide and a platinum agent with or without bleomycin or ifosfamide. Adjuvant surgery and radiotherapy were used in selected patients. Survival, clinical response and factors affecting treatment success were analyzed retrospectively. RESULTS: The overall survival rate was 93.3% (28 of 30). Of the 30 patients treated with EMA-CO, 20 (66.7%) had a lasting clinical response, 8 (26.7%) developed resistance but were subsequently placed in remission with platinum-based chemotherapy, and 2 (6.7%) died of widespread metastatic disease. Clinical complete response to EMA-CO was significantly influenced by human chorionic gonadotropin level (<100,000 mIU/ mL, 82%, vs. > 100,000 mIU/mL, 46%), metastatic site (lung and pelvis, 75%, vs. other, 33%) and International Federation of Gynecology and Obstetrics (FIGO) risk factor score (< 7, 92% vs. >7, 50%). Surgical procedures were performed on 12 patients, and 4 patients received brain irradiation. Eight (80%) of 10 patients who received secondary platinum-based chemotherapy or without surgery were cured. The 2 patients who died had stage IV disease (brain and/or liver metastases) with FIGO scores of 13 and 14. CONCLUSION: Over 93% of 30 patients with metastatic high-risk gestational trophoblastic neoplasia treated initially with the EMA-CO protocol, often in conjunction with brain irradiation, surgical resection of sites of persistent tumor and salvage platinum-based chemotherapy, were cured.     

Salvage chemotherapy for high-risk gestational trophoblastic tumor

OBJECTIVE: To evaluate the efficacy and safety of etoposide/methotrexate/actinomycin D (MEA regimen) as initial chemotherapy and 5-fluorouracil/actinomycin D (FA regimen) as salvage chemotherapy for high-risk gestational trophoblastic tumor (GTT). STUDY DESIGN: From 1985 to 2001, 36 patients with World Health Organization (WHO)--defined high-risk GTT were treated with MEA or FA at Chiba University Hospital. Thirty-three patients were initially treated with MEA. FA was administered to 11 patients; 1 had had no previous chemotherapy, 7 had developed drug resistance to MEA, 1 had relapsed following MEA, and 2 had relapsed following etoposide/methotrexate/actinomycin D/ cyclophosphamide/vincristine (EMA/CO) combination chemotherapy. RESULTS: The primary remission rate with MEA was 69.7% (23 of 33). With FA the survival rate was 81.8% (9 of 11) for a mean follow-up period of 11.5 years. Two patients died due to multidrug resistance, and 2 patients relapsed subsequently. The 2 relapse cases were successfully salvaged again with MEA. The toxicity of FA was evaluated in 89 cycles. Myelosuppression seemed to be the dose-limiting toxicity, and the incidence of WHO grade 4 leukocytopenia and thrombocytopenia were 5.6% and 3.4%, respectively. CONCLUSION: Although etoposide-containing chemotherapy is currently the most effective and well tolerated regimen for high-risk GTT, 20-30% of patients develop drug resistance to these regimens. Salvage combination chemotherapy with FA is effective for refractory patients, and the toxicity is predictable and manageable.     

妊娠滋养细胞肿瘤化疗应当注意的问题

化疗是妊娠滋养细胞肿瘤的主要治疗手段,化疗耐药导致的疾病进展是妊娠滋养细胞肿瘤的主要致死因素。为达到最佳疗效,在应用化疗中应当注意以下4个方面的问题:(1)重视妊娠滋养细胞肿瘤诊治的特殊性,提倡由专科医生进行相对集中的化疗。(2)根据妊娠滋养细胞肿瘤的特点,合理、规范地进行化疗,并辅以必要的综合治疗。(3)重视化疗毒副反应的认识与处理,保障化疗安全、可行。(4)化疗是一个需要团队合作的系统工程,需要沟通、协作与培训。     

依托泊苷联合顺铂治疗高危、耐药及复发性妊娠滋养细胞肿瘤的疗效分析

目的探讨依托泊苷联合顺铂（EP）方案治疗高危、耐药及复发性妊娠滋养细胞肿瘤（GTN）的疗效及安全性。方法回顾性分析接受EP方案化疗的39例GTN患者的临床资料,其中初治高危患者25例,耐药患者9例,复发患者5例。39例患者中10例患者辅以手术治疗,所有患者均随访,观察其疗效及毒副反应,并追踪继发性肿瘤的发生情况和其中30例保留生育功能患者的生育情况。结果39例GTN患者共接受了221个疗程的EP方案化疗,平均疗程数5．7个,总的完全缓解率为74％（29／39）。其中,25例初冶高危患者总疗程数139个,平均疗程数5．6个,19例完全缓解,6例耐药,完全缓解率为76％（19／25）;9例耐药患者化疗总疗程数55个,平均疗程数为6．1个,6例获完全缓解,3例再次耐药,完全缓解率为6／9;5例复发患者化疗总疗程数27个,平均疗程数为5．4个,4例完全缓解,1例耐药死亡,完全缓解率为4／5。该方案主要的毒副反应是骨髓抑制、消化道反应及脱发,骨髓抑制较轻,均为Ⅰ-Ⅲ度,未发生致死性毒副反应。30例保留生育功能患者共获妊娠8例次,其中人工流产2例次,足月妊娠分娩6例次,共获新生儿6个,均无先天性畸形发生,随访期内（随访时间最长者5年）小儿牛长发育正常。所有存活患者尢继发性肿瘤发生。结论EP方案作为一种安全、有效的化疗方案,口丁用于高危、耐药及复发性GTN患者的治疗。     

Treatment of high-risk gestational trophoblastic neoplasia with weekly high-dose methotrexate-etoposide

ObjectiveTo assess toxicity and efficacy of weekly high-dose methotrexate–etoposide (HD MTX–ETO) in high-risk gestational trophoblastic neoplasia (GTN).MethodsRetrospective chart review of high-risk GTN patients treated with HD MTX–ETO (methotrexate 1000 mg/m² day 1, etoposide 100 mg/m² days 1 and 2, q 1 wk).Results134 cycles of HD MTX–ETO were administered to twelve patients; median number of cycles was 8 (range 2–39 cycles). Median follow up was 25.5 months (range 11–69). 7 of these patients switched due to ototoxicity from EP–EMA (etoposide 150 mg/m², cisplatin 75 mg/m² i.v. day 1; etoposide 100 mg/m², methotrexate 300 mg/m², dactinomycin 0.5 mg i.v. day 8, q 14 d) to HD MTX–ETO, after an average of 7 cycles of EP-EMA. Six achieved complete remission without disease recurrence. One patient with a placental site trophoblastic tumour died due to progressive disease. Five patients received HD MTX–ETO primarily; 1 patient with choriocarcinoma presenting with metastases to the brain and liver (WHO score 19) was switched to EP–EMA and died due to complications under EP–EMA. The other 4 achieved complete remission without disease recurrence.HD MTX–ETO was well tolerated; non-haematological toxicity was low except for alopecia and fatigue. Nine patients had grade 2–4 anaemia and received packed cells. Eight patients had grade 3–4 neutropenia and received G-CSF. Two patients developed febrile neutropenia without sepsis.ConclusionsThese preliminary results show a better toxicity profile with HD MTX–ETO than EP–EMA and encouraging efficacy. HD MTX–ETO might be a treatment option for some patients with high-risk GTN and needs further investigation.     

妊娠滋养细胞肿瘤的化疗

由于妊娠滋养细胞肿瘤(GTN)对化疗高度敏感,绒毛膜促性腺激素(HCG)可作为理想的肿瘤标志物,以及应用预后评分可使其治疗达到分层个体化,GTN成为了少数几个能通过化疗而达到治愈的肿瘤之一。文章介绍了近年来有关妊娠滋养细胞肿瘤化疗进展。     

Diagnosis and treatment of high-risk metastatic gestational trophoblastic neoplasia in Hungary

OBJECTIVE: To review results in treatment of high-risk metastatic gestational trophoblastic neoplasia (GTN) in Hungary. STUDY DESIGN: Between January 1, 1977, and December 31, 2006, 142 patients with high-risk metastatic GTN were treated. Patients were 14-51 years of age (average 27.9). We selected primary chemotherapy based on patient GTN stage and prognostic score. RESULTS: Methotrexate, actinomycin-D and cyclophosphamide (MAC) as a primary therapy was used in 100 cases and as second-line chemotherapy in 6 cases. Of the 100 cases, 95 achieved complete remission. Twenty-one high-risk patients were treated with etoposide, high-dose methotrexate with folinic acid rescue, actinomycin-D, cyclophosphamide and vincristine (EMA-CO). Of 17 primary therapies, 13 patients achieved complete remission. Primary cisplatin, etoposide and bleomycin (CEB) was successful in 12 of 14 high-risk cases. Hysterectomy was performed in 42 of 142 high-risk patients; metastases were resected in 26 of 142 of high-risk patients. Comparison of mean prognostic scores resulted in significant differences between CEB and MAC, CEB and EMA-CO and MAC and EMA-CO. CONCLUSION: Results support that patients with high-risk metastatic GTN should primarily be treated with combination chemotherapy. Our data support the effectiveness of MAC, EMA-CO and CEB regimens.     

Role of surgery in the management of high-risk gestational trophoblastic neoplasia

OBJECTIVE: To evaluate the role of surgery in the management of high-risk gestational trophoblastic neoplasia. STUDY DESIGN: Twenty-four (48%) of 50 patients treated with etoposide, methotrexate, actinomycin D, cyclophosphamide and vincristine (EMA-CO) regimen as primary or secondary chemotherapy for high-risk gestational trophoblastic neoplasia between 1986 and 2005 underwent 28 adjuvant surgical procedures. The procedures included hysterectomy (17), lung resection (5), salpingectomy (1), uterine wedge resection (1), small bowel resection (1), suturing of the liver or uterus for bleeding (2) and uterine artery embolization (1). RESULTS: Twenty-one (87.5%) of 24 patients who had surgical procedures as part of their treatment for high-risk disease survived. Fifteen (88%) of 17 patients undergoing hysterectomy were cured. Four (80%) of 5 patients who had resistant foci of choriocarcinoma in the lung were cured by pulmonary resection. The patients who had suturing of the uterus, uterine artery embolization, small bowel resection and salpingectomy for bleeding as well as the patient who had uterine wedge resection of resistant choriocarcinoma survived. CONCLUSION: Adjuvant surgical procedures, especially hysterectomy and pulmonary resection for chemotherapy-resistant disease as well as procedures to control hemorrhage, are important components in the management of high-risk gestational trophoblastic neoplasia. Twenty-four (48%) of 50 patients with high-risk gestational trophoblastic neoplasia in this series underwent surgical procedures, and 21 (87.5%) were cured.     

Risk factors for gestational trophoblastic neoplasia

A case-control study to determine the gynecologic and reproductive risk factors for gestational trophoblastic neoplasia was conducted in the Baltimore Metropolitan Area. All cases (N = 190) that were pathologically diagnosed from 1975 to 1982 as hydatidiform mole, invasive mole, or choriocarcinoma were ascertained. Slides were independently reviewed by two pathologists. Cases were matched by age, race, and last menstrual period to controls who were delivered of normal pregnancies at term. In the analysis of medical record and interview data, factors found to be positively associated with gestational trophoblastic neoplasia included professional occupations (odds ratio = 2.56, p less than 0.0001), prior spontaneous abortions (odds ratio = 2.32, p = 0.02), and the mean number of months from the last pregnancy to the index pregnancy (cases = 35.9, controls = 28.2; p = 0.03). Factors found not to be associated with disease included contraceptive history, irradiation, ABO blood group, and smoking factors of the male partner. The findings suggest that gestational trophoblastic neoplasia may be part of a continuum of early (first-trimester) reproductive abnormalities.     

低危型妊娠滋养细胞肿瘤耐药高危因素探讨

目的探讨低危型妊娠滋养细胞肿瘤耐药的相关高危因素。方法收集2000年1月至2010年1月浙江大学附属妇产科医院收治的452例低危型妊娠滋养细胞肿瘤患者的资料,根据耐药与否分为耐药组(86例)和非耐药组(366例)进行回顾性分析。结果耐药发生率为19.03%。初始化疗前高HCG值(尤其是血HCG值>10000U/L)者、肺部有多处转移灶、有远处转移、子宫大病灶者易发生耐药。绒癌较侵蚀性葡萄胎易发生耐药。另外化疗副反应大、对化疗药物敏感导致疗程和剂量不足、疗程间隔过长的也易产生耐药。而年龄、临床分期、先期妊娠性质、化疗药物及给药途径、初次化疗至末次妊娠终止的间隔时间方面两组比较差异无统计学意义(P>0.05)。结论化疗方案应个体化,对耐药的高危人群应及早合理联合用药,重视结合手术等综合治疗,可降低耐药率,提高治愈率。     

Poor-prognosis metastatic gestational trophoblastic neoplasia

Despite recent advances in therapy, patients with poor-prognosis metastatic GTN continue to present the clinician with challenging management problems. The optimal care for these patients is best delivered in centers specializing in the treatment of trophoblastic disease. Not only does the coordination of chronic aggressive multiagent chemotherapy, irradiation therapy, and surgical therapy require considerable expertise, but the proximity of a reliable and sensitive hCG assay aids in the rapid identification of the development of drug-resistant disease. Although recognition of the poor-prognosis group and the development of effective multiagent chemotherapy have increased the survival of these patients, progress in therapy for these patients will require continuing intensive efforts.     

Decision making for chemotherapy administration in patients with low risk gestational trophoblastic neoplasia

The thrust in the management of low risk gestational trophoblastic neoplasia (GTN) has been to find the most effective agent with the least toxicity that causes the least disruption of the patient's activities. We have studied biweekly actinomycin-D 1.25 mg M⁻² (pulsed act-D, 18 evaluable patients) to determine whether it has the same primary efficacy rate as the 5-day course of actinomycin-D 12 mcg kg⁻¹ (5-day act-D, 43 evaluable patients) in low risk GTN. The primary cure rate was 88.4% for the 5-day act-D group and 77.8% for the pulsed act-D group. The data appear to show a therapeutic advantage for the use of the 5-day regimen. However, the difference between 22.2% failure for pulsed act-D and 11.6% failure for the 5-day act-D is not statistically significant; P =0.45 (Fisher's exact test, two tails). Many studies, both of act-D and of methotrexate, may be invalid because the criteria for diagnosing GTN are not sufficiently stringent, yet all our current practice is based on the reported literature. The data from the present study illustrates the difficulties of drawing valid conclusions from the information available in the literature. Before assuming that less drug for less time is the best procedure a prospective randomized study embodying stringent diagnostic criteria and uniform patient attributes appears to be indicated.     

Treatment of high-risk gestational trophoblastic neoplasia with etoposide, methotrexate, actinomycin D, cyclophosphamide, and vincristine chemotherapy

OBJECTIVE: The objective of the study was to evaluate the efficacy and toxicity of etoposide, methotrexate, actinomycin D, cyclophosphamide, and vincristine (EMA-CO) chemotherapy for the treatment of high-risk gestational trophoblastic neoplasia. METHODS: Forty-five patients with high-risk gestational trophoblastic tumors received 257 EMA-CO treatment cycles between 1986 and 2001. Twenty-five were treated primarily with EMA-CO because of the presence of one or more high-risk factors and 20 were treated with EMA-CO secondarily after failure of single-agent chemotherapy. Patients who had incomplete responses or developed resistance to EMA-CO were treated with drug combinations employing cisplatin and etoposide with or without bleomycin or ifosfamide. Adjuvant surgery and radiotherapy were used in selected patients. Survival, clinical response, and toxicity were analyzed retrospectively. RESULTS: The overall survival rates was 91% (41/45); survival rates were 92% (23/25) for primary treatment and 90% (18/20) for secondary treatment with EMA-CO. Of the 45 patients treated with EMA-CO, 32 (71%) had a complete clinical response, 9 (20%) developed resistance but were subsequently placed into remission with cisplatin-based chemotherapy, and 4 (9%) died of widespread metastatic disease. Clinical complete response to EMA-CO was significantly influenced by duration of disease from antecedent pregnancy to treatment (<6 months, 84%, vs >6 months, 43%), metastatic site (lung and pelvis, 73%, vs other, 40%), and WHO score (< or =7, 96%, vs >7, 36%). The EMA-CO chemotherapy regimen produced no life-threatening toxicity, caused grade 3-4 hematologic toxicity in 1.6% of cycles, and was associated with neutropenia necessitating a 1-week delay in treatment in only 13.5% of cycles. CONCLUSION: EMA-CO chemotherapy is a well-tolerated and highly effective treatment for high-risk gestational trophoblastic neoplasia, yielding a 71% complete response rate and a 91% survival rate in this series.     

Pelvic imaging in gestational trophoblastic neoplasia

OBJECTIVE: To assess the accuracy of Doppler ultrasound (DU) compared with magnetic resonance imaging (MRI) in high-risk patients with gestational trophoblastic neoplasia (GTN). STUDY DESIGN: From January 2005 to October 2007, patients with proven high-risk GTN or suspicion of relapse who had both DU and MRI of the pelvis were reviewed retrospectively for tumor detection and tumor extent and vascularity. RESULTS: There were a total of 54 patients who had both DU and MRI performed; of these, 40 were first-time presentation and 14 had either residual disease not responding to chemotherapy or suspicion of recurrent GTN based on rising human chorionic gonadotropin (hCG). Extrauterine extension and extent of endometrial encroachment were better assessed on MRI than on DU in 10 of 46 patients with visible uterine lesion. CONCLUSION: MRI and DU are complementary investigations of the pelvis in patients with GTN. Tumor vascularity is better assessed on DU, tumor extension and detection are better with MRI.     

Immunological parameters in gestational trophoblastic neoplasia

Immunological function were studied in 22 patients with hydatidiform mole and 29 patients with malignant trophoblastic disease before and after treatment; normal pregnant and post-pregnant women served as controls. The only significant abnormality in hydatidiform mole was a low granulocyte chemotaxis before evacuation. In malignant trophoblastic disease the total lymphocyte counts, T-cell counts. B-cell counts, lymphocyte responses to mitogens and serum IgA levels were significantly lower than in normal women 6 wk after pregnancy. In those who responded to chemotherapy, these indices rose to the levels of post-pregnancy controls. An 'immune profile score' based on these indices was found to be a useful prognostic index. All patients with hydatidiform mole who had a score of 7 or less developed malignant trophoblastic disease, while the two patients with malignant trophoblastic disease who died had the lowest scores of the series.