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Outcome of Gestational Trophoblastic Neoplasia: Experience from a Tertiary Cancer Centre in India
Abstract
Gestational trophoblastic neoplasms (GTN) comprise a spectrum of interrelated conditions originating from the placenta. With sensitive assays for human chorionic gonadotropin (β-hCG) and current approaches to chemotherapy, most women with GTN can be cured with preservation of reproductive potential. The purpose of this analysis was to address the outcome of GTN from a developing country, as data are largely sparse from this region.
We undertook a retrospective review of GTN cases treated at our centre from 2001 to 2008. Patients of GTN were assigned to low-risk (score ≤ 6) or high-risk (score ≥ 7) categories as per the modified World Health Organization scoring system. The low-risk group was treated with single-agent methotrexate (MTX) and the high-risk group received the EMA/CO regimen. Salvage therapies were EMA/EP or BEP. Treatment was continued until serum β-hCG values were normal for three consecutive chemotherapy cycles, after which the patients were kept on follow-up.
In total, 70 GTN patients were treated at our institution during this period; 48 (68%) were low-risk and 22 (32%) were in the high-risk category. The median β-hCG level was 50 000 IU/l. The lung was the most common site of metastasis, seen in 15 (21%) patients. Among 48 low-risk patients, 37 (77%) received chemotherapy, of whom 25 (68%) were treated with MTX and 24 (96%) achieved a complete response. Twelve low-risk patients (32%) received EMA/CO therapy; 10 (83%) achieved a complete response. The 22 high-risk patients received EMA/CO and of these 16 (73%) achieved a complete response, two (9%) progressed, two (9%) died of progressive disease and two (9%) were lost to follow-up. Grade 3/4 toxicities with MTX included mucositis in two (8%) and neutropenia in five (21%) patients. At a median follow-up of 16.6 months, overall survival in the low- and high-risk groups was 100 and 88.8%, respectively.
Risk-stratified treatment of GTN was associated with acceptable toxicity and resulted in outcome that was comparable with international standards.
... In most of the other studies, the highest incidence had occurred after molar pregnancies. 5 But, in another study from the eastern part of our country, abortions were the commonest type of pregnancy preceding GTN. 6 We hypothesize that this may be due to the very high numbers of abortions performed outside of appropriate healthcare facilities in India where there is a very high chance of the diagnosis of molar pregnancy being missed. ...
... The median β-HCG value in our study is 90,000 mIU/mL that is significantly higher than this study probably as our study has a higher proportion of high-risk GTN patients. 5 Again, this may be due to different referral patterns or maybe because more patients from our region come at a later stage. Also, variation in β-HCG levels may occur if samples are tested without dilution at levels more than 1000 mIU/mL. ...
... This is as expected for a highly curable malignancy. 5 The toxicity profile was favorable. As most of the patients with these malignancies are young, this is as expected and in tune with other studies. ...
Anuj Gupta
Objectives The aim of this study was to do a retrospective analysis of patients of gestational trophoblastic neoplasia (GTN) treated at our center concerning their clinical features and treatment outcomes.
Materials and Methods Patients diagnosed and treated from May 2018 to December 2021 were included. All relevant information pertaining to eligible patients was retrieved from the electronic medical records. Patients were risk-stratified based on the World Health Organization (WHO) risk scoring system with a score of seven and above being classified into the high-risk category. Patients were monitored for response by measuring β-human chorionic gonadotrophin (β-HCG) levels before each consecutive cycle.
Statistical Analysis Appropriate statistical analysis was performed using SPSS version 26.
Results Records of 39 eligible patients were analyzed for clinical features out of which 38 were eligible for response assessment. The median age of presentation was 28 years with the majority of patients (79.4%) diagnosed based on β-HCG levels and clinical history alone. The most common symptom was bleeding per vagina (64%), while the majority of antecedent pregnancies were abortions (59%).
Of the 14 low-risk category patients, 12 received single-agent methotrexate/actinomycin D, while 2 received etoposide, methotrexate actinomycin D (EMACO) regimen. Overall response rates were 85.7% with the others responding to the second-line EMACO regimen. Five patients in this group had a WHO score of 5 or 6 and all of them responded to single-agent treatment.
Among the 25 high-risk category patients, all received the EMACO regimen with high-dose methotrexate added to those with brain metastasis. The response rate was 87.5% with all the nonresponders having features of ultra-high risk of liver/brain metastasis and/or a WHO score of more than 12. While one nonresponder had expired despite treatment, the other two responded to the etoposide methotrexate and actinomycin D/ etoposide and cisplatin regimen.
Conclusion Our results are in consonance with other reported studies. The subcategories of low-risk GTN with a WHO score of 5 and 6 and high-risk GTN with ultra-high-risk features deserve further research in the form of multicenter prospective studies.
... [7] Another study by Gulia et al. showed that overall survival (OS) in the low-and high-risk groups were 100% and 88.8%, respectively, at a median follow-up of 16.6 months. [8] However, another retrospective study by Hussain et al. reported the clinicopathological features but not the survival data of patients with choriocarcinoma. [9] Due to the rarity of the disease, most of the evidence is based on retrospective data. ...
... Choriocarcinoma is a rare disease, and most of the available data have been obtained from retrospective analyses. The largest study on choriocarcinoma from India was conducted by Gulia et al.; [8] this study included 70 patients. In this study, nearly 70% of the patients were low-risk, and 30% were high-risk. ...
... This has also been reported in other studies. [8][9][10] The most common antecedent pregnancy event in our study was abortion. This is different from that observed in other studies, where molar pregnancy was the most common event. ...
Background: Choriocarcinoma is the most common form of gestational trophoblastic neoplasia seen by medical oncologists. It is a rare condition and data related to its long-term outcomes from the Indian subcontinent are sparse.
Objectives: The primary objective of this study was to assess the clinicopathological characteristics and clinical outcomes of patients with of choriocarcinoma; the secondary objective was to assess the correlation of outcomes with risk stratification.
Materials and Methods: This single-center retrospective study was conducted at the Tata Medical Center, a tertiary cancer center in West Bengal, India. We identified all the cases of choriocarcinoma treated at our hospital from the electronic medical records and noted their baseline characteristics, treatment details, and clinical outcomes. Descriptive statistics were used for baseline characteristics, and the Kaplan–Meier method was used for the survival analysis.
Results: A total of 24 patients were included in the study. The median age of the patients was 29 years (interquartile range, 25.9–39.5). The median time interval from the last pregnancy was 5 months (range, 0 months to 11 years). The World Health Organization risk score was low in 8 (33.3%) and high in 16 (66.7%) patients. There were 6 (25%) patients who received single-agent chemotherapy, 14 (66.7%) received the EMA-CO (etoposide, methotrexate, actinomycin D, cyclophosphamide, and vincristine) regimen, and 1 (4.7%) received the VIP (etoposide, ifosfamide, and cisplatin) regimen, with the latter 2 being given only to high-risk patients. The median follow-up was 10.9 months (95% confidence interval [CI], 4.2–28.5). The median progression-free survival was not reached (NR) (95% CI, 7.2–NR). Similarly, the median overall survival was NR (95% CI, 10.56–NR).
Conclusion: Our study provides real-world data for this rare malignancy and reinforces the fact that choriocarcinoma is a highly curable disease. Despite the clinicopathological variations in the different parts of the country, the long-term outcomes are favorable.
... Methotrexate, actinomycin D, and cyclophosphamide regimen was used in the 1970s and 1980s [4]. Subsequently, etoposide was introduced with methotrexate and actinomycin D alternating weekly with cyclophosphamide and vincristine (EMA/CO) [5]; this regimen remains widely used and has complete remission (CR) rates of 71%-86.4% [6][7][8][9][10][11][12][13][14][15][16][17][18][19]. ...
... Currently, EMA/CO is the most commonly used multiagent chemotherapy regimen for high-risk GTN worldwide, reportedly producing CR rates of 71%-86.4% and survival rates of 83.6%-98.1% [6][7][8][9][10][11][12][13][14][15][16][17][18][19]. In some Chinese regional centers, FAEV has been the first-line multiagent chemotherapy for high-risk GTN since the 1960s. ...
... Regarding the hematological toxicity of EMA/CO, the incidence rates of grade 3-4 neutropenia, thrombocytopenia, and anemia were 6.9%-19.5%, 4.6%, and 2.3%, respectively [15,16,18]. However, it is unreasonable to compare the hematological toxicities of FAEV and EMA/CO because different supportive treatments are used worldwide. ...
Background:
5-fluorouracil-based multiagent chemotherapy has been used as the primary treatment for high-risk gestational trophoblastic neoplasia (GTN) in China for a few decades. This study aims to assess the efficacy and toxicity of floxuridine, actinomycin D, etoposide, and vincristine (FAEV) as primary treatment for patients with GTN who had International Federation of Gynecology and Obstetrics (FIGO) scores ≥5.
Methods:
A total of 207 patients with GTN who had FIGO scores ≥5 were treated with FAEV as first-line chemotherapy at Peking Union Medical College Hospital between January 2002 and December 2017. Complete remission (CR), resistance, survival, toxicity, and reproductive outcomes were analyzed.
Results:
Of the 207 patients treated with FAEV, 9 (4.3%) required a change of chemotherapy owing to toxicity and 1 (0.5%) died of cerebral hernia 5 weeks after commencing treatment. The remaining 197 patients were assessable to determine the response to FAEV; among them, 168 (85.3%) achieved CR with FAEV and 29 (14.7%) developed resistance to FAEV. The 5-year overall survival rate of the entire cohort was 97.4%. Grade 3-4 neutropenia, thrombocytopenia, and anemia occurred in 28.4%, 6.8%, and 6.2% of cycles, respectively. No acute toxicity-related deaths occurred. Five patients developed acute myeloid leukemia 10-50 months after exposure to chemotherapy; another patient developed duodenal cancer 2 years after completing therapy. Sixty-one patients who preserved fertility wanted to become pregnant; 56 of them conceived.
Conclusion:
The FAEV regimen is an effective primary treatment for patients with GTN who have FIGO scores ≥5, and has predictable and manageable toxicity.
Implications for practice:
The most commonly used multiagent chemotherapy for high-risk gestational trophoblastic neoplasia (GTN) is EMA/CO worldwide. However, 5-fluorouracil-based multiagent chemotherapy has been used as the primary treatment for high-risk GTN in China for a few decades. This study evaluated the efficacy and toxicity of FAEV as a primary treatment for patients with GTN who have FIGO scores ≥5. Our data demonstrated that FAEV as primary treatment achieved favorable outcomes for patients with FIGO scores ≥5. Toxicities that result from the FAEV regimen are predictable and manageable. The FAEV regimen may provide another option for the treatment of GTN.
... There are several retrospective studies from both developing and developed countries in which MTX toxicity has been studied. [9][10][11][12] However, underreporting of toxicities and non-documentation of minor toxicities are common in such retrospective studies. We did this prospective study to accurately report on the toxicity profile and efficacy of 8-day MTX/FA regimen. ...
... 19 A retrospective study from India where 25 out of 48 cases of low risk GTN were treated with 8-day MTX/FA regimen achieved 96% remission rate. 9 The median number of cycles required for complete remission in our study was 5; similar number of cycles were administered in other studies. 9 Although there were no recurrences in our study, some studies have reported recurrence rates ranging from 1.4% to 3.6%. ...
... 9 The median number of cycles required for complete remission in our study was 5; similar number of cycles were administered in other studies. 9 Although there were no recurrences in our study, some studies have reported recurrence rates ranging from 1.4% to 3.6%. 8,19 Most studies have reported 100% survival in low risk GTN which was evident in this study also. ...
Background: Gestational trophoblastic neoplasia (GTN) is a rare malignancy that arises from abnormal proliferation of trophoblastic cells. Low risk GTN responds well to single agent chemotherapy with good survival rate. Objective of the study was to assess the efficacy and toxicity of methotrexate chemotherapy in low risk GTN patients receiving 8-day methotrexate (MTX)/folinic acid (FA) regimen. A prospective observational study done in a tertiary care hospital in South India.Methods: This prospective observational study was conducted at a tertiary care hospital in south India between July 2015 and July 2018 and included 56 patients with low risk GTN treated with 8-day MTX/FA regimen.Results: Among the 56 patients treated, complete remission was achieved in 50 (89.3%). Molar pregnancy was the most common preceding pregnancy event (96.7%) and 63.3% of them developed GTN within 4 months of evacuation. Six non responders were treated with EMACO regimen and achieved complete remission. The most common toxicities were mucositis (46.4%) and neutropenia (17.8%). Overall survival of low risk GTN was 100% at the end of median follow up period of 14.4 months.Conclusions: For patients with low risk GTN, 8-day MTX/FA regimen is associated with a high rate of remission and low toxicity.
... Only 2 patients had a history of prior failed chemotherapy and both of them were in high-risk group. The number of chemotherapy cycles received on average for normalization of serum β-hCG levels was 4.82 (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12). In high-risk group, on average, patients received 5.1 (3)(4)(5)(6)(7)(8), while in low-risk group, patients received 4.46 cycles (2-12) for normalization of serum β-hCG levels. ...
... Total number of chemotherapy cycles received on average was 7.08 (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14). In high-risk patients, average number of cycles received was 7.6 (4-11), while in low-risk patients, it was 6.13 (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14). ...
... Total number of chemotherapy cycles received on average was 7.08 (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14). In high-risk patients, average number of cycles received was 7.6 (4-11), while in low-risk patients, it was 6.13 (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14). ...
Aims:
The purpose of this analysis was to address the outcome of GTN from a tertiary care centre of India.
Materials and methods:
We undertook a retrospective and prospective review of GTN cases treated at our centre from 2006 to 2014. Patients of GTN were assigned to low-risk or high-risk categories as per the FIGO scoring system. The low-risk group was treated with combination of actinomycin-D and methotrexate (MTX) and the high-risk group received the EMA/CO regimen. Salvage therapy was EP/TP. Treatment was continued for 3 cycles after normalization of β-hCG level, after which the patients were kept on follow-up.
Results:
In total, 52 GTN patients were treated at our institution during this period; 21 were low-risk and 31 were in the high-risk category. The lung was the most common site of metastasis. All low risk patients achieved complete remission. Among high risk patients one patient died while receiving first cycle chemotherapy, one patient relapsed and 29 patients achieved complete remission. The single relapsed patient also achieved remission with 2nd line chemotherapy.
Conclusion:
1. Two drug combination of Actinomycin-D and Methotrexate is a better alternative to single drug chemotherapy especially in developing countries were proper risk stratification is not always possible. 2. Patients with high disease burden should initially be treated with low dose chemotherapy to avoid life threatening visceral haemorrhage.
... Only two patients had history of prior failed chemotherapy, and both of them belonged to high-risk group. The average number of chemotherapy cycles received for normalization of serum b-hCG levels was 4.82 (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12).In high-risk group, patients received on average 5.1 cycles (3-8), while in low-risk group, patients received on average 4.46 cycles (2-12) for normalization of serum b-hCG levels. ...
... The total number of chemotherapy cycles received on average was 7.08 (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14). In high-risk patients, average number of cycles received was 7.6 (4-11), while in lowrisk patients, it was 6.13 (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14). ...
... The total number of chemotherapy cycles received on average was 7.08 (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14). In high-risk patients, average number of cycles received was 7.6 (4-11), while in lowrisk patients, it was 6.13 (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14). ...
Aims
Gestational trophoblastic neoplasia (GTN) comprise a spectrum of interrelated
conditions originating from the placenta. With sensitive assays for human chorionic gonadotropin (β-hCG) and current approaches to chemotherapy, most women with GTN can be cured with preservation of reproductive potential. The purpose of this analysis was to address the outcome of GTN in patients from a tertiary care center of India.
Materials and Methods
We undertook a retrospective and prospective review of GTN cases treated at our center over a period of 7 years from 2008 to 2014. Patients of GTN were assigned to low-risk or high-risk categories as per the FIGO scoring system. The low-risk group was treated with combination of actinomycin-D and methotrexate and the high-risk group received the Etoposide, Methotrexate, Actinomycin-D/ Cyclophosphamide, Vincristine (EMA/CO) regimen. Salvage therapy was Etoposide, Paclitaxel /Paclitaxel, Cisplatin (EP/TP). Treatment was continued for three cycles after normalization of β-hCG level, after which the patients were followed up regularly.
Results
In total, 41 GTN patients were treated at our institution during the above period; 17 were in the low-risk and 24 were in the high-risk category. The lung was the most common site of metastasis. All low-risk patients achieved complete remission. Among high-risk patients, one patient died while receiving first cycle chemotherapy, one patient relapsed, and 22 patients achieved complete remission. The single relapsed patient also achieved remission with second-line chemotherapy.
Conclusion
Risk-stratified treatment of GTN was associated with acceptable toxicity and resulted in outcome that was comparable with international standards. The use of two-drug combination in low-risk patients is a better option especially in developing countries.
... For EMA-CO, grade 3 or grade 4 neutropenia was observed in 7.0% to 19.5% of treatment cycles. 11,16,17,19 Thrombocytopenia was uncommon with the EMA-CO regimen; grade 3 or 4 thrombocytopenia was observed in 1.3% to 4.6% of cycles, 11,17 which was slightly higher than that observed with the CHAMOC regimen in the current study. ...
... For EMA-CO, grade 3 or grade 4 neutropenia was observed in 7.0% to 19.5% of treatment cycles. 11,16,17,19 Thrombocytopenia was uncommon with the EMA-CO regimen; grade 3 or 4 thrombocytopenia was observed in 1.3% to 4.6% of cycles, 11,17 which was slightly higher than that observed with the CHAMOC regimen in the current study. ...
... On the contrary, there were studies that did not show any secondary malignancies in their patients after EMA-CO chemotherapy. 11,17,19 However, they had only a small number of patients (33Y35 patients), with a relatively short duration of follow-up (median, 16.6Y54 months). In our center, we advised lifelong follow-up for all our GTN patients; therefore, we had the privilege of monitoring the long-term side effects of the chemotherapy. ...
The aim of this study was to evaluate the efficacy and toxicity profile of the cyclophosphamide, hydroxyurea, actinomycin D, methotrexate, and vincristine (CHAMOC) regimen in the treatment of high-risk gestational trophoblastic neoplasia (GTN).
We conducted a retrospective study of all patients with GTN treated with the CHAMOC regimen between 1985 and 2012 in a tertiary referral center in Hong Kong. Medical records were reviewed, and data were analyzed. Response rate and toxicity profile were assessed.
The CHAMOC regimen was given to 79 patients from 1985 to 2012, with a total of 388 cycles administered. Among the 79 patients, CHAMOC was given to 68 as the primary treatment of high-risk GTN, whereas it was used as the salvage chemotherapy in 11 patients for failure with other chemotherapy regimens or recurrent disease. Complete remission was achieved in 58 patients (85.3%) in the primary treatment group and 8 patients (72.7%) in the salvage treatment group. Grade 3 and grade 4 neutropenia were observed in 13.0% and 3.4% of the chemotherapy cycles, respectively. Grade 3 or 4 thrombocytopenia was rare (1.3% of all treatment cycles). No secondary malignancy was observed in our patients with a mean duration of follow-up of 9.7 to 13 years, except 1 patient with advanced colon cancer diagnosed shortly after chemotherapy, which was unlikely to represent a secondary malignancy from the chemotherapy.
The CHAMOC regimen should be considered as an alternative to other chemotherapy regimens in the primary treatment of high-risk gestational trophoblastic disease, with comparable efficacy, similar short-term side-effects profile, and potentially fewer long-term complications.
... Compared with those in other studies, survival outcomes for high-risk GTN at BCCOE fell below expected treatment outcomes in established GTN treatment centers. [20][21][22] However, the Kaplan-Meier curves were highly influenced by the relatively short follow-up time. More-accurate comparisons may be made in the future with additional follow-up and an expanded patient population. ...
... Both incomplete information and incomplete documentation affect appropriate risk stratification, a challenge in GTN management that has been noted in cancer centers in lowresource settings. 21,26 Additional study limitations include the short duration of follow-up and information only on patients with GTN at BCCOE, providing a partial representation of the country. ...
Purpose Gestational trophoblastic neoplasia (GTN) is a highly treatable disease, most often affecting young women of childbearing age. This study reviewed patients managed for GTN at the Butaro Cancer Center of Excellence (BCCOE) in Rwanda to determine initial program outcomes.
Patients and Methods A retrospective medical record review was performed for 35 patients with GTN assessed or treated between May 1, 2012, and November 30, 2014. Stage, risk score, and low or high GTN risk category were based on International Federation of Gynecology and Obstetrics staging and the WHO scoring system and determined by beta human chorionic gonadotropin level, chest x-ray, and ultrasound per protocol guidelines for resource-limited settings. Pathology reports and computed tomography scans were assessed when possible. Treatment was based on a predetermined protocol stratified by risk status.
Results Of the 35 patients (mean age, 32 years), 26 (74%) had high-risk and nine (26%) had low-risk disease. Nineteen patients (54%) had undergone dilation and curettage and 11 (31%) had undergone hysterectomy before evaluation at BCCOE. Pathology reports were available in 48% of the molar pregnancy surgical cases. Systemic chemotherapy was initiated in 30 of the initial 35 patients: 13 (43%) received single-agent oral methotrexate, 15 (50%) received EMACO (etoposide, methotrexate, dactinomycin, cyclophosphamide, and vincristine), and two (7%) received alternate regimens. Of the 13 patients initiating methotrexate, three had their treatment intensified to EMACO. Four patients experienced treatment delays because of medication stockouts. At a median follow-up of 7.8 months, the survival probability for low-risk patients was 1.00; for high-risk patients, it was 0.63.
Conclusion This experience demonstrates the feasibility of GTN treatment in rural, resource-limited settings. GTN is a curable disease and can be treated following the BCCOE model of cancer care.
... Both category had one relapse each which were treated successfully. Nine out of 90 patients Indian and South African case series had reported mortality rates of 9% and 10%, similar results in somewhat identical set ups. 13,14 However there is improvement from previously reported mortality figures in the study conducted at our institution from 20% to 10% due to improvement in medical care, social, economic and education changes 15 . Korean study showed improved outcomes in GTN in 30 years and mortality rates decreased significantly from 32.6% to 2.6%. ...
ABSTRACT
Objective: To analyze the risk factors associated with mortality in patients receiving treatment for Gestational Trophoblast Neoplasia (GTN).
Material and Methods: Rertospective, cross- sectional study done at Department of Obstetrics and Gynaecology,
Hayatabad Medical Complex, Peshawar, Pakistan, from June 2005 to June 2014. Ninety women with the diagnosis of
GTN were hospitalized and treated according to standard chemotherapeutic regimens. Hospital records of patients
demographic profile, age, parity, antecedent pregnancy, serum β-hCG levels, site of metastasis, FIGO score, type of
chemotherapy, and treatment outcomes including mortality were studied. Data analysis done through SPSS 16.
Results: In 90 patients diagnosed with GTN, 59(65.6%) patients were low risk and 31(34.4 %) were in high risk category.
Nine out of 90 patients diagnosed with GTN died during initial treatment giving overall mortality of 10%. All patients
who died were in high risk category with stage IV GTN. Six out of nine patients had term pregnancy as antecedent
pregnancy. Five out of 9 patients that died had serum β-hCG levels of >100000IU/ml. Eight out 9 patients had FIGO
scored between 9-12. Metastasis was present in all the patients that died. Three patients had metastasis present both
in Brain and Liver and two had metastasis only in liver, while other two had lung metastasis.
Conclusions: High FIGO score, high pretreatment serum β-hCG levels, previous term pregnancy, liver and brain metastasis have been associated with adverse outcome like mortality in patients with gestational trophoblast neoplasia:
a rare but highly curable malignancy.
Key Words: Gestational, Trophoblast Neoplasia, FIGO Prognostic score (International federation of Gynaecologistand
Obstetrician), Mortality, Chemotherapy
... They have potential for local invasion and metastasis 3,4 . Although they are rare tumors but 95% cure rates are expected in even those patients with molar pregnancies whoget additional treatment after evacuation 3,6,7 . ...
Background: Gestational trophoblastic neoplasia develops from the trophoblastic cells which later form the placenta. It ranges from the relatively benign partial and complete hydatidiform mole while choriocarcinoma and the rare placental site trophoblastic tumor are its malignant variants. The risk of developing gestational trophoblastic neoplasia (GTN) is 15-17% after complete mole and 3.5-4% after partial mole1,2. This risk is more in patients with high-risk molar pregnancy1,2. Aim: To evaluate the role of prophylactic chemotherapy in prevention of gestational trophoblastic neoplasia in patients who fall in high-risk molar category. Place and duration of study: Ghurki Trust Teaching Hospital and Surgimed Hospital, 2016-2020 (4 years duration) Study design: Descriptive case series Methodology: Twenty three patients who presented with high-risk molar pregnancy in the study period were included in this study after takinginformed consent.These patients were divided into two groups. Group A included those patients who underwent suction evacuation followed by prophylactic chemotherapy; they were 13 in number, while group B had 10 patients and they underwent suction and evacuation only. Single dose of methotrexate 1mg/kg body weight was given to the patients in group A. Patients were asked about the history of excessive vaginal bleeding and serial beta hcg levels were carried out on follow up. Results: The patients average age was 32 years with the range between 25-42 years.14 patients (61%) were more than 40 years old while 9 patients (39%) were less than 40 years old. Three patients had beta hcg levels above 100,000 IU/ml. Patients were followed up withserial beta hcg levels till they became negative.No patient (0%) in group A developed gestational trophoblastic neoplasia while two patients (15.3%) in group B developed persistent vaginal bleeding and 1 patient (7%) developed choriocarcinoma involving the brain. Conclusion: Prophylactic chemotherapy reduces the risk of development of gestational trophoblastic neoplasia as concluded by thisstudy. However, only 16% of patients in high-risk molar category develop gestational trophoblastic neoplasia2 which means this will expose 84% patients to unnecessary chemotherapy. This will increase the cost of treatment also. Keywords: Molar pregnancy, Prophylactic chemotherapy, Gestational trophoblastic neoplasia
... Chemotherapy for GTN is well tolerated, and the incidence of grade 3/4 toxicity is 4-15 per cent 12,16,22 . Surgical treatment is not a routine, except for resection of the resistant, relapsed or septic focus of disease 23,24 . ...
Background & objectives:
Gestational trophoblastic neoplasia (GTN) is a chemosensitive malignancy with an excellent cure rate. The primary objective of the present study was to determine the predictors of chemoresistance and disease relapse, and the secondary objective was to appraise the WHO/FIGO risk scoring and course of disease in women with GTN.
Methods:
In this retrospective study, case records of women treated for GTN from January 2011 to June 2019 were reviewed. For the purpose of comparison, sub-stratification of FIGO/WHO low risk group (≤6) into low (0-4) and intermediate (5-6) risk was done. Similarly, WHO high risk (≥7) group was sub-stratified into high (7-12) and ultra-high risk (≥13) groups.
Results:
Case records of 116 patients were included: 51.7 per cent (60/116) were of low risk disease and 48.2 per cent (56/116) were of high risk disease. Chemoresistance developed in 28.4 per cent (33/116) and relapse in 10.3 per cent (12/116) cases. Risk of chemoresistance was higher in low risk (0-6) while risk of relapse was more in high risk (≥7) group. On sub-stratification, chemoresistance was more with intermediate [0-4: 28.5% (10/35), 5-6: 44% (11/25), 7-12: 22.5% (9/40), ≥13: 18.7% (3/16)] and relapse with ultra-high risk score [0-4: 5.7% (2/35), 5-6: 4% (1/25), 7-12:10% (4/40), ≥13: 31.2% (5/16)]. Age, myometrial invasion, serum beta-human chorionic gonadotropin and tumour size were not related to chemoresistance or relapse.
Interpretation & conclusions:
WHO risk score and presence of metastatic disease predict the probability of developing chemotherapy resistance and disease relapse. Risk of chemotherapy resistance was higher in women with intermediate-risk score (5-6), and risk of relapse was more in those with ultra-high risk score (≥13).
... Methotrexate (MTX) as a first-line treatment remains the most commonly prescribed drug for low-risk GTN patients [1][2][3]. However, 4.00%-46.73% of patients develop resistance to MTX [1,3,[4][5][6][7][8][9], while 1.41%-3.69% of patients experience intolerable toxicity to MTX [1,2,10,11], requiring salvage chemotherapy or even surgery [12]. ...
Objective:
To assess the outcomes and toxic effects of 5-day actinomycin D (Act-D) salvage therapy and to explore the predictors of Act-D resistance in patients with low-risk gestational trophoblastic neoplasia (GTN)who failed 5-day methotrexate (MTX) chemotherapy.
Methods:
This retrospective study analyzed patients with low-risk GTN administered Act-D salvage therapy after failing MTX chemotherapy at Women's Hospital, Zhejiang University School of Medicine between January 2000 and December 2015. The clinical parameters of these patients were collected and analyzed.
Results:
The final analysis included 89 cases. Of these, 73 cases (82.02%) responded to salvage Act-D. The remaining 16 resistant cases were switched to etoposide, MTX, Act-D/cyclophosphamide, and vincristine chemotherapy and achieved complete remission. Serum human chorionic gonadotrophin levels before Act-D salvage therapy (hCGAct-D)in the Act-D-resistant cases were significantly higher than those in the Act-D responders (median 605 vs. 103 IU/L, p=0.009). However, the range of hCGAct-D values in Act-D responders was wider than that in Act-D-resistant cases (5.76-16,664 IU/L vs. 11.43-6,732 IU/L). Thus, assigning a general cut-off value was difficult considering the individual setting. Except for 2 cases requiring other salvage regimens due to Act-D toxicity, 97.80% of cases (89/91) tolerated the toxicity. During at least 1-year follow-up, the survival rate was 100.00% and no case developed recurrence.
Conclusion:
Based on the good therapeutic effect and tolerable toxicity, we recommend Act-D salvage therapy for all patients with low-risk GTN who fail primary MTX chemotherapy. The higher serum hCG levels before Act-D salvage therapy may be associated with resistance to this treatment.
... The disease is unique from other GTDs, because of slow growth, low hCG serum levels, late onset metastasis and the relative insensitivity to chemotherapy. [7,8] Due to the rarity of this type of GTD, reporting new cases and their presentations are important to improve PSTT diagnosis and treatment. ...
Placental site throphoblastic tumor (PSTT) is a rare manifestation of gestational trophoblastic neoplasia that may complicate any type of pregnancy. The disease is unique from other type, and is defined by slow growth, low human chorionic gonadotropin (hCG) serum levels, the late-onset metastatic potential, and most significantly, insensitivity to chemotherapy. We describe a case of a 31-year-old woman with prolonged amenorrhea and slightly elevated serum beta hCG (βhCG) level, referred for termination of abnormal pregnancy. During curettage, necrotic tissue was removed and severs vaginal bleeding was controlled with medical therapy. Histology examination showed neoplastic intermediate trophoblastic cells with invasion to the vessel wall compatible with PSTT. After that, hysterectomy was down and serum βhCG declined to undetectable level 2 weeks after surgery and was followed for 2 years without complication.
... At a median follow-up of 16.6 months, OS in the LR and HR groups was 100% and 88.8%, respectively. [62] Another study reported the outcomes of HR GTN. Women with HR GTN received EMA-CO as the first-line chemotherapy. ...
Gynecological cancers are among the most common cancers in women and hence an important public health issue. Due to the lack of cancer awareness, variable pathology, and dearth of proper screening facilities in developing countries such as India, most women report at advanced stages, adversely affecting the prognosis and clinical outcomes. Ovarian cancer has emerged as one of the most common malignancies affecting women in India and has shown an increase in the incidence rates over the years. Although cervical cancer is on a declining trend, it remains the second most common cancer in women after breast cancer. Many researchers in India have published important data in the field of gynecologic oncology, covering all domains such as basic sciences, preventive oncology, pathology, radiological imaging, and clinical outcomes. This work has given us an insight into the in-depth understanding of these cancers as well as the demographics and survival rates in the Indian population. This aim of this review is to discuss the important studies done in India for all gynecological cancers.
... High risk choriocarcinoma, WHO prognostic score >7 is treated with EMA-CO regime with a cure rate between 67 and 85 percentage. 5,6 These women should be managed in centers with expertise to deal with such cases as future fertility may also be an issue in young women. Our case despite being in poor general condition on presentation could be saved due to timely diagnosis and appropriate chemotherapy thus achieving complete remission. ...
Gestational trophoblastic disease (GTD) encompasses a range of pregnancy-related disorders categorized by an autonomous overgrowth of fetal chorionic tissue or trophoblast that includes benign, premalignant conditions, complete and partial hydatidiform mole, malignant disorders of invasive mole like choriocarcinoma, epithelial trophoblastic tumor and placental site trophoblastic tumor. Hydatidiform mole is the most common and benign subtype of the disease. The persistent/malignant forms of the disease are called gestational trophoblastic neoplasia (GTN). This chapter describes the management of GTN.
Background:
High-risk gestational trophoblastic neoplasia (GTN) is rare and treated with diverse approaches. Limited published institutional data has yet to be systematically reviewed.
Objectives:
To compile global high-risk GTN (prognostic score ≥7) cohorts to summarize treatments and outcomes by disease characteristics and primary chemotherapy.
Search strategy:
MEDLINE, Embase, Scopus, ClinicalTrials.gov, and Cochrane were searched through March 2021.
Selection criteria:
Full-text manuscripts reporting mortality among ≥10 high-risk GTN patients.
Data collection and analysis:
Binomial proportions were summed, and random-effects meta-analyses performed.
Main results:
From 1,137 records, we included 35 studies, representing 20 countries. Among 2,276 unique high-risk GTN patients, 99.7% received chemotherapy, 35.8% surgery, and 4.9% radiation. Mortality was 10.9% (243/2,236; meta-analysis: 10%, 95%CI 7-12%), and likelihood of complete response to primary chemotherapy was 79.7% (1,506/1,890; meta-analysis: 78%, 95%CI 74-83%). Across 24 reporting studies, modern preferred chemotherapy (EMA/CO or EMA/EP) was associated with lower mortality (overall: 8.8% vs. 9.5%; comparative meta-analysis: 8.1% vs. 12.4%, OR=0.42, 95%CI 0.20-0.90, 14 studies) and higher likelihood of complete response (overall: 76.6% vs. 72.8%; comparative meta-analysis: 75.9% vs. 60.7%, OR=2.98, 95%CI 1.06-8.35, 14 studies), though studies focused on non-preferred regimens reported comparable outcomes. Mortality was increased for ultra-high-risk disease (30% vs. 7.5% high-risk; meta-analysis OR=7.44; 95%CI 4.29-12.9) and disease following term delivery (20.8% versus 7.3% following molar pregnancy; meta-analysis OR=2.64; 95%CI 1.10-6.31). Relapse rate estimates ranged 3-6%.
Conclusions:
High-risk GTN is responsive to several chemotherapy regimens, with EMA/CO or EMA/EP associated with improved outcomes. Mortality is increased in patients with ultra-high-risk, relapsed, and post-term pregnancy disease.
Introduction: Gestational trophoblastic neoplasia (GTN) is a group of interrelated lesions that results from abnormal proliferation of placental trophoblastic cells. Early diagnosis and treatment of GTN results in successful outcomes with fertility preservation.This study was intended to stratify GTN cases using WHO scoring system, to diagnose and manage cases as per protocol and to identify complications of treatment of GTN. Methodology: This was a single center prospective observational study conducted at Medical college Kolkata from June 2017 to December 2018. All the diagnosed cases of GTN fulfilling the inclusion criteria were incorporated in the study, data were collected from history, clinical examination and investigations. All the data were tabulated and analyzed by standard statistical methods Results: In this study, primiparous are more prone to have GTN and molar pregnancy was the commonest antecedent event (71.4% of cases). 74.3% (26 out of 35) patients developed disease within four months of previous pregnancy. Anemia and vaginal bleeding were the presenting symptoms in >48.0% cases whereas hemoperitoneum,seizure, hemoptysis and respiratory distress were the rare presenting symptoms.In this study, the cases were diagnosed by histopathology or serial estimation of serum β-hcg. In our study, 91.4% patients were successfully treated with methotrexate and only three cases received EMACO. Conclusion: To conclude this study established that cases of GTN can be successfully treated by early diagnosis and timely management.
Purpose
To investigate the survival and fertility outcomes of the patients treated for gestational trophoblastic neoplasia (GTN).
Methods
The clinical records of all the GTN patients registered and treated between January 1, 2008, and December 31, 2013, at a regional cancer center (RCC) in Tamil Nadu, India, were reviewed. About 35 patients with GTN were identified; 29 patients were included in the study. Methotrexate and the EMACO (Etoposide, Methotrexate, Adriamycin, Cyclophosphamide, and Vincristine) regimen were administered based on the risk score evaluation, beta human chorionic gonadotropin (HCG) levels were tested during follow-ups, and annual ultrasonography and chest radiography were performed.
Results
Approximately 15 (51.7%) and 14 (48.3%) patients had low- and high-risk scores, respectively. Five patients (17.2%) underwent hysterectomy, and 21 (72.4%) underwent chemotherapy. Twenty-eight patients (96.6%) survived, and only one (3.4%) died after the treatment because of lung metastasis and pulmonary infections. The overall survival rate in the primary setting was 96.6%. With regard to child-bearing outcomes, 14 patients (48.3%) did not desire a child. Of 15 women who wished to conceive after the treatment, 9 could not conceive, 3 had abortions, and 3 had a normal delivery.
Conclusion
The diagnosis was made using radiological imaging and beta HCG levels for low- and high-risk patients, and the follow-up management was effective in yielding a fertility outcome where patients were able to resume normal reproductive functions. GTN is a highly curable malignancy regardless of the stage and its metastatic nature.
Choriocarcinoma is a malignant neoplasm that classically displays biphasic morphology (syncytiotrophoblasts, cytotrophoblasts and trophoblastic cells). The incidence after term pregnancy is unusual, being diagnosed in most of them because of symptoms due to metastases. We report a case of puerperal choriocarcinoma after a normal uncomplicated pregnancy. After the diagnosis, it was classified as FIGO Stage III malignant gestational trophoblastic neoplasia and high-risk choriocarcinoma. The patient began multiagent systemic chemotherapy biweekly (EMA-CO). Although her tumor marker was normalized after the 3rd cycle, the full-body scan showed a diminishing of the uterine mass but persistent lung metastases. The patient underwent an uncomplicated laparotomy hysterectomy and bilateral salpingectomy procedure. She completed 6 cycles of EMA-CO in total, after which lung lesions disappeared. She remains disease-free 12 months after diagnosis.
Objective:
To define the factors associated with methotrexate (MTX) resistance in patients with low-risk gestational trophoblastic neoplasia (GTN).
Methods:
A total of 63 patients with low-risk GTN according to International Federation of Gynecology and Obstetrics (FIGO) criteria were included. A total of 37 (58.7%) patients were treated with successive doses of 1 mg/kg intramuscular (IM) MTX on days 1, 3, 5, and 7, and 0.1 mg/kg IM folinic acid (FA) on days 2, 4, 6, and 8, until β-human chorionic gonadotropin (hCG) levels were normalized. After the β-hCG value dropped to the normal level, an additional cycle of MTX/FA was administered. This protocol is defined as the standard protocol. In a watchful waiting protocol, the same 8-day IM MTX/FA regimen was given only once (n = 8) or twice (n = 18) to 26 (41.3%) patients and patients in whom β-hCG values declined were subjected to follow-up and no additional cycles were administered as long as there was a decrease in β-hCG value. Clinical response and factors affecting therapeutic outcomes were analyzed retrospectively.
Results:
Of 63 patients, 47 (74.3%) were cured with primary MTX/FA treatment irrespective of any protocol. Of the 16 patients who were not able to be treated with primary MTX/FA, 3 were treated with single-agent actinomycin-D and 11 were treated with multi-agent chemotherapy. Univariate analysis showed that a pretreatment β-hCG level of ≥5000 IU/L was related to reduced therapeutic response (p = 0.001). The FIGO score, antecedent gestational pathology, and treatment with standard or watchful waiting protocol were not related to treatment response.
Conclusions:
The level of β-hCG prior to therapy is an important factor for predicting therapeutic outcomes. It should be noted that the success of the therapy decreases notably in case of high β-hCG level.
Gestational trophoblastic neoplasia (GTN) after a hydatidiform mole is either treated with single- or multi-agent chemotherapy determined by a multifactorial scoring system. Women with human chorionic gonadotrophin (hCG) levels >100 000 IU l(-1) can remain within the low-risk/single-agent category and usually choose one drug therapy. Here we compare the success and duration of single- vs multi-agent chemotherapy in this patient group.
Between 1980 and 2008, 65 women had a pre-treatment hCG >100 000 IU l(-1) and were low risk. The initial hCG level, treatment regimens, changes and duration and overall survival were recorded.
Of 37 patients starting low-risk/single-agent treatment, 11 (29.7%) were treated successfully, whereas 26 (70.3%) required additional multi-agent chemotherapy to achieve complete remission (CR). Combination chemotherapy was initially commenced in 28 women, and 2 (7%) required additional drugs for CR. The overall duration of therapy for those commencing and completing single- or multi-agent chemotherapy was 130 and 123 days (P=0.78), respectively. The median-treatment duration for patients commencing single-agent but changing to multi-agent chemotherapy was 13 days more than those receiving high-risk treatment alone (136 vs 123 days; P=0.07). All 3 patients with an initial hCG >400 000 IU l(-1) and treated with single-agent therapy developed drug resistance. Overall survival for all patients was 100%.
Low-risk post-molar GTN patients with a pre-treatment hCG >100 000 and <400 000 IU l(-1) can be offered low-risk single-agent therapy, as this will cure 30%, is relatively non-toxic and only prolongs treatment by 2 weeks if a change to combination agents is required. Patients whose hCG is >400 000 IU l(-1) should receive multi-agent chemotherapy from the outset.
Gestational trophoblastic diseases (GTD) represent a group of malignancies classified as invasive mole, choriocarcinoma, and placental-site trophoblastic tumors. The overall cure rate in the treatment of this malignant disorder now exceeds 90%. The aim of this study is retrospectively to evaluate the clinical characteristics and effectiveness of single-agent chemotherapy (CT) and combination chemotherapy according to the World Health Organization (WHO) risk groups of gestational trophoblastic diseases. Thirty one patients with GTD were treated in our institute between 1990-1998. Median age at presentation was 29 years (range 19-70 years). All patients were classified with respect to the WHO scoring system. According to this system, patients were divided into three clinical groups: low-risk nonmetastatic (low-risk group with good prognosis), low-risk metastatic, and high-risk metastatic (high risk group with poor prognosis). Eighteen patients in the nonmetastatic low-risk group with favorable prognostic factors received single agent CT (methotrexate and folinic acid), while 3 patients with metastatic low-risk and 10 patients in the metastatic high-risk group with poor prognosis received combination CT (EMA-CO). Complete response (CR) was obtained in all patients in the low risk group with good prognosis, whereas 9/13 (69%) patients in the poor prognosis group achieved CR and 4 (31%) had partial responses. This clinical classification system may be currently prefer for determining initial therapy in women with malignant gestational trophoblastic tumors. And, our report confirms that the alternating EMA/CO regimen is a well-tolerated and effective combination for the treatment of women with high-risk GTD.
The aim of this study was to evaluate the efficacy and toxicity of low-dose methotrexate with folinic acid rescue in a large series of consecutively treated patients with low-risk persistent gestational trophoblastic disease. Between January 1987 and December 2000, 250 patients were treated with intramuscular methotrexate (50 mg on alternate days 1, 3, 5, 7) with folinic acid (7.5 mg orally on alternate days 2, 4, 6, 8) rescue. The overall complete response rate without recurrence was 72% for first-line treatment and 95% for those who required second-line chemotherapy. Eight women (3.2%) had recurrence following remission and two (0.8%) had new moles. Two women (0.8%) died of their disease giving an overall cure of 99%. Only 10 women (4%) experienced grade III/IV toxicity during the first course of treatment and 13 women (5.2%) subsequently. Toxicity included mucositis and stomatitis, pleuritic chest pain, thrombocytopenia, uterine bleeding, abdominal pain, liver function changes, rash and pericardial effusion. A total of 59 women (23.6%) required second-line chemotherapy; 48 women had methotrexate resistance, eight had methotrexate toxicity and an empirical decision to change therapy was made in three. In all, 11 women (4.4%) had a hysterectomy before, during or after treatment; 141 women (56.4%) became pregnant following treatment: in 128 (90.7%), the outcome was successful. Methotrexate with folinic acid rescue is an effective treatment for low-risk persistent trophoblastic disease. It has minimal severe toxicity, excellent cure rates and does not appear to affect fertility.
Following hydatidiform mole, women are at increased risk of persistent gestational trophoblastic neoplasia (pGTN) and are therefore monitored using serum human chorionic gonadotrophin (hCG) concentration measurements. We retrospectively evaluated the policy of extended (2 year) follow up for women with hCG concentrations returning to normal >56 days after evacuation. Of 6701 women registered for hCG follow up, 422 (6%) developed pGTN, 412 (98%) of these women presented within 6 months after evacuation. Three developed pGTN at 402, 677 and 1267 days after evacuation following spontaneous normalisation of hCG levels. Only one woman was detected by routine extended follow up. Prolonged surveillance after molar pregnancy causes significant anxiety and is not cost-effective. Therefore, the current revised protocol comprises hCG follow up for 6 months after spontaneous return of hCG levels to normal for all women.
The aim of this study was to evaluate the efficacy and toxicity of EMA/CO (etoposide, methotrexate, actinomycin D, cyclophosphamide, vincristine) regimen for the treatment of high-risk gestational trophoblastic neoplasia (GTN). Thirty-three patients with high-risk GTN, scored according to World Health Organization, received 159 EMA/CO treatment cycles between 1994 and 2004. Twenty-three patients were treated primarily with EMA/CO, and 10 patients were treated secondarily after failure of single agent or MAC (methotrexate, actinomycin D, cyclophosphamide, or clorambucile) III chemotherapy. Adjuvant surgery and radiotherapy were used in selected patients. Survival, response, and toxicity were analyzed retrospectively. The overall survival rate was 90.9% (30/33). Survival rates were 91.3% (21/23) for primary treatment and 90% (9/10) for secondary treatment. Six (18.2%) of 33 patients had drug resistance. Four of them underwent surgery for adjuvant therapy. Three of these patients with drug resistance died. Survival and complete response to EMA/CO were influenced by liver metastasis, antecedent pregnancy, and histopathologic diagnosis of choriocarcinoma. Survival rate was also affected by blood group. The treatment was well tolerated. The most severe toxicity was grade 3–4 leukopenia that occurred in 24.3% (8/33) of patients and 6.9% (11/159) of treatment cycles. Febrile neutropenia occurred in one patient (3%). EMA/CO regimen is highly effective for treatment of high-risk GTN. Its toxicity is well tolerated.
Gestational trophoblastic disease (GTD) is a spectrum of abnormal trophoblastic hyperplasia resulting from abnormal conception; there is imbalance in the genetic input from the ovum and sperm. The genetic makeup in complete hydatidiform mole (CHM) and partial hydatidiform mole (PHM) is different. In both types of mole, there is an excess of paternal chromosomes resulting in rapidly multiplying trophoblastic cells of both the cytotrophoblastic and the syncytiotrophoblastic layers, which is capable of producing excess of human chorionic gonadotropin (hCG) with potential to progress to gestational trophoblastic neoplasia (GTN). Gestational trophoblastic neoplasia can also develop from previously normal trophoblasts as in cases of choriocarcinoma and placental site trophoblastic tumor (PSTT) following term delivery and abortion. All types of GTN, irrespective of their genetic origin, share the feature of producing high level of hCG. Gestational trophoblastic neoplasia is one of the most chemosensitive and highly curable cancers, even in the presence of widespread metastatic disease, and in most cases with preservation of fertility. GTD is unique because the maternal lesions arise from the fetal tissue.
Objectives:The Gynecologic Oncology Group conducted arandomized phase III trial that prospectively compared weeklymethotrexate at 30 mg/m2(arm I) as initial treatment for low-risk gestational trophoblastic neoplasia (GTN) against biweeklydactinomycin at 1.25 mg/m2(arm II). The primary endpoint wasnormalization of theβhuman chorionic gonadotropin (hCG)(minimum: 4 weeks). Toxicity assessment was a secondaryendpoint.Methods:Patients with untreated, histologically confirmedlow-risk GTN (WHO risk score: 0–6), defined as one of thefollowing, were eligible:b10% decrease inβhCG over threeconsecutive weekly levels, a persistently elevatedβhCG levellonger four months following the initial curettage, or histolo-gically proven nonmetastatic choriocarcinoma.
Results:Between June 1999 and February 2007, 240 patientswere enrolled; 215 were deemed eligible. Age, ethnicity, race,type of molar gestation, WHO risk score, andβhCG level atregistration were equally distributed between the treatmentgroups. The pelvic ultrasound scan was abnormal in 67 and80% (arms I, II); the chest X-ray was abnormal in nine and 13%,respectively. Among responding patients, a median of eightweekly cycles was required in arm I and four biweekly cycles inarm II. Commonly reported toxic effects in arms I and IIrespectively were: nausea (50/107, 61/106), vomiting (14/107,33/106), and stomatitis (9/107, 9/106); all were grade 1 or 2.Grade 1 alopecia was observed in 14 of 107 patients in arm Iand 26 of 106 in arm II. Two patients (arm II) experienced grade4 toxicity: hematologic (1) and neutropenia (1). No grade 5toxicity was reported. Among eligible patients, completeresponse was observed in 53% on arm I and 69% on arm II(P=0.015). Younger patient age, lower WHO risk score, andlower registrationβhCG were each associated with an increasedodds of response relative to the respective reference group.Conclusions:Both regimens were well tolerated. This study hasdemonstrated that biweekly dactinomycin at 1.25 mg/m2is statistically superior to weekly parenteral methotrexate at30 mg/m2as initial management for low-risk GTN
Objective. Controversy exists regarding the use of oral contraceptives following hydatidiform mole and possible increased risk of persistent trophoblastic neoplasia. The purpose of this study is to perform a systematic review of the literature to assess the evidence for and against a possible link between oral contraceptive use and the need for chemotherapy after molar evacuation. Methods. We searched the computerized database, MEDLINE, EMBASE, Popline, Web of Sciences, LILACS and the Cochrane Controlled Trials Register, ISI Proceedings, performed a hand search of references and wrote to experts to identify randomized controlled trials and observational Studies comparing oral contraceptives with other methods of contraception. Quality assessment included: concealment of allocation, intention to treat analysis; Plus attrition bias for trials; confounding factors and selection bias for observational studies. We collected or calculated risk ratios for the incidence of gestational trophoblastic neoplasia and hCG regression time associated with oral contraceptive use. Results. Two randomized controlled trials were included for analysis. The risk ratios for OC use were similar in both Studies: 0.69 (0.12-3.98) and 0.71 (0.46-1.10) respectively. No attempt to summarize these results was made because the Studies observed different disease stages. In five of the seven observational studies, the risk ratio ranged from 0.57 (CI = 0.14-2.37) to 1.46 (Cl = 0.56-3.79). Conclusion. No clear evidence for an association between oral contraceptive use during post-molar follow-up period and the incidence of gestational trophoblastic neoplasia was found. Practitioners Should no longer avoid their use because of a Supposed effect which we have shown here to be unsupported by evidence in the literature.
To analyze the causes of therapeutic success and failure in the management of patients with high-risk gestational trophoblastic tumors (GTTs).
Analysis of 272 consecutive high-risk patients treated at the trophoblastic disease center at the Charing Cross Hospital between 1979 and 1995.
EMA (etoposide, methotrexate, actinomycin D)/CO (cyclophosphamide, vincristine) chemotherapy is our treatment of choice for patients with high-risk GTT. In 272 consecutive patients the cumulative five-year survival was 86.2% (95% confidence interval, 81.9-90.5%). No deaths occurred from GTT more than two years after the start of treatment. In patients whose disease became resistant to EMA/CO or relapsed after receiving EMA/CO, the majority (70%) could be salvaged with further chemotherapy (usually with the EP (etoposide, cisplatin)/EMA chemotherapy with or without surgery. Multivariate analysis identified the following adverse prognostic factors: presence of liver metastases (P < .0001), prolonged interval from antecedent pregnancy (P < .0001), presence of brain metastases (P = .0008) and term delivery of antecedent pregnancy (P = .045). Intensive chemotherapy for treating high-risk GTT carries a small risk of inducing second malignancies, and two patients developed acute myeloid leukemia, 2 cervical malignancy and 1 gastric adenocarcinoma after receiving EMA/CO chemotherapy.
EMA/CO is an effective and well-tolerated regimen for high-risk GTT. Salvage chemotherapy with EP/EMA is effective in the majority of patients whose disease is resistant to EMA/CO and should be combined with surgery when the dominant site of resistant disease is known. Major adverse prognostic variables have been identified, and patients with combinations of these factors should be considered for innovative therapeutic approaches from the outset.
There is no consensus on the best regimen for the primary treatment of low-risk gestational trophoblastic neoplasia (GTN).
Two commonly used single-drug regimens were compared with respect to the proportion of patients meeting the criteria for a complete response (CR) in a randomized phase III trial conducted by the Gynecologic Oncology Group. Eligibility was purposefully broad to maximize the generalizability of the results and included patients with a WHO risk score of 0 to 6 and patients with metastatic disease (limited to lung lesions < 2 cm, adnexa, or vagina) or choriocarcinoma.
Two hundred forty women were enrolled, and 216 were deemed eligible. Biweekly intravenous dactinomycin 1.25 mg/m² was statistically superior to weekly intramuscular (IM) methotrexate 30 mg/m² (CR: 70% v 53%; P = .01). Similarly, in patients with low-risk GTN as defined before the 2002 WHO risk score revisions (risk score of 0 to 4 and excluding choriocarcinoma), response was 58% and 73% in the methotrexate and dactinomycin arms, respectively (P = .03). Both regimens were less effective if the WHO risk score was 5 or 6 or if the diagnosis was choriocarcinoma (CR: 9% and 42%, respectively). There were two potential recurrences; one at 4 months (dactinomycin) and one at 22 months (methotrexate). Not all patients completed follow-up. Both regimens were well tolerated.
The biweekly dactinomycin regimen has a higher CR rate than the weekly IM methotrexate regimen in low-risk GTN, a generally curable disease.
To assess the efficacy, toxicity and survival in patients with high risk GTT treated with the EMA/CO regimen (etoposide, methotrexate, actinomycin D, cyclophosphamide, vincristine/oncovine).
Open non-randomized study of 148 consecutive patients referred to the Charing Cross Hospital between 1979 and 1989.
Trophoblastic disease centre in a London teaching hospital.
148 consecutive patients with high risk GTT were treated with the EMA/CO regimen. 76 patients had received no prior chemotherapy and 72 had received prior chemotherapy.
Survival, causes of treatment failure and toxicity were analysed.
Of 76 patients who had received no prior chemotherapy, 62 (82%) are in remission; an overall survival of 85% for the 148 patients. Ten of the 76 patients without prior chemotherapy died from extensive disease within 3 weeks of starting chemotherapy. The complete and partial response rates to EMA/CO chemotherapy were 80% and 18% respectively. The addition of cisplatin salvaged 9 of 11 (82%) who developed drug resistance and did not require surgery. Salvage surgery alone resulted in 7 of 8 (87%) having complete remissions. Relapse after EMA/CO chemotherapy is uncommon (5.4%) but survival is still relatively good with further chemotherapy and/or surgery with 6 (75%) of 8 patients obtaining a further sustained remission. Complications from EMA/CO chemotherapy are acceptable with myelosuppression being dose-limiting. Late sequelae are uncommon: menstruation usually returns with a few months, and no fetal abnormalities have been recorded in subsequent pregnancies. One patient developed what we presume to be a therapy-induced acute myeloid leukaemia.
At present EMA/CO chemotherapy is our treatment of choice for patients with high risk GTT. Its toxicity is predictable and reversible. In patients developing drug resistance, salvage surgery is important. Future developments may include further dose intensification with the addition of haemopoietic growth factors, earlier diagnosis and the separation of gestational from non-gestational trophoblastic tumours.
This report describes a 53-year-old white woman with metastatic gestational trophoblastic neoplasia that recurred after evacuation of an accidental pregnancy and did not respond sufficiently to treatment with a combination of methotrexate, actinomycin D, and chlorambucil. After second-line treatment with a combination of cisplatin, etoposide, and bleomycin, there was a complete remission. Afterward, the patient suffered from a moderate bleomycin pneumonitis, which resolved spontaneously. She is now free of disease and feeling well 60 months after her last treatment.
Methotrexate and folinic acid was administered as primary therapy in 185 patients with gestational trophoblastic disease between 1974 and 1984. Methotrexate and folinic acid induced complete remission in 147 (90.2%) of 163 patients with nonmetastatic disease and in 15 (68.2%) of 22 patients with low-risk metastatic disease. Sustained remission was achieved in 132 (81.5%) patients following only one course of chemotherapy. All patients with methotrexate resistance subsequently achieved remission with Actinomycin D or combination chemotherapy. Methotrexate when administered with folinic acid was associated with granulocytopenia, thrombocytopenia, and hepatotoxicity in 11 (5.9%), 3 (1.6%), and 26 (14.1%) patients, respectively. The human chorionic gonadotropin (hCG) regression curve served as a reliable guide for the administration of chemotherapy and enabled the attainment of a high remission rate while limiting chemotherapy exposure. Methotrexate and folinic acid achieves an excellent therapeutic outcome with limited chemotherapy exposure and effectively limits systemic toxicity.
To define management options for women presenting with gestational trophoblastic disease (GTD) which had already metastasised to the liver.
Retrospective analysis of case records between 1958 and 1994.
A national referral centre for trophoblastic disease.
The database containing 1676 treated patients was reviewed and 46 patients with hepatic metastases were identified (2.7%). The median age was 32 years (range 19-52 years). The antecedent pregnancy to the GTD was normal in 65% (30/46), and the time interval between the antecedent pregnancy and presentation was longer than one year in 50% (22/44). Lung metastases were present in 43 patients (93%) and brain deposits in 15 patients (33%). Forty-five patients (98%) were high risk by WHO criteria. The five-year overall survival was 27%. The five-year survival of the subgroup of patients having both hepatic and cerebral metastases was 10%. There was no significant survival difference between the different chemotherapy regimens used in the study period (pre-1979 CHAMOCA: methotrexate, actinomycin D, cyclophosphamide, doxorubicin, melphalan, hydroxyurea and vincristine; 1979 onwards EMA/CO-EP: etoposide, methotrexate, adriamycin-D/ cyclophosphamide, vincristine-etoposide and cis-platinum). Multivariate analysis revealed that a prognostic score > 12 was significant (Hazard ratio 5.4, 95% CI 0.7-41.9; P = 0.04).
The outcome for women presenting with hepatic metastases from GTD is poor with an even worse prognosis if cerebral metastases are also present. Alternative therapeutic measures, such as high dose therapy or new drugs, should be explored in these women.
To evaluate the results of etoposide, methotrexate, and dactinomycin alternating with cyclophosphamide and vincristine (EMA/CO) chemotherapy in women with high-risk gestational trophoblastic tumors (GTT) and to document the middle- and long-term toxicity of the regimen.
A total of 272 consecutive women with high-risk GTT, including 121 previously treated patients, were treated with weekly EMA/CO. The median follow-up duration is 4.5 years (range, 1 to 16).
The cumulative 5-year survival rate is 86.2% (95% confidence interval, 81.9% to 90.5%). No deaths from GTT have occurred later than 2 years after the end [corrected] of EMA/CO. In a multivariate model, adverse prognostic factors were the presence of liver metastases (P < .0001), interval from antecedent pregnancy (P < .0001), brain metastases (P = .0008), and term delivery of antecedent pregnancy (P = .045). There were 11 (4%) early deaths, while 213 patients (78%) achieved a complete remission. Forty-seven (17%) developed drug resistance to EMA/CO, of whom 33 (70%) were salvaged by further cisplatin-based chemotherapy and surgery. Two women developed acute myeloid leukemia, two cervical malignancy, and one gastric adenocarcinoma after EMA/CO. More than half (56%) of the women who had fertility-conserving surgery and who have been in remission at least 2 years have become pregnant since the completion of EMA/CO, with 112 live births, including three infants with congenital abnormalities.
EMA/CO is an effective and well-tolerated regimen for high-risk GTT. More than half of the women will retain their fertility; however, there is a small but significant risk of second malignancy.
To evaluate the results of etoposide, cisplatin/etoposide, methotrexate, and actinomycin D (EP/EMA) chemotherapy in patients with gestational trophoblastic tumors (GTTs), who have relapsed after or who have become refractory to EMA/cyclophosphamide and vincristine (CO) chemotherapy, and in patients presenting with metastatic placental site trophoblastic tumors (PSTTs).
We have treated a total of 34 patients with GTT and eight patients with metastatic PSTT with the EP/EMA chemotherapy schedule.
Twenty-two patients received EP/EMA because of apparent drug resistance to EMA/CO, and because the human chorionic gonadotropin (hCG) was near normal, they were not assessable for response. Twenty-one of these patients (95%) are alive and in remission. In the group where the hCG was high enough to confirm a response (greater than one log fall in hCG) to EP/EMA, all 12 patients responded and nine of these patients (75%) are alive and in remission. We have treated three patients with PSTT where the interval from antecedent pregnancy was less than 2 years, and all patients (100%) are alive and in remission. We have treated five patients where the interval from antecedent pregnancy was greater than 2 years and one fifth (20%) remain in remission. The survival for patients with GTT is 30 (88%) out of 34 patients and four (50%) out of eight patients for PSTT, giving an overall survival for these two cohorts of 34 (81%) out of 42 patients. The toxicity of this schedule is significant, with grade 3 or 4 toxicity (National Cancer Institute common toxicity criteria) recorded in hemoglobin (21%), WBC (68%), and platelets (40%). The role of surgery in this group of patients is important and contributed to sustained remission in five patients (23%) and possibly helped an additional seven patients (32%).
EP/EMA is an effective but moderately toxic regimen for patients with high-risk GTT who become refractory to or relapse from EMA/CO chemotherapy. Also, EP/EMA clearly has activity in patients with metastatic PSTT.
Partial hydatidiform moles (PMs) rarely require chemotherapy and have never previously been proven to transform into choriocarcinoma, the most malignant form of gestational trophoblastic disease (GTD). Consequently, some have questioned whether women with PMs need human chorionic gonadotropin (hCG) follow-up. Here, we investigate whether PMs can transform into choriocarcinomas.
Patients with a PM who developed a subsequent choriocarcinoma were identified from our GTD database. The histology of both PM and ensuing choriocarcinoma was reviewed and flow cytometry used to verify the triploid status of the PMs. To determine whether the choriocarcinoma arose from the PM, DNA from the PM and choriocarcinoma in each patient was compared using microsatellite polymorphisms.
Of the 3000 patients with PM, 15 required chemotherapy for persisting GTD. This was identified as choriocarcinoma in three cases. In one patient, the local pathologist could not differentiate between a PM or a hydropic abortion and neither central histological review nor hCG follow-up were obtained. This patient nearly died before the diagnosis of choriocarcinoma was made. Fortunately, the local pathologists correctly diagnosed PM in the two other patients who were then registered for hCG follow-up. Some months later, the hCG was rising and repeat uterine evacuation revealed choriocarcinoma. The PM was confirmed to be triploid in all three cases and genetic analysis showed that the subsequent choriocarcinomas contained identical single maternal and two paternal alleles at several independent loci.
Our results show that PMs can transform into choriocarcinoma. All patients with suspected PM should be reviewed centrally and, if confirmed, need hCG follow-up.
Kohorn EI. The new FIGO 2000 staging and risk factor scoring system for gestational trophoblastic disease: description and critical assessment.
The classification of the International Federation of Obstetrics and Gynecology (FIGO) for Trophoblastic Disease was changed at the meeting in Washington in September 2000 by combining the basic FIGO anatomic staging with the modified World Health Organization (WHO) risk factor scoring system. This presentation outlines the new system and provides a critical evaluation of the issues that have been resolved and those that are still outstanding.
We have simplified the treatment of gestational trophoblastic disease (GTD) in order to reduce the number of patients exposed to potentially carcinogenic chemotherapy. Patients who score 0 to 8 on the Charing Cross scoring system are classified as low-risk and receive methotrexate (MTX) and folinic acid (FA), whereas those who score higher than 8 are classified as high-risk and receive the etoposide, methotrexate, and dactinomycin (EMA)/cyclophosphamide and vincristine (CO) regimen.
Between 1992 and 2000, 485 women with GTD were commenced on MTX/FA at Charing Cross Hospital, London, United Kingdom. If patients developed MTX resistance or toxicity, treatment was altered according to the level of beta human chorionic gonadotropin (hCG). If serum hCG was < or = 100 IU/L, patients received dactinomycin; if hCG was greater than 100 IU/L, patients received EMA/CO.
The median duration of follow-up was 4.7 years. Overall survival was 100% and the relapse rate was 3.3% (16 of 485 patients). hCG values normalized in 324 (66.8%) of 485 patients with MTX alone, whereas 161 (33.2%) of 485 patients required a change in treatment, 11 because of MTX toxicity and 150 because of MTX resistance. Sixty-seven patients changed to dactinomycin, of whom 58 achieved normal hCG values, and nine required third-line chemotherapy with EMA/CO. hCG values normalized in 93 (98.9%) of 94 patients who changed directly to EMA/CO from MTX.
Single-agent dactinomycin has activity in patients with low-risk GTD who develop MTX resistance and whose hCG is low. Simplifying the stratification of GTD into two classes (low- and high-risk) does not compromise overall outcome and may reduce the risk of second tumors.
To describe 34 cases of placental site trophoblastic tumor (PSTT) treated at Charing Cross Hospital over 25 years.
Between 1975 and 2001, 1,685 patients with gestational trophoblastic disease (GTD) were treated; 34 of them had PSTT (2%). The computer database clinical notes and the pathology reports were accessed to obtain data on this patient group. The data were subsequently analyzed using Excel computer software.
The mean age of the group was 33 years (95% CI 25-41). The antecedent pregnancy was a full-term, normal one in 18 cases (53%), a molar pregnancy in 7 (21%) and a missed abortion in 5 (15%). The mean interval from the last pregnancy to diagnosis was 3.4 years (95% CI 1.9-4.9). The range of serum hCG concentrations at diagnosis was 0-58,000, 79% with levels < 1,000 and 58% < 500. hCG was raised in all with active disease. The most frequent presenting complaint was vaginal bleeding, in 27 cases (79%). At diagnosis, the disease was localized to the uterus in 15 (44%); there was pelvic involvement in 8 (24%) and lung secondaries in 10 (29%). All seven deaths were disease related (21%); all had lung secondaries and presented more than four years since the last pregnancy. Excluding the seven deaths, the primary treatment was surgery alone in 10 cases (37%) (8 hysterectomies and 2 dilatation and curettages); 4 had surgery followed by adjuvant chemotherapy; 5 had neoadjuvant chemotherapy followed by surgery; 1 had chemotherapy alone, and the disease recurred and was successfully rechallenged; and 5 had surgery between chemotherapy cycles. The most common regimens consisted of EMA/CO and EP/EMA.
Risk factors for death include lung metastatic involvement (50%) and an antecedent pregnancy interval of four years or more (100%). In contrast, those with no extrapelvic disease or a pregnancy interval of less than four years had 100% survival. In two-thirds of patients with disease limited to the uterus, surgery alone was curative. The WHO scoring system for GTD did not correlate with this outcome. Patients with PSTT should be managed separately from those with other types of GTD, as the disease behavior is different.
To determine the timescale of the registration process for gestational trophoblastic disease and its impact on hCG level at registration and subsequent need for chemotherapy.
A prospective observational study using a standardised protocol for registration, assessment and treatment for molar pregnancy.
A supra-regional tertiary referral centre for gestational trophoblastic disease.
A total of 2046 consecutive women registered between January 1994 and December 1998 with a diagnosis of molar pregnancy.
Data at and after registration, collected prospectively on a computerised database, were statistically analysed (by multiple logistic regression and ANOVA).
Relationship between length of time to and hCG value at registration; also the subsequent need for chemotherapy.
A total of 2046 women with a diagnosis of molar pregnancy were registered in the study period. The mean time interval between first evacuation and registration at the referral centre was 47 days (median 37, range 0-594). One hundred and five out of 2046 (5.1%) women needed chemotherapy. Sixty-three precent of the women (1296 out of 2046) had a normal level of urinary hCG (less than 40 IU/24 hours) at the time of registration and only one (0.08%) needed chemotherapy. Binary logistic regression analysis showed a statistically significant relationship between time to registration, hCG value, histology, pretreatment risk score and decision to administer chemotherapy.
Women with gestational trophoblastic disease who were registered late were significantly more likely to have normal levels of hCG and were less likely to need chemotherapy. A less intensive follow up may be justified in women with gestational trophoblastic disease who are registered with a normal hCG level.
Controversy exists regarding the use of oral contraceptives following hydatidiform mole and possible increased risk of persistent trophoblastic neoplasia. The purpose of this study is to perform a systematic review of the literature to assess the evidence for and against a possible link between oral contraceptive use and the need for chemotherapy after molar evacuation.
We searched the computerized databases MEDLINE, EMBASE, Popline, Web of Sciences, LILACS and the Cochrane Controlled Trials Register, ISI Proceedings, performed a hand search of references and wrote to experts to identify randomized controlled trials and observational studies comparing oral contraceptives with other methods of contraception. Quality assessment included: concealment of allocation; intention to treat analysis; plus attrition bias for trials; confounding factors and selection bias for observational studies. We collected or calculated risk ratios for the incidence of gestational trophoblastic neoplasia and hCG regression time associated with oral contraceptive use.
Two randomized controlled trials were included for analysis. The risk ratios for OC use were similar in both studies: 0.69 (0.12-3.98) and 0.71 (0.46-1.10) respectively. No attempt to summarize these results was made because the studies observed different disease stages. In five of the seven observational studies, the risk ratio ranged from 0.57 (CI = 0.14-2.37) to 1.46 (CI = 0.56-3.79).
No clear evidence for an association between oral contraceptive use during post-molar follow-up period and the incidence of gestational trophoblastic neoplasia was found. Practitioners should no longer avoid their use because of a supposed effect which we have shown here to be unsupported by evidence in the literature.
The aim of this study was to evaluate the efficacy and toxicity of EMA/CO (etoposide, methotrexate, actinomycin D, cyclophosphamide, vincristine) regimen for the treatment of high-risk gestational trophoblastic neoplasia (GTN). Thirty-three patients with high-risk GTN, scored according to World Health Organization, received 159 EMA/CO treatment cycles between 1994 and 2004. Twenty-three patients were treated primarily with EMA/CO, and 10 patients were treated secondarily after failure of single agent or MAC (methotrexate, actinomycin D, cyclophosphamide, or clorambucile) III chemotherapy. Adjuvant surgery and radiotherapy were used in selected patients. Survival, response, and toxicity were analyzed retrospectively. The overall survival rate was 90.9% (30/33). Survival rates were 91.3% (21/23) for primary treatment and 90% (9/10) for secondary treatment. Six (18.2%) of 33 patients had drug resistance. Four of them underwent surgery for adjuvant therapy. Three of these patients with drug resistance died. Survival and complete response to EMA/CO were influenced by liver metastasis, antecedent pregnancy, and histopathologic diagnosis of choriocarcinoma. Survival rate was also affected by blood group. The treatment was well tolerated. The most severe toxicity was grade 3-4 leukopenia that occurred in 24.3% (8/33) of patients and 6.9% (11/159) of treatment cycles. Febrile neutropenia occurred in one patient (3%). EMA/CO regimen is highly effective for treatment of high-risk GTN. Its toxicity is well tolerated.
To study the incidence of postmolar gestational trophoblastic disease (GTD) following hydatidiform mole and to evaluate the effectiveness of single-agent chemotherapy using methotrexate with folinic acid rescue.
A prospective study of all cases of hydatidiform mole diagnosed and treated in the department of obstetrics and gynecology, Medical College, Calicut, India, was started in June 1990 to determine the incidence of postmolar GTD and the effectiveness of single-agent chemotherapy with methotrexate and folinic acid in postmolar nonmetastatic GTD.
For the 15-year period from June 1990 to May 2005, 1,569 cases of hydatidiform mole were diagnosed and managed at our institution. The incidence of postmolar GTD among 1,569 cases of hydatidiform mole was 20.4%. Of the 321 cases of postmolar GTD diagnosed, 284 patients (88.5%) achieved complete remission with the methotrexate/folinic acid regimen. Fourteen multiparous patients (4.4%) underwent hysterectomy with methotrexate/folinic acid and achieved remission. Thus, 92.9% of patients with postmolar GTD had complete remission with the methotrexate/folinic acid regimen. The rest of the cases required multiagent therapy.
Regular follow-up of patients after evacuation of hydatidiform mole will detect cases of postmolar GTD at an early stage. Single-agent chemotherapy with methotrexate was effective in 92.9% of our cases.
Results with the EMA/CO (etoposide, methotrexate, actino-mycin D, cyclophosphamide, vincristine) regimen in high risk gestational trophoblastic tumors
- Newlands Es Bagshawe Kd
- Rustin Gj Begent Rh
- Holden
Newlands ES, Bagshawe KD, Begent RH, Rustin GJ, Holden L. Results with the EMA/CO (etoposide, methotrexate, actino-mycin D, cyclophosphamide, vincristine) regimen in high risk gestational trophoblastic tumors, 1979 to 1989. Br J Obstet Gynaecol 1991;98:550e557.
Low risk persistent gestational trophoblastic disease: outcome following initial treatment with low-dose methotrexate and folinic acid, 1992–2000.
- McNeish I.A.
- Strickland S.
- Holden L.
McNeish IA, Strickland S, Holden L, et al. Low risk persistent
gestational trophoblastic disease: outcome following initial
treatment with low-dose methotrexate and folinic acid,
1992e2000. J Clin Oncol 2002;20:1838e1844.
Green-top Guideline No. 38.
- Royal Colleges of Obstetricians and Gynecologists