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EMA/CO for High-Risk Gestational Trophoblastic Tumors: Results From a Cohort of 272 Patients

PURPOSE 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. PATIENTS AND METHODS 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). RESULTS 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. CONCLUSION 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.

Combination but not single-agent methotrexate chemotherapy for gestational trophoblastic tumors increases the incidence of second tumors.

PURPOSE No increase in second tumor incidence was found in a previous analysis of women treated with chemotherapy for gestational trophoblastic tumors (GTT). More patient years at risk enabled a further analysis of the risk of second tumors to be performed in the 1,377 women treated in this until up to 1990. PATIENTS AND METHODS Health questionnaires were returned on 93.3% of patients who successfully completed chemotherapy and were living in the United Kingdom. The remainder were flagged for death or developing further cancers by the Office of Population Census and Surveys and by the Thames Cancer Registry. Incidence density analysis was performed based on 15,279 person-years of observation available. Standardized incidence ratio (SIR) was used to estimate the relative risk (RR) of second tumors associated with the treatment. To calculate the expected number, the actual incidence rates observed by the Thames Cancer Registry during the same calendar period of observation were used. RESULTS An overall 50% excess of risk (RR = 1.5; 95% confidence interval [CI], 1.1 to 2.1; P < .011) was observed: there were 37 second tumors, when 24.5 were expected. For specific second tumors, the risk was significantly increased for myeloid leukemia (RR = 16.6; 95% CI, 5.4 to 38.9), colon (RR = 4.6; 95% CI, 1.5 to 10.7), and breast cancer when the survival exceeded 25 years (RR = 5.8; 95% CI, 1.2 to 16.9). The risk was not significantly increased among the 554 women receiving single-agent therapy (RR = 1.3; 95% CI, 0.6 to 2.1). Leukemias only developed in patients receiving etoposide plus other cytotoxic drugs. CONCLUSION This study suggests that there is a slight increased risk of second tumors after sequential or combination chemotherapy for GTT. This has become apparent since the introduction of etoposide and longer follow-up.

Salvage chemotherapy of relapsed or high-risk gestational trophoblastic neoplasia (GTN) with paclitaxel/cisplatin alternating with paclitaxel/etoposide (TP/TE)

OBJECTIVES 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). PATIENTS AND METHODS 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). RESULTS 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. CONCLUSION 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.

EMA/CO for High-Risk Gestational Trophoblastic Neoplasia: Good Outcomes With Induction Low-Dose Etoposide-Cisplatin and Genetic Analysis

PURPOSE Patients with high-risk (International Federation of Gynecology and Obstetrics score ≥ 7) gestational trophoblastic neoplasia (GTN) frequently receive etoposide, methotrexate, and dactinomycin alternating weekly with cyclophosphamide and vincristine (EMA/CO). Between 1979 and 1995, overall survival (OS) with this regimen at our institute was 85.4% with a significant proportion of early deaths (< 4 weeks). Here, we determine whether survival rates have improved in a more recent patient cohort (1995 to 2010). PATIENTS AND METHODS Patients receiving EMA/CO were identified using the Charing Cross GTN database. Genetic analysis identified nongestational trophoblastic tumors (nGTTs). The use of induction low-dose etoposide 100 mg/m(2) and cisplatin 20 mg/m(2) (EP; days 1 and 2 every 7 days) since 1995 to reduce early deaths before commencing EMA/CO was noted. RESULTS Four hundred thirty-eight patients received EMA/CO between 1995 and 2010. Six patients had nGTTs, 140 had high-risk disease, and 250 had relapsed/resistant low-risk GTN. OS was 94.3% in high-risk patients (90.4% including nGTTs) and 99.6% in the low-risk group, with a median follow-up time of 4.2 years. All patients with nGTT and seven patients with high-risk GTNs died as a result of drug-resistant disease. EP induction chemotherapy was given to 23.1% of high-risk patients (33 of 140 patients) with a large disease burden, and the early death rate was only 0.7% (n = 1; 95% CI, 0.1% to 3.7%) compared with 7.2% (n = 11 of 151 patients; 95% CI, 4.1% to 12.6%) in the pre-1995 cohort. CONCLUSION OS after EMA/CO for high-risk GTN has increased by nearly 9%. This reflects a more accurate estimate of OS by excluding nGTTs (3.9%) in patients with atypical presentations using genetic diagnosis. Low-dose induction EP in selected individuals also allows near complete elimination of early deaths. The latter should be considered routinely in high-risk GTN.

The management and outcome of women with post-hydatidiform mole 'low-risk' gestational trophoblastic neoplasia, but hCG levels in excess of 100 000 IU l(-1).

Background: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.Methods: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.Results: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%.Conclusion: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.

Treatment outcomes for 618 women with gestational trophoblastic tumours following a molar pregnancy at the Charing Cross Hospital, 2000–2009

Background:Post-molar pregnancy gestational trophoblastic tumours (GTT) have been curable with chemotherapy treatment for over 50 years. Because of the rarity of the diagnosis, detailed structured information on prognosis, treatment escalations and outcome is limited.Methods:We have reviewed the demographics, prognostic variables, treatment course and clinical outcomes for the post-mole GTT patients treated at Charing Cross Hospital between 2000 and 2009.Results:Of the 618 women studied, 547 had a diagnosis of complete mole, 13 complete mole with a twin conception and 58 partial moles. At the commencement of treatment, 94% of patients were in the FIGO low-risk group (score 0–6). For patients treated with single-agent methotrexate, the primary cure rate ranged from 75% for a FIGO score of 0–1 through to 31% for those with a FIGO score of 6.Conclusion:In the setting of a formal follow-up programme, the expected cure rate for GTT after a molar pregnancy should be 100%. Prompt treatment and diagnosis should limit the exposure of most patients to combination chemotherapy. Because of the post-treatment relapse rate of 3% post-chemotherapy, hCG monitoring should be performed routinely.

Infertility rates following POMB/ACE chemotherapy for male and female germ cell tumours - a retrospective long-term follow-up study.

The risk of chemotherapy-induced infertility in male and female germ cell tumour (GCT) survivors is unclear, but may correlate with cisplatin dose. Here, we examine a large series of GCT patients for the effect of chemotherapy on those attempting to have children. Our GCT database was screened for nonseminomatous GCT patients who had (1) received POMB/ACE chemotherapy (cisplatin, vincristine, methotrexate, bleomycin alternating with actinomycin D, cyclophosphamide and etoposide) and (2) stage I male GCT patients who were untreated between 1977 and 1996. Fertility was assessed by questionnaire and medical records. A total of 64 of 153 treated and 35 of 115 untreated men attempted to have children. In all, 28% (18 out of 64) receiving POMB/ACE were unsuccessful. Radiotherapy (six), atrophic remaining testis (one) or prior infertility (three) were implicated in 10 cases, so chemotherapy-induced infertility may have occurred in only 11% (eight out of 64). Strikingly, 26% (nine out of 35) of untreated stage I patients also failed to have children (three had radiotherapy, three prior infertility). Moreover, in treated men, no association was seen between cisplatin dose and infertility. In contrast, radiotherapy significantly increased male infertility (P=0.001). Of 28 treated women who attempted to have children, 25% (seven out of 28) were unsuccessful. One previously had infertility and one subsequently had successful IVF so chemotherapy-induced infertility potentially occurred in only 18% (five out of 28) and was not related to cisplatin dose. In conclusion, the risk of chemotherapy-induced infertility is low in both male and female GCT patients and does not clearly correlate with the cumulative cisplatin dose.

The effect of early pregnancy following chemotherapy on disease relapse and foetal outcome in women treated for gestational trophoblastic tumours

Little literature exists on the safety of early pregnancy following chemotherapy. Here we assess the rate of relapse and foetal outcome in women who have completed single and multi-agent chemotherapy for gestational trophoblastic tumours. The records of 1532 patients treated for persistent gestational trophoblastic tumours at Charing Cross Hospital between 1969 and 1998 were reviewed. Patients were defined as receiving single agent or multi-agent treatment. Relapse rates and foetal outcome were reviewed in the 230 patients who became pregnant within 12 months of completing chemotherapy. In the single agent group 153 (22%) of 691 patients conceived early. Three subsequently relapsed. In the multi-agent group, 77 (10%) of 779 patients conceived early, two then relapsed. Relapse rates were 2% (3 out of 153) and 2.5% (2 out of 77) for each group compared to 5% and 5.6% in the comparative non-pregnant groups. Outcomes of 230 early pregnancies: 164 (71%) delivered at full term, 35 (15%) terminations, 26 (11%) spontaneous abortions, three (1.3%) new hydatidiform moles and two (1%) stillbirths. Early pregnancies were more common in the single agent group (P<0.001), but spontaneous miscarriages and terminations were more likely to occur in the multi-agent group (P=0.04 and 0.03, respectively). Of the full-term pregnancies, three (1.8%) babies were born with congenital abnormalities. Patients in either group who conceive within 12 months of completing chemotherapy are not at increased risk of relapse. Though, we still advise avoiding pregnancy within 12 months of completing chemotherapy, those that do conceive can be reassured of a likely favourable outcome.

Chemotherapy and human chorionic gonadotropin concentrations 6 months after uterine evacuation of molar pregnancy: a retrospective cohort study

Summary Background Indications for chemotherapy in gestational trophoblastic disease include raised human chorionic gonadotropin (hCG) concentrations 6 months after uterine evacuation of hydatidiform mole, even when values are falling. We aimed to establish whether chemotherapy is always necessary in these patients. Methods We retrospectively identified women registered between January, 1993, and May, 2008, at Charing Cross Hospital, London, UK, who had persistently high hCG concentrations 6 months after evacuation of hydatidiform mole. Rates of hCG normalisation, relapse, and death were assessed in patients continued under surveillance and those who received chemotherapy after 6 months. We postulated that a surveillance policy would be clinically acceptable if hCG values returned to normal in 75% of patients or more. Findings 76 (<1%) of 13 960 patients with hydatidiform moles had persistently high hCG concentrations of more than 5 IU/L 6 months after evacuation. 66 (87%) patients continued under surveillance and hCG values spontaneously returned to normal without chemotherapy in 65 (98%) of these patients. Values in one patient did not become normal because of chronic renal failure, but she remains healthy. Ten patients received chemotherapy, and hCG concentrations returned to normal in eight (80%) of these individuals (surveillance vs chemotherapy groups p=0·044) and remained slightly high (6–11 IU/L) in two without any associated clinical problems off treatment. We noted no significant differences between individuals in the surveillance and chemotherapy groups, apart from lower median hCG concentrations 6 months after evacuation in those under surveillance than in those given chemotherapy (13 IU/L, range 5–887, vs 157 IU/L, range 6–6438; p=0·004). Overall, there were no deaths in this series. Interpretation A surveillance policy seems to be clinically acceptable in patients with low and declining concentrations of hCG 6 months after evacuation of hydatidiform mole. Funding National Commissioning Group, Imperial Experimental Cancer Medicine Centre, Imperial Biomedical Research Centre, and Cancer Research UK.

Uterine artery pulsatility index: a predictor of methotrexate resistance in gestational trophoblastic neoplasia

Background:Neo-angiogenesis is a hallmark of cancer. The aim of this study was to test the hypothesis, in a prospective patient cohort, that in low-risk gestational trophoblastic neoplasia (LR-GTN) the uterine artery pulsatility index (UAPI), a measure of tumour vascularity, can predict resistance to methotrexate chemotherapy (MTX-R).Methods:286 LR-GTN patients (Charing Cross Hospital (CXH) score 0–8, or FIGO score 0–6) were treated with methotrexate between January 2008 and June 2011 at CXH. During staging investigations, patients underwent a Doppler ultrasound to assess the UAPI.Results:239 patients were assessable for both UAPI and MTX-R. The median UAPI was lower (higher vascularity) in MTX-R compared with MTX-sensitive patients (0.8 vs 1.4, P<0.0001). In multivariate logistic regression, UAPI⩽1 predicted MTX-R, independent of both CXH and FIGO scores. The risk of MTX-R in patients with a FIGO score of 6 and UAPI⩽1 was 100% vs 20% in patients with UAPI>1 (χ2 P<0.0001).Conclusion:UAPI represents an independently validated clinically useful predictor of MTX-R in LR-GTN. Further, consideration of whether to incorporate UAPI into the FIGO scoring system is now warranted so that patients with a score of 6 and a UAPI ⩽1 might be upstaged and offered combination chemotherapy rather than MTX.