Gestational choriocarcinoma accounts for 5% of gestational trophoblastic neoplasms. Approximately 50%, 25%, and 25% of gestational choriocarcinoma occur after molar pregnancies, term pregnancies, and other gestational events, respectively. The FIGO scoring system categorizes patients into low (score 0 to 6) and high risk (score 7 or more) choriocarcinoma. Single-agent and multi-agent chemotherapy are used in low- and high-risk patients, respectively. Chemotherapy for localized disease has a goal of eradication of disease without surgery and is associated with favorable prognosis and fertility preservation. Most patients with gestational choriocarcinoma are cured with chemotherapy; however, some (<5.0%) will die as a result of multi-drug resistance, underscoring the need for novel approaches in this group of patients. Although there are limited data due to its rarity, the treatment response with immunotherapy is high, ranging between 50-70%. Novel combinations of immune checkpoint inhibitors with targeted therapies (including VEGFR-2 inhibitors) are under evaluation. PD-L1 inhibitors are considered a potential important opportunity for chemo-resistant patients, and to replace or de-escalate chemotherapy to avoid or minimize chemotherapy toxicity. In this review, the Rare Tumor Working Group and the European Organization for Research and Treatment of Cancer evaluated the current landscape and further perspective in the management of patients diagnosed with gestational choriocarcinoma.© IGCS and ESGO 2023. No commercial re-use. See rights and permissions. Published by BMJ.

To investigate the demographics, natural history and treatment outcomes of non‐molar gestational choriocarcinoma.

We investigated the clinical characteristics, treatments, and survival of patients with gestational trophoblastic neoplasia (GTN) who experienced recurrence. Factors predictive of recurrence were also investigated.

To evaluate the usefulness of positron emission tomography with 18-fluorodeoxyglucose (18FDG-PET) in locating residual or relapsed gestational trophoblastic neoplasia (GTN).The Charing Cross GTN database was screened, and 11 patients who had undergone 18FDG-PET were identified. A retrospective analysis was conducted to determine the value of this investigation as compared with other imaging modalities in clinical care.All patients had elevated beta-human chorionic gonadotropin (beta-hCG) at the time of the investigation; none were false positive. In 7 patients the 18FDG-PET scans correctly confirmed the presence (4 of 7 cases) or absence (3 of 7 cases) of disease sites defined by other imaging investigations. In 2 patients positive PET-guided appropriate surgical resection of lung lesions that appeared of equivocal significance on computed tomography (CT) resulted in -hCG normalization. One patient had a pulmonary metastasis on CT not considered positive on 18FDG-PET (false negative). One patient with enlarged mediastinal lymph nodes on CT that were 18FDG-PET positive also had a vascular uterus on magnetic resonance imaging/Dopper ultrasound that was negative on PET (false negative). Hysterectomy led to hCG normalization and cure. The mediastinal lymph nodes were positive on CT and PET due to sarcoidosis (false positive). Patients with serum hCG levels <10 IU/L could have positive PET scans; that can contribute to patient care.18FDG-PET can aid in identifying residual disease sites in women relapsing from previously treated GTN. However, careful evaluation in combination with other imaging modalities is required to reduce the risk of false positive and negative results.

Risk has different meanings even within the confines of trophoblastic disease. One unquantifiable risk for patients is treatment by physicians or surgeons with limited knowledge of this rare disease and its modern management. Risk can be immediate at the time of presentation because the disease has sometimes progressed to a life-threatening state before the diagnosis is established. Special problems at that time need consideration on the basis of which organs are involved. Placental-site trophoblastic disease presents distinctive features and requires different management. A major long-term risk is drug resistance, and a high proportion of late treatment failures in choriocarcinoma arise from inappropriate therapy at an early stage in treatment. "Prognostic," or "risk," scoring identifies the propensity of a tumor to become resistant to chemotherapy and enables treatment to be planned from the outset to minimize that risk.

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.

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.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.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.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.

To evaluate the efficacy of etoposide, cisplatin-etoposide, methotrexate, actinomycin-D (EP-EMA) chemotherapy as the frontline treatment for gestational trophoblastic neoplasia (GTN) patients with very high (≥ 12) FIGO prognostic scores.Nine patients with very-high-risk GTN were treated with EP-EMA at the Cancer Institute, Adyar, India, between January 1, 2001, and December 31, 2007. Salvage chemotherapy, adjuvant surgery, and radiotherapy were used when indicated. Clinical response, toxicity, and survival were analyzed separately.The median FIGO score was 15. Six (66.7%) patients had a complete clinical response, whereas progressive disease occurred for 3 (33.3%) women. None of the patients relapsed. This translated to an overall survival rate of 66.7% in the primary setting. All patients with liver-only metastases were survivors after treatment with EP-EMA. Grade 3 neutropenia was detected in 3 (33.3%) patients only. No life-threatening toxicity was observed after EP-EMA treatment.EP-EMA was highly effective for the primary management of very-high-risk GTN.Copyright © 2011 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.

Although most patients with gestational trophoblastic neoplasia (GTN) are cured by conventional chemotherapy, some develop drug resistance or relapse. The use of new combination drugs has been studied to treat those with resistant or relapsed disease. We evaluated the results of floxuridine, dactinomycin, etoposide, and vincristine (FAEV) chemotherapy in patients with relapsed/chemoresistant GTN.Clinical data and outcome of the patients with relapsed/chemoresistant GTN from 1 January 2005 to 30 June 2008 were retrospectively reviewed. Eligible patients had received at least one cycle of FAEV chemotherapy. The primary end points were response rate and toxicity of FAEV regimen; the secondary end point was assessment of clinical predictors of response.In total, 91 patients were included. Fifty-five of these patients (60.4%) achieved serologic complete remission (SCR), 29 patients had no response, 7 patients experienced recurrent grade ≥3 or intolerable toxicity. SCR of FAEV chemotherapy was significantly associated with number of previous chemotherapy regimens (≤2) in multivariate analysis (P = 0.005). The most serious adverse events were greater than or equal to grade 3 neutropenia (26.4%), febrile neutropenia (6.6%), and greater than or equal to grade 3 thrombocytopenia (3.3%).FAEV is an effective regimen with manageable toxicity for patients with relapsed/chemoresistant GTN. Further studies of this regimen are warranted.

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.

To evaluate the efficacy and toxicity of paclitaxel and cisplatin alternating with paclitaxel and etoposide doublet regimen (TP/TE), for salvage of patients with high-risk gestational trophoblastic neoplasia (GTN).Twenty-four patients with GTN received TP/TE. Sixteen had failed previous chemotherapy including six with cisplatin-based regimens (group A) and eight changed to TP/TE because of prior treatment-induced toxic effects (group B).In group A, three patients (19%) achieved a complete response (CR) and five (31%) a partial response (PR). All CR and four PR patients remain alive with a median follow-up of 25 months (range 9-48). The eight patients failing TP/TE subsequently died. Thus, the overall survival of the 16 patients in group A was 44% (seven of 16), rising to 70% (seven of 10) if the six patients who had failed prior cisplatin-based chemotherapy were excluded. In group B, four patients were assessable for response (two CR, two PR) and six remain alive (median follow-up 19 months) giving an overall survival of 75%. TP/TE was well tolerated, with only one patient discontinuing therapy because of toxic effects.TP/TE is an effective, well-tolerated, salvage treatment for relapsed patients who are heavily pretreated for GTN. Further studies of this regimen are warranted.

High-risk gestational trophoblastic neoplasia (GTN) can lead to fatal complications; however, few reports have assessed emergency surgery as a treatment option for such complications. Thus, this study aimed to analyze the clinical features and prognosis of patients with GTN who underwent emergency surgery.Thirteen patients with high-risk or ultra-high-risk GTN who underwent emergency surgery for fatal complications in the First Affiliated Hospital of Zhejiang University, School of Medicine from 2013 to 2020 were analyzed, and their medical records were reviewed. The patients' characteristics and treatment were evaluated with respect to outcomes.Thirteen patients with GTN who underwent 15 emergency surgical procedures were identified in our center. The mean International Federation of Gynecology and Obstetrics score of these patients was 14.8 (range, 11-19). Of the 13 patients, six underwent brain surgeries, such as tumor resection (n = 5) and conservative surgery (n = 1). All the patients received multi-agent chemotherapy after emergency surgery, and the mean time from emergency surgery to subsequent chemotherapy was 12.7 days. Of the 13 patients, 10 (77%) were cured and disease-free, with a follow-up period ranging from 3 months to 8 years. All the patients (n = 6) who underwent emergency brain surgery survived and achieved complete remission.For patients with high-risk GTN with fatal complications, especially brain lesions, emergency surgery combined with subsequent chemotherapy may provide a favorable prognosis.© 2022 Wang et al.

Despite the undoubted effectiveness of chemotherapeutic treatment in gestational trophoblastic neoplasia (GTN), problems related to toxicity of chemotherapy and chemo-resistant disease have led to reconsideration of the use of hysterectomy. Aim of the present study was to evaluate indications for and outcome of hysterectomy in patients with GTN in a nation-wide cohort.Between 1977 and 2012, we identified all patients diagnosed with GTN and treated with hysterectomy from the Dutch national databases. Demographics, clinical characteristics and follow-up were recorded retrospectively.One hundred and nine patients (16.5% of all registered patients with GTN) underwent hysterectomy as part of their management for GTN. The majority of patients was classified as low-risk disease (74.3%), post-molar GTN (73.5%) and disease confined to the uterus (65.1%). After hysterectomy, complete remission was achieved in 66.2% of patients with localized disease and in 15.8% of patients with metastatic disease. For patients with localized disease, treated with primary hysterectomy, treatment duration was significantly shorter (mean 3.2weeks and 8.0weeks respectively, p=0.01) with lower number of administered chemotherapy cycles (mean 1.5 and 5.8 respectively, p<0.01) than patients in a matched control group.In selected cases, a hysterectomy may be an effective means to either reduce or eliminate tumor bulk. Primary hysterectomy should mainly be considered in older patients with localized disease and no desire to preserve fertility, whereas patients with chemotherapy-resistant disease may benefit from additional hysterectomy, especially when disease is localized. For patients with widespread metastatic disease, the benefit of hysterectomy lies in the removal of chemotherapy-resistant tumor bulk with subsequent effect on survival.Copyright © 2017 Elsevier Inc. All rights reserved.

The aim of the study was to assess the effectiveness of a combined treatment modality of salvage chemotherapy and pulmonary resection in chemo-resistant/relapsed gestational trophoblastic neoplasia (GTN) with lung metastasis and identify predictors of treatment failure. Data of patients with chemo-resistant/relapsed GTN with lung metastasis who received salvage chemotherapy combined with pulmonary resection were retrospectively analyzed. Among 134 included patients, the number of preoperative chemotherapy regimens ranged from 2–8 (median, 3), and courses ranged from 4–37 (median, 14). Pulmonary lobectomies, segmentectomies, wedge resections, and lobectomies plus wedge resections were performed in 84, 5, 35, and 10 patients, respectively. After completion of treatment, 130 (97.0%) patients achieved complete remission. In the entire cohort, the 5-year overall survival (OS) rate was 87.6%. OS rates were similar between stage III and stage IV disease cohorts (89.4% vs. 75.0%, p = 0.137). Preoperative β-human chorionic gonadotropin (β-hCG) levels &gt; 10 IU/L (p = 0.027) and number of preoperative chemotherapy regimens &gt; 3 (p = 0.018) were predictors of treatment failure. The combined treatment modality of salvage chemotherapy and pulmonary resection is effective in patients with chemo-resistant/relapsed GTN with lung metastasis, improving their prognoses. Patients with preoperative serum β-hCG &gt;10 IU/L and those with &gt;3 chemotherapy regimens preoperatively may not benefit from this multidisciplinary treatment.

The lungs are the most common site of metastasis in patients with gestational trophoblastic neoplasia. We investigated surgical management and prognostic factors of patients with refractory gestational trophoblastic neoplasia to assess the value of lung metastasis resection.The clinical data of patients with refractory gestational trophoblastic neoplasia and lung metastasis treated at Peking Union Medical College Hospital from January 2005 to December 2020 were retrospectively analyzed. Surgical characteristics and survival outcomes were analyzed.In total, 213 patients with refractory gestational trophoblastic neoplasia and lung metastasis were screened, and 148 patients who underwent unilateral lung resection were analyzed. Patients' median age was 32 years. Lobectomy was performed in 65.5% of patients, while wedge resection was performed in 34.5%. The rate of postoperative complications was 12.2%. The pathological rate was 66.2%. Video-assisted thoracoscopic surgery showed better surgical characteristics than thoracotomy did. Compared with lobectomy, wedge resection had a shorter operative time, shorter duration of chest tube placement, shorter postoperative hospital stay, and fewer postoperative complications. The median follow-up period was 36 months. During follow-up, 90.5% of patients achieved complete remission. The 5-year disease-free and overall survival rates were 80.4% and 92.6%, respectively. More previous chemotherapy courses and failure to achieve normal β-human chorionic gonadotropin levels postoperatively were predictors of poor prognosis.Surgical treatment of lung metastasis is valuable and safe for patients with refractory gestational trophoblastic neoplasia. The minimally invasive video-assisted thoracoscopic approach and wedge resection are recommended.Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.

The efficacy of immune checkpoint blockade in gestational trophoblastic neoplasia (GTN) remains uncertain. We report the results of the GTN cohort of SWOG S1609 dual anti–CTLA-4 and anti–PD-1 blockade in rare tumors (DART).

To evaluate clinical characteristics, treatment technique, and results in patients with gestational trophoblastic disease metastatic to the brain.From 1962 to 1994, 26 (4.1%) of 631 patients who underwent treatment for trophoblastic disease had or developed evidence of brain metastases (patients were aged 14-43 years). All patients received multiagent systemic chemotherapy and whole-brain irradiation. Total doses of radiation were 2,386-4,000 cGy (200-300 cGy per fraction). No patient received intrathecal chemotherapy. Patients were divided into three groups: group A, symptomatic brain metastases at presentation; group B, asymptomatic or minimally symptomatic brain disease at presentation; and group C, development of brain metastases during systemic chemotherapy.The overall 5-year actuarial survival rate was 51%. Multivariate analysis findings indicated that age, preceding pregnancy event, human chorionic gonadotropin level, World Health Organization score, performance of craniotomy, and number of brain metastases did not influence survival. The difference in the 5-year overall survival rates between groups A (39%) and B (100%) was significant (P =.03).Gestational trophoblastic disease metastatic to the brain is curable with systemic chemotherapy and whole-brain irradiation. The authors suggest treatment with steroids, chemotherapy (etoposide, high-dose methotrexate [1 g/m2], dactinomycin, cyclophosphamide, and vincristine sulfate), and concurrent whole-brain irradiation (3,000 cGy in 200-cGy fractions).

An estimated 20% of patients with cancer will develop brain metastases. Approximately 200,000 individuals in the United States alone receive whole-brain radiotherapy (WBRT) each year to treat brain metastases. Historically, the prognosis of patients with brain metastases has been poor; however, with new therapies, this is changing. Because patients are living longer following the diagnosis and treatment of brain metastases, there has been rising concern about treatment-related toxicities associated with WBRT, including neurocognitive toxicity. In addition, recent clinical trials have raised questions about the use of WBRT. To better understand this rapidly changing landscape, this review outlines the treatment roles and toxicities of WBRT and alternative therapies for the management of brain metastases.

To evaluate characteristics of patients with central nervous system (CNS) lesions of gestational trophoblastic disease (GTD) and determine prognostic and therapeutic implications applicable to management.We retrospectively reviewed the records of 454 patients treated at the Southeastern Regional Trophoblastic Disease Center between 1966 and 1992 with at least 2 years of follow-up, and identified 42 (9.3%) with CNS metastases. Sixteen patients presented for primary therapy and 27 patients had received significant therapy prior to presentation. Three heavily treated moribund patients died before their first cycle of chemotherapy and were excluded from analysis. Brain metastases were documented by physical exam and radionuclide imaging (before 1976), computed tomography scan (after 1976), or magnetic resonance imaging (after 1986). Patients received multiagent chemotherapy with methotrexate, actinomycin D, and chlorambucil (MAC)- or etoposide-based regimens. All patients received radiation therapy. No intrathecal chemotherapy was given. Craniotomy was employed in seven cases. Remission was defined as three weekly hCG levels below assay sensitivity (< 5 mIU/ml).Overall survival was 44%. Twelve of 16 patients (75%) who presented with CNS metastases with no prior therapy (Group A), 5 of 13 (38%) patients who had prior treatment (Group B), and none of 10 patients who developed CNS metastases during therapy (Group C) survived (P < 0.05). Two of four patients who failed in the CNS after treatment for CNS lesions were salvaged. Demographic characteristics of Groups A and B were similar. No significant differences with respect to WHO score, interval from pregnancy to onset of disease, or age among these groups were found. Group B patients had a four-fold higher incidence of liver metastases. Survival of Group A patients was not related to conventional clinical prognostic factors. Inverse (nonsignificant) correlations were found for Group B patients between survival and WHO score, hCG level, size and number of metastatic lesions, but not type of prior therapy. Survival was higher in those with prior molar pregnancies (56%) as contrasted with aborted (50%) or term (27%) gestations. Selective use of craniotomy helped alleviate intracranial pressure and resect refractory foci.Chemotherapy combined with radiation therapy in GTD patients with CNS metastases yields survival rates comparable to those reported for intrathecal methotrexate regimens. Tumor burden as indicated by hCG level and size/number of metastases in previously treated patients may correlate with survival. Patients who develop CNS metastases during active therapy have a very poor outcome.