Quimioterapia para la neoplasia trofoblástica gestacional resistente o recidivante
Resumen
Antecedentes
La neoplasia trofoblástica gestacional (NTG) es un grupo de tumores relacionados con el embarazo altamente curables; sin embargo, aproximadamente el 25% de los tumores de la NTG serán resistentes o tendrán una recidiva después de la quimioterapia inicial. Estas lesiones resistentes y recidivantes requerirán quimioterapia de rescate con o sin cirugía. En todo el mundo se utilizan diversos regímenes de rescate. No está claro qué regímenes son los más efectivos y los menos tóxicos.
Objetivos
Determinar qué régimen/es de quimioterapia para el tratamiento de la NTG resistente o recidivante es/son el/los más eficaz/eficaces y menos tóxico/s.
Métodos de búsqueda
Se realizaron búsquedas en el Registro especializado del Grupo Cochrane de Cáncer Ginecológico (Cochrane Gynaecological Cancer Group), en el Registro Cochrane Central de Ensayos Controlados (Cochrane Central Register of Controlled Trials) (CENTRAL, Número 4), MEDLINE y EMBASE hasta octubre de 2011. Además, se realizaron búsquedas manuales en las actas de congresos de sociedades relevantes y en las listas de referencias de los estudios. Para la revisión actualizada, se hicieron búsquedas en el Registro especializado del Grupo Cochrane, CENTRAL, MEDLINE y EMBASE hasta el 16 de noviembre de 2015. También se realizaron búsquedas de ensayos en curso en los registros electrónicos de ensayos clínicos.
Criterios de selección
Sólo se incluyeron ensayos controlados aleatorizados (ECA).
Obtención y análisis de los datos
Se diseñó un formulario de extracción de datos y se planificó utilizar los métodos de efectos aleatorios de Review Manager 5.1 para los metanálisis.
Resultados principales
La búsqueda no identificó ECA; por lo tanto, no fue posible realizar metanálisis.
Conclusiones de los autores
Los ECA en la NTG son escasos debido a la prevalencia baja de esta enfermedad y su naturaleza sumamente sensible a la quimioterapia. Como los agentes quimioterapéuticos se pueden asociar con efectos secundarios significativos, el tratamiento ideal debe lograr la máxima eficacia con efectos secundarios mínimos. Para la NTG de bajo riesgo resistente a metotrexato o recidivante, la práctica habitual es utilizar dactinomicina secuencial por cinco días, seguida de MAC (metotrexato, dactinomicina, ciclofosfamida) o EMA/CO (etopósido, metotrexato, dactinomicina, ciclofosfamida, vinblastina) si se requiere tratamiento de rescate adicional. Sin embargo, la dactinomicina por cinco días se asocia con más efectos secundarios que la dactinomicina por pulsos, por lo que se recomienda un ECA que compare la eficacia y la seguridad relativas de estos dos regímenes en el contexto del fracaso del tratamiento primario con metotrexato.
Para la NTG de alto riesgo, EMA/CO es el tratamiento de primera línea utilizado con mayor frecuencia y como tratamiento de rescate se prefieren las combinaciones con platino‐etopósido, particularmente EMA/EP (etopósido, metotrexato, dactinomicina / etopósido, cisplatino). Las alternativas, que incluyen TP/TE (paclitaxel, cisplatino/ paclitaxel, etopósido), BEP (bleomicina, etopósido, cisplatino), FAEV (floxuridina, dactinomicina, etopósido, vincristina) y FA (5‐fluorouracilo [5‐FU], dactinomicina), pueden ser tan efectivas como EMA/EP y asociarse con menos efectos secundarios; sin embargo, no está claro a partir de la evidencia disponible y necesita ser probado en ECA bien diseñados. Realizar en el Reino Unido un ECA que compare intervenciones para la NTG resistente/recidivante será muy desafiante debido al escaso número de pacientes con estas características. Por lo tanto, se necesita de la colaboración multicéntrica internacional para proporcionar evidencia de alta calidad para determinar qué régimen/es de rescate tiene/n el mejor cociente efectividad/toxicidad en la enfermedad de bajo y alto riesgo. Los estudios de investigación futuros deben incluir evaluaciones económicas y vigilancia a largo plazo para las neoplasias secundarias.
PICO
Resumen en términos sencillos
Tratamiento farmacológico anticanceroso para la neoplasia trofoblástica gestacional (NTG) que no responde al tratamiento de primera línea o que recidiva
Esta revisión está relacionada con el tratamiento farmacológico anticanceroso para las pacientes con NTG que no responde al tratamiento de primera línea o que recidiva. NTG es el nombre dado a un tipo de cáncer que surge del tejido placentario después de un embarazo, con mayor frecuencia de un embarazo molar. Los embarazos molares son crecimientos anormales benignos del tejido placentario dentro de la matriz. La mayoría se cura mediante la evacuación (D&C) de la matriz, pero hasta el 20% de los casos se convierten en malignos. Habitualmente la NTG responde bien a los fármacos anticancerosos (quimioterapia); sin embargo, estos fármacos pueden ser tóxicos, por lo que el objetivo del tratamiento es lograr la curación con efectos secundarios mínimos. Para ayudar a los médicos a seleccionar el tratamiento más apropiado para las pacientes con NTG, la enfermedad se clasifica como de bajo o de alto riesgo según factores de riesgo específicos.
El tratamiento con quimioterapia para la NTG de bajo riesgo generalmente sólo requiere un fármaco único, mientras que los tumores de alto riesgo se tratan con una combinación de fármacos. La combinación más frecuente consiste en cinco fármacos y se abrevia como EMA/CO. Los médicos evalúan la respuesta al tratamiento al verificar los niveles de la hormona del embarazo (hCG) en la sangre. Si se considera que la quimioterapia no funcionó, se debe comenzar un tratamiento alternativo (o de rescate). Lo anterior es necesario en alrededor del 25% de los casos y se utilizan diversas combinaciones farmacológicas.
Esta revisión se realizó porque no estaba claro cuál de las diversas combinaciones de rescate, si había alguna, era la más efectiva y menos tóxica. Se realizaron búsquedas en la bibliografía hasta noviembre de 2015 para encontrar todos los estudios relevantes. Desafortunadamente, no fue posible encontrar estudios de buena calidad que compararan los diferentes tipos de tratamientos de rescate. Lo anterior se debió en parte a que la enfermedad tiene una tasa de curación alta con varias opciones de quimioterapia combinada, pero también a la poca frecuencia de la enfermedad, lo que hace difícil el reclutamiento para estudios grandes. Por lo tanto, no fue posible establecer conclusiones acerca de cómo se comparan estas combinaciones farmacológicas con respecto a su efectividad y efectos secundarios y se estimula a los investigadores en este campo a colaborar para aportar esta evidencia importante.
Authors' conclusions
Background
Description of the condition
Gestational trophoblastic disease (GTD) encompasses a spectrum of pregnancy‐related disorders that includes benign, pre‐malignant disorders (complete and partial hydatidiform mole), and persistent, malignant disorders of invasive mole, choriocarcinoma, placental site trophoblastic tumour (PSTT) and epithelial trophoblastic tumour (ETT). Gestational trophoblastic neoplasia (GTN) is a term used for the persistent/malignant disorders.
The incidence of GTD varies across the world. In North America and Europe it is less than two per 1000 pregnancies, whereas higher rates have been reported in parts of Asia, Africa and South America (Lee 2009; Palmer 1994; Tham 2003). GTD can affect women at any reproductive age; however, the risk is higher in women under 16 years and over 45 years of age (Sebire 2002).
Persistent disorders or GTN usually arise following molar pregnancies, but may occur after any antecedent pregnancy (Seckl 2009). Complete moles (CMs) are paternally derived and have a diploid karyotype, whereas partial moles (PMs) are usually triploid, deriving two sets of haploid genes paternally and one maternally. Molar pregnancies usually resolve spontaneously following one or more uterine evacuations, with or without chemotherapy. However, in approximately 6% to 20% of CMs and 0.5% to 1% of PMs the disease persists and transforms to GTN (Hancock 2006; Seckl 2009), which usually requires chemotherapy. The most common forms of GTN are invasive mole and choriocarcinoma; PSTT and ETT are rare.
Various scoring systems have been used to stratify GTN according to risk (Bagshawe 1976; Hammond 1973; WHO 1983). Most recently the combined WHO‐FIGO system (Table 1; Table 2; FIGO 2009; Nagan 2002) was adopted in 2002 by the International Society for the Study of Trophoblastic Diseases (ISSTD) (Kohorn 2000; Nagan 2002). The revised scoring system differs from the WHO system in that the ABO blood group risk factor has been eliminated and the risk factor for liver metastases has been upgraded from two to four. Low‐risk is defined as a score of six or less (FIGO stages I‐III) owing to the merging of the old intermediate‐risk group (scores five and six) into the low‐risk category (score zero to four). A score of seven or more (or FIGO stage IV) is classed as high risk.
| Stage I | Disease confined to the uterus |
| Stage II | GTN extends outside of the uterus, but is limited to the genital structures (adnexa, vagina, broad ligament) |
| Stage III | GTN extends to the lungs with or without known genital tract involvement |
| Stage IV | All other metastatic sites |
| Scores | 0 | 1 | 2 | 4 |
| Age (years) | < 40 | ≥ 40 | – | – |
| Antecedent pregnancy | mole | abortion | term | – |
| Interval months from index pregnancy | < 4 | 4 to 6 | 7 to 12 | > 12 |
| Pre‐treatment serum hCG (IU/L) | < 103 | 103–104 | 104 to 105 | > 105 |
| Largest tumour size (including uterus) | < 3 | 3 to 4 cm | ≥ 5 cm | – |
| Site of metastases | lung | spleen, kidney | gastrointestinal | liver, brain |
| Number of metastases | – | 1 to 4 | 5 to 8 | > 8 |
| Previous failed chemotherapy | – | – | single drug | ≥ 2 drugs |
| To stage and allot a risk factor score, a patient's diagnosis is allocated to a stage as represented by a Roman numeral I, II, III and IV. This is then separated by a colon from the sum of all the actual risk factor scores expressed in Arabic numerals, i.e. stage II:4, stage IV:9. This stage and score will be allotted for each patient (FIGO 2009). A score ≤ 6 indicates low risk; > 6 indicates high risk. | ||||
Invasive moles and choriocarcinomas are highly chemosensitive tumours and chemotherapy (with or without surgery) will cure virtually all low‐risk lesions and 80% to 90% of high‐risk lesions. However, approximately 25% of these tumours will be resistant to primary treatment or relapse after cure and will require salvage chemotherapy. Low‐risk GTN is more common than high‐risk GTN and more easily salvaged. Treatment failure or drug‐resistance is variably defined in the literature and may be considered to have developed if three consecutive serum hCG values decline by less than 10% over two weeks or by one log hCG level over six weeks, if two consecutive hCG values rise, or if new metastases develop (Covens 2006; Homesley 2009; McGrath 2010). These criteria may not be clinically helpful for patients with low hCG levels (Covens 2006; Homesley 2009). Relapse or recurrence has occurred if there is a rise in serum hCG levels after reaching normal values with treatment.
Description of the intervention
Chemotherapy regimens differ for low‐risk and high‐risk lesions:
Low‐risk GTN
Women with low‐risk GTN are usually treated with single‐agent chemotherapy, methotrexate (with or without folinic acid) or dactinomycin. However, 5‐fluorouracil (5‐FU) has been used in China for many years and is considered very effective and less toxic (Song 1998). Five‐ and eight‐day methotrexate regimens are the first‐line treatment of choice at many centres in Europe and the North America (May 2011; McGrath 2010). Dactinomycin is generally considered to be associated with more side effects than methotrexate, particularly alopecia and nausea; however, one Cochrane review of first‐line chemotherapy for low‐risk GTN found that dactinomycin was more likely to result in primary cure than methotrexate with comparable side effects, especially when bi‐weekly pulsed dactinomycin was used (Alazzam 2012a).
Tumour resistance to first‐line chemotherapy has been reported in up to 45% of women with low‐risk GTN, depending on the regimen used (Homeseley 1988; Khan 2003; Lurain 1995; McNeish 2002; Osborne 2011), with higher primary cure rates reported with the five‐ and eight‐day methotrexate regimens (10% to 33%) than with weekly low‐dose methotrexate. Resistance in low‐risk GTN is more likely to develop when pre‐treatment hCG levels are high (Hammond 1973; Lurain 1995; McGrath 2010). A study from Charing Cross hospital (London, UK) found that single‐agent chemotherapy (methotrexate) only cured 30% of low‐risk women with hCG levels greater than 100,000 mIU/mL and was futile in low‐risk lesions where hCG levels were greater than 400,000 mIU/mL (McGrath 2010). Other risk factors for drug resistance in low‐risk GTN include higher risk scores (i.e. five or six) (El‐Helw 2009; Osborne 2011), non‐molar antecedent pregnancy and a histological diagnosis of choriocarcinoma (Hammond 1973; Lurain 1995). Drug resistance to primary therapy is associated with higher relapse rates (Matsui 2005).
When first‐line chemotherapy fails, secondary chemotherapy, with or without surgery, is used to achieve remission. Several secondary treatment regimens have been described with various success rates and toxicity profiles, including:
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single‐agent pulsed dactinomycin (Covens 2006) (where first‐line therapy has been methotrexate);
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five‐day dactinomycin (McNeish 2002);
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etoposide and dactinomycin (EA) (Dobson 2000);
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methotrexate, dactinomycin, cyclophosphamide (MAC) (Goldstein 2012);
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etoposide, methotrexate, dactinomycin/cyclophosphamide, vincristine (EMA/CO) (McNeish 2002).
High‐risk GTN
Women with high‐risk GTN are at a higher risk of first‐line treatment failure and therefore require multi‐agent combination chemotherapy to achieve a cure. Various combinations are and have been used as first‐line treatment of high‐risk GTN, including:
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EMA/CO, as reported in Newlands 1986, whereby EMA and CO are given on alternate weeks, is the most widely used;
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MEA (methotrexate, etoposide, dactinomycin), is reported to have comparable success rates with relatively reduced toxicity (Dobson 2000; Matsui 2004);
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MAC or methotrexate, dactinomycin, chlorambucil (Curry 1989; Hammond 1973);
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FA (5‐FU, dactinomycin) or FAV (5‐FU, dactinomycin, vincristine) are commonly used regimens in China (Feng 2011; Zhao 2009);
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MEF (methotrexate, etoposide, 5‐FU) (Wang 2006);
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EMA/EP (etoposide, methotrexate, dactinomycin/etoposide, cisplatin) whereby EMA and EP are alternated weekly (Cyriac 2011; Ghaemmaghami 2004);
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CHAMOCA (methotrexate, dactinomycin, cyclophosphamide, doxorubicin, melphalan, hydroxyurea, vincristine) (Bagshawe 1976) was found to be more toxic and less effective than MAC (Curry 1989) and has been superseded by EMA/CO.
PSTT and ETT are less chemo‐sensitive than GTN owing to invasive mole or choriocarcinoma and more likely to relapse. The first‐line treatment for these rare tumours is usually surgery (hysterectomy with pelvic lymph node sampling), with the administration of adjuvant chemotherapy to women with metastatic disease (Goldstein 2012; Seckl 2010).
Deng 2009 conducted a systematic review of chemotherapy for high‐risk GTN and were unable to draw any firm conclusions about the best primary treatment regimen as only one small RCT was found (EMA/CO versus CHAMOCA; Curry 1989). EMA/CO is the most widely used primary combination therapy for high‐risk GTN, however 30% to 40% of women will develop resistance or will relapse after remission and need salvage chemotherapy (Goldstein 2012; Lurain 2011). Salvage chemotherapy in high‐risk GTN is a much more difficult clinical scenario than salvage chemotherapy in low‐risk GTN. Risk factors for resistance to treatment in high‐risk GTN include the number and sites of metastases (brain, liver and gastrointestinal metastases have a worse prognosis), incomplete previous treatments, and the age of the tumour (Kim 1998). Salvage therapy is more likely to fail in heavily pre‐treated patients (Feng 2011; Theodore 1989; Wang 2008), hence hysterectomy and other adjuvant treatments play an important role in the management of these women. Several salvage regimens have been reported in the literature, mostly small case series (see Table 3), including:
| Study | Dates | Participants | Characteristics | Primary treatment | Salvage treatment | Complete response | Severe adverse effects (≥ G3) | Investigators' conclusions |
| 1977 to 1985 | 22 women | Drug‐resistant high‐risk GTN (14 women; WHO scores ≥ 8). Also included 8 women who underwent primary treatment for high‐risk GTN | Methotrexate/vinca alkaloid with or without sequential dactinomycin (12/14 women) | EP with dactinomycin (APE; 8) or without (EP; 6) every 4 weeks | CR = 13/14 (93%) and 11/14 were cured (79%; defined as CR sustained for 12 months). 1 woman died | Data for the drug‐resistant group could not be separated. Leukopenia 11/22 (50%); thrombocytopenia 8/22 (36%); alopecia 22/22 (100%); sepsis 3/22 (14%); renal 4/22 (18%); nausea and vomiting 6/22 (27%). SAEs were more likely to occur with the APE than with the EP regimen | APE/PE regimens compare favourably with other regimens such as MAC and EMA/CO | |
| 1977 to 1985 | 8 women | Drug resistant high‐risk GTN (WHO score > 11) | Methotrexate/vincristine alternated with vincristine/dactinomycin weekly (6/8 women) | PVB (every 21 days) | CR = 6/8 (75%; including 2 woman who had a partial response initially but a CR following hysterectomy). 1 woman relapsed and 5/8 were cured | All toxicities were grade 1/2 | PVB is a well‐tolerated regimen. Hysterectomy plays an important role in the treatment of drug resistant GTN | |
| 1984 to 1992 | 7 women | Median WHO score = 16 (range 10 to 20). Heavily pre‐treated women | Not reported in detail. Various regimens of which 6/7 included etoposide | EP (days 1 to 5; 14 to 21 day cycles) | CR = 6/7 (86%) but only 3/7 had sustained remissions, and 4 died within 18 months | Neutropenia = 5/7 (71%); neutropenic sepsis = 4/7 (57%); thrombocytopenia = 2/7 (29%); renal toxicity = 2/7 (29%) | EP therapy is an active salvage regimen for GTN but has significant haematological and renal toxicity | |
| 1980 to 1997 | 42 women | 34/42 women had relapsed/resistant high‐risk GTN; 8 women had PSTT. 22/34 relapsed/resistant women had hCG levels approaching normal | EMA/CO | EMA/EP | The 22 women with low levels of hCG could not be assessed for response. Of the remaining 12 relapsed/resistant women, CR = 9/12 (75%). OS = 30/34 (88%) | Neutropenia (68%); anaemia (21%); thrombocytopenia (40%). (These data may include data from women with PSTT.) Myelosuppression caused delays in chemotherapy in 88% of patients and dose reductions in 38% | EMA/EP is an effective regimen for relapsed/resistant high‐risk GTN (with surgery in selected cases) but toxicity is significant | |
| 1985 to 2001 | 10 women | 7 women had resistant high‐risk GTN and 3 women had relapsed after treatment | EMA/CO (2) and MEA (8) | FA | OS = 8/10 (80%). Mean follow‐up of 11.5 years. 2 patients died of multidrug resistance and 2 relapsed subsequently and were treated successfully with MEA | Neutropenia (6.4% of cycles) and thrombocytopenia (3.8% of cycles) | FA is an effective and well‐tolerated salvage therapy | |
| Unclear | 15 women | 12 women had resistant high‐risk GTN and 3 had PSTT | Unclear | EMA/EP | CR = 11/15 (73.3%) | Myelosuppression and gastrointestinal SAEs | EMA/EP is an effective salvage therapy for chemo‐refractory GTN | |
| 1980 to 2001 | 26 women | Relapsed or resistant high‐risk GTN | EMA/CO (10). MA‐based without E (16) | All salvage treatment contained E + P. BEP (19), EMA/EP (3), VIP/ICE (3), PVB. Repeated every 21 days | CR = 73%; OS = 61.5% | Not reported | BEP is first choice for high‐risk patients with drug resistance or relapse following treatment with EMA/CO and EMA/EP. This regimen resulted in a 74% CR and 58% OS in this study | |
| 1992 to 2003 | 26 women | 9 women had relapsed or resistant high‐risk GTN. Also included 17 women undergoing primary treatment. Risk score range was 7 to 12 | MA (4); MEA (2); MAC (1); EMA/CO (2) | MEF | CR = 7/9 (78%); OS = 8/9 (96%) at mean follow‐up of 37 months (range 14 to 124 months) | 1 death occurred owing to multi‐drug resistant GTN. Toxicity data could not be separated (reported as % of 167 cycles): neutropenia (26.4%); nausea/vomiting (39%); thrombocytopenia (5.6%). G‐CSF given as necessary | MEF is a well‐tolerated, less‐toxic regimen that is effective as salvage therapy | |
| 1999 to 2005 | 18 women | 11 women had resistant high‐risk GTN and 7 women had relapsed after treatment | EMA/CO | EMA/EP | CR = 12/18 (66.6%) including 9/11 (82%) resistant patients and 3/7 (43%) relapsed patients | Neutropenia (28% of cycles); nausea/vomiting 15% of cycles). Myelosuppression and hepatotoxicity led to dose reductions and delays in 43% of cycles despite the use of G‐CSF as necessary | EMA/EP was more effective in patients with drug resistance than those who have relapsed after treatment with EMA/CO. Toxicity caused treatment delays that might have been prevented with prophylactic G‐CSF | |
| 2001 to 2004 | 11 women | Resistant high‐risk GTN with median risk score of 9 (range 7 to 13) | Various | FAEV | CR = 7/11 (63.6%) | Myelosuppression was treated with G‐CSF in 98.4% of courses | FAEV could be an effective treatment for drug‐resistant GTN | |
| 1996 to 2005 | 13 women | 10 woman had resistant high‐risk GTN and 3 women had relapsed after treatment | EMA/CO | EMA/EP | CR = 11/13 (84.6%); 5 patients had adjuvant surgery/brain irradiation | Not reported | EMA/EP is a highly effective salvage therapy for those patients failing EMA/CO treatment | |
| 1999 to 2006 | 24 women | Group A: 16 women with relapsed/resistant GTN (9 high‐risk, 5 low‐risk and 2 PSTT) Group B: 8 women switched owing to toxicity on previous regimen (4 high‐risk, 1 low‐risk and 3 PSTT). 10/24 women (42%) had received 2 or more previous chemotherapy regimens | Group A: EMA/CO or EMA/EP, or both (5) or BEP (1) Group B: EMA/EP (5), EMA/CO (2), EMA/EP + EMA/CO (1) | TP/TE | Group A: CR = 3/16 (19%); OS = 7/16 (44%; median follow up of 25 months) Group B: CR = 2/4 assessable (50%); OS = 6/8 (75%; at median of 19 months follow up) | Neutropenia = 10/24 (42%); neuropathy = 1/24 (4%); thrombocytopenia = 3/24 (13%). Treatment discontinued in 1 patient owing to neuropathy (grade 2). No dose reductions or delays | TP/TE was more likely to fail if previous chemotherapy had included a platinum agent. Out of 10 patients who had not previously received EMA/EP, 7/10 survived (70%). TP/TE is relatively less toxic than EMA/EP | |
| 1995 to 2007 | 12 women | High‐risk drug‐resistant GTN | FA | BEP | CR = 10/12 (83%) | Not reported | BEP is more convenient than EMA/CO and is well tolerated | |
| 2005 to 2008 | 91 women | 80/91 women had relapsed or resistant high‐risk GTN; 11/91 had relapsed or resistant low‐risk GTN. 63/91 women (69.1%) had received 2 or more previous chemotherapy regimens | Mainly FAV (60), EMA/CO (29) and 5‐FU (22) but several other regimens administered | FAEV | CR = 55/91 (60.4%); NR = 29/91 (31.9%) OS at 3 years = 74.9% | Neutropenia 24/91 (26.4%); febrile neutropenia 6/91 (6.6%); thrombocytopenia 3/91 (3.3%). 7/91 (7.7%) discontinued FAEV owing to toxicity. No neutropenic sepsis or treatment‐related deaths | FAEV is an effective salvage regimen in this cohort of heavily pre‐treated patients. It is more convenient (21‐day cycle) and less toxic than other regimens | |
| 2009 to 2011 | 5 women | Heavily pre‐treated high‐risk women (≥ 3 previous regimens; risk scores of 9, 10, 17, 17 and 18) | Various including EMA, EMA/CO, ICE, VAC, EMA/EP, TP/TE, PT, PI | FA | CR = 1/5 (20%) | Neutropenia 3/12 cycles (25%); diarrhoea 1/12 cycles (8%); mucositis 8/12 cycles (67%) | FA had modest efficacy with tolerable side effects in this group of heavily pre‐treated patients |
5‐FU: 5‐fluorouracil; APE: etoposide, cisplatin, dactinomycin; BEP: bleomycin, etoposide, cisplatin; CR: complete response; E: etoposide; EMA: etoposide, methotrexate, dactinomycin; EMA/CO: etoposide, methotrexate, dactinomycin/cyclophosphamide, vincristine; EMA/EP: etoposide, methotrexate, dactinomycin/ etoposide, cisplatin; EP: etoposide, cisplatin; FA: 5‐fluorouracil, dactinomycin; FAEV: floxuridine, dactinomycin, etoposide, vincristine; FAV: 5‐fluorouracil, dactinomycin, vincristine; G‐CSF: granulocyte colony stimulating factor; GTN: gestational trophoblastic neoplasia; hCG: human chorionic gonadotrophin; MA: methotrexate, dactinomycin; MAC: methotrexate, dactinomycin, cyclophosphamide; MEA: methotrexate, etoposide, dactinomycin; MEF: methotrexate, etoposide, 5‐fluorouracil; NR: no response; OS: overall survival; PI: cisplatin, ifosfamide; PSTT: placental site trophoblastic tumour; PT: carboplatin, paclitaxel; PVB: cisplatin, vinblastine, bleomycin; SAE: severe adverse effects; TP/TE: paclitaxel, cisplatin/paclitaxel, etoposide; VAC: vincristine, actinomycin, cyclophosphamide; VIP/ICE: ifosfamide, etoposide, cisplatin; WHO: World Health Organization.
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EMA/EP (Lurain 2005; Lu 2008; Mao 2007; Newlands 2000);
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BEP (bleomycin, etoposide, cisplatin) (Lurain 2005; Zhao 2009);
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VBP or PVB (cisplatin or carboplatin, vinblastine, bleomycin) (Azab 1989; Rodriguez 2010)
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VIP or ICE (ifosfamide, etoposide, cisplatin) (Lurain 2005);
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EP (etoposide, cisplatin) (Soper 1995; Theodore 1989);
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TP/TE (paclitaxel, cisplatin/paclitaxel, etoposide) whereby TP and TE are alternated weekly (Wang 2008);
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FAEV (floxuridine, dactinomycin, etoposide, vincristine) every 21 days (Feng 2011; Wan 2007).
Approximately 90% of high‐risk patients treated initially with EMA/CO, followed by salvage therapy with a platinum‐etoposide combination if required, will survive (Lurain 2010). In three series of EMA/EP salvage treatment following EMA/CO treatment failure, cure rates of 75% (nine out of 12 women; Newlands 2000) 66.6% (12 out of 18 women; Mao 2007) and 84.9% (11 out of 13 women; Lu 2008) were reported; however, EMA/EP was associated with significant myelosuppression and hepatotoxicity, leading to treatment delays and dose reductions. Myelosuppression may be minimised by administering granulocyte‐colony stimulating factor (G‐CSF) (El‐Helw 2005; Lurain 2005; Seckl 2010).
In another small series, the taxane‐containing regimen, TP/TE, was found to be associated with comparable cure rates to EMA/EP (70% of 10 patients who had not been exposed to previous EP treatment were cured) but with relatively reduced toxicity and no dose delays or reductions (Wang 2008).
Regimens including 5‐FU are favoured in some parts of China. In a study of 222 patients, FA was found to be effective as primary treatment for low‐ and high‐risk GTN (with remission rates of 99% and 84%, respectively), except in patients with extensive metastases (Zhao 2009). FA has also been used as salvage therapy in a Japanese study in which it was shown to be a well‐tolerated active regimen, resulting in an cure rate of eight of 10 patients (80%) at one year (Matsui 2002); however, two of these women subsequently relapsed and were cured with MEA.
BEP is favoured by Zhao 2009 as salvage therapy in FA‐resistant GTN, citing greater convenience compared with EMA/CO, and reporting a remission rate of 80% (10 out of 12) in high‐risk cases. One study of 91 women with resistant or relapsed high‐risk GTN, who had been heavily pre‐treated before commencing salvage therapy, reported a 60.4% cure rate and 75% three‐year overall survival rate with FAEV (Feng 2011). Reported myelosuppression with this regimen was lower than those reported with EMA/EP and TP/TE.
Patient characteristics in these case series vary widely with regard to the type and number of previous regimens administered, risk scores and other factors (see Table 3), hence direct comparisons of these results do not provide good evidence of the relative effects of these treatments.
Why it is important to do this review
Several salvage chemotherapeutic regimens are used for treating resistant or recurrent GTN; however, it is not known which regimens are the most effective and the least toxic. Furthermore, other considerations relating to salvage chemotherapy, such as quality of life (QoL), cost and convenience, are important and require clarification. To our knowledge, there have been no other systematic reviews in this field.
Objectives
To assess the efficacy and safety of the various salvage chemotherapy regimens in the treatment of women with resistant or recurrent GTN.
Methods
Criteria for considering studies for this review
Types of studies
RCTs comparing different chemotherapy regimens following failed first‐line treatment for GTN.
Types of participants
Women with GTN (staged and risk scored) who developed resistance (as defined by investigators, e.g. hCG plateau or decline by less than 10% over three weeks or a rise in hCG or new metastases) to first‐line chemotherapy or who relapsed after cure (as defined by investigators, e.g. normalisation of hCG levels, undetectable hCG or hCG less than 5 IU/L).
Types of interventions
Any chemotherapy regimen used to treat recurrent or resistant GTN in any dose, duration, combination or frequency.
For example, possible intervention comparisons for resistant or recurrent low‐risk GTN would include:
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pulsed dactinomycin versus five‐day dactinomycin;
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dactinomycin (pulsed or five‐day) versus EA;
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EA versus MAC or EMA/CO;
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dactinomycin (pulsed or five‐day) versus MAC or EMA/CO.
Possible intervention comparisons for resistant or recurrent high‐risk GTN would include:
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EMA/EP versus TP/TE;
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EMA/EP verses BEP.
Types of outcome measures
Primary outcomes
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Remission/complete response (CR) rate.
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Treatment failure.
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Overall survival (OS).
Secondary outcomes
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Toxicity graded according to CTCAE 2010, including: haematological (anaemia, neutropenia, abnormal liver function); gastrointestinal (pain, nausea, vomiting); genitourinary (vaginal bleeding); skin (stomatitis, mucositis, alopecia, allergy); neurological (peripheral and central) and respiratory (pain, shortness of breath, pleural effusion).
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Mean number of courses (time) to cure.
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Mean number of courses (time) to failure.
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QoL.
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Secondary cancers.
Search methods for identification of studies
Electronic searches
We searched the Cochrane Gynaecological Cancer Group Specialised Register (October 2011), Cochrane Central Register of Controlled Trials (CENTRAL, Issue 4, 2011) (Appendix 1), MEDLINE (1950 to October week 3, 2011) (Appendix 2) and EMBASE (1980 to 2011, week 43) (Appendix 3). For this update we searched Cochrane Central Register of Controlled Trials (CENTRAL, Issue 10, 2015), MEDLINE (2011 to 2015, week 46) and EMBASE (2011 to 2015, week 46).
Searching other resources
We searched the following for ongoing trials: National Research Registry, National Cancer Institute (www.cancer.gov/), Metaregister of Controlled Trials (www.controlled‐trials.com/mrct/), Medical Research Council Clinical Trial Directory (www.ctu.mrc.ac.uk/), Australian New Zealand Clinical Trial Registry (www.anzctr.org.au/).
We handsearched conference proceedings of the following societies: ISSTS, International Gynecological Cancer Society, European Gynaecological Cancer Society, Society of Gynecologic Oncologist, American Society of Clinical Oncology and British Gynaecological Cancer Society.
In addition, we searched the reference lists of relevant articles/reviews, and used the 'related articles' feature in PubMed, to identify additional articles. We sought expert opinion to identify relevant but unpublished studies.
Data collection and analysis
Selection of studies
Two review authors (MA and TL) sifted the search results and identified no RCTs to include in this review.
Data extraction and management
There were no data to extract for meta‐analysis using RevMan 2011 software. For future versions of this review, two review authors will independently extract data from new RCTs to a pre‐designed data collection sheet. We will also record the following information:
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study methodology: description of randomisation, blinding, number of study centres, study duration, length of follow‐up and number of study withdrawals;
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participants: number, mean age, mean risk score;
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intervention: type of intervention; dose and schedule;
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outcomes:
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data will be extracted to allow intention‐to‐treat (ITT) analysis where possible;
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for dichotomous outcomes (e.g. cure, adverse events and number of patients who relapsed or died), we will extract outcome rates to estimate a risk ratio (RR);
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for continuous outcomes (e.g. QoL measures and duration of treatment) we will extract means and standard deviations (SD) to estimate a mean difference (MD);
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for time‐to‐event outcomes (e.g. OS) we will extract the log of the hazard ratio [log(HR)] and its standard error from trial reports. If these are not reported, we will attempt to estimate the log (HR) and its standard error using Parmar's methods (Palmer 1998).
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Assessment of risk of bias in included studies
Risk of bias in included RCTs in future versions of this review will be assessed using The Cochrane Collaboration's tool (Higgins 2011) and the following criteria:
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selection bias: random sequence generation and allocation concealment;
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performance bias: blinding of participants and personnel (patients and treatment providers);
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detection bias: blinding of outcome assessment;
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attrition bias: incomplete outcome data;
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reporting bias: selective reporting of outcomes;
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other possible sources of bias.
Subgroup analysis and investigation of heterogeneity
We had planned to subgroup data according to low‐ and high‐risk groups. For future meta‐analysis, random‐effects models will be used (DerSimonian 1986) and we will perform sensitivity analyses to investigate the impact of bias or poor‐quality trials on our results.
Results
Description of studies
Our search identified no RCTs for classification.
Results of the search
Our electronic searches produced 1970 records after de‐duplication (see Figure 1 for search flow diagram). Two review authors (MA and TL) sifted the search and identified no RCTs for evaluation. For the 2015 update an additional 274 records were identified, however, we did not find any studies eligible for inclusion.
Study flow diagram of search results.
Risk of bias in included studies
Not applicable as there were no included studies.
Effects of interventions
Not applicable as there were no included studies.
Discussion
GTN is a highly chemosensitive disease with almost all low‐risk lesions and 80% to 90% of high‐risk lesions eventually attaining cure (Khan 2003; McNeish 2002). However, owing to its chemosensitivity and low prevalence in developed countries, very few RCTs have been conducted to evaluate and compare primary treatments, and no RCTs have been conducted to compare salvage treatments for GTN.
Low‐risk GTN
From the limited available evidence, the most suitable first‐line options for low‐risk GTN appear to be methotrexate (five‐ and eight‐day regimens) or pulsed dactinomycin; however, in China, 5‐FU is considered highly effective (Song 1998). In one meta‐analysis of four RCTs, bi‐weekly pulsed dactinomycin was shown to be at least as effective and safe as methotrexate, although this evidence was downgraded from high to moderate quality as most of the included trials utilised the weekly low‐dose methotrexate regimen (Alazzam 2012a). Bi‐weekly pulsed dactinomycin may also have other benefits compared with methotrexate with regard to cost and convenience (Covens 2006). An ongoing trial of pulsed dactinomycin versus five‐ or eight‐day methotrexate for first‐line treatment in low‐risk GTN should provide the vital 'missing' evidence (NCT01535053). However, administered alone, both interventions are considered to achieve primary remission approximately 75% of the time (McNeish 2002; Osborne 2011). This means that approximately 25% of women with low‐risk GTN will require salvage treatment.
Women with GTN should be treated with the least toxic and most effective therapy (Goldstein 2012). However, no RCTs have been conducted to compare the various treatment options for salvage therapy, and non‐RCTs are subject to differing selection criteria and other biases that render them incomparable. Sequential methotrexate/dactinomycin (MA) single‐agent therapy is considered to be the least toxic route, as well as being highly effective. Indeed, this sequential treatment (usually with five‐day dactinomycin) is considered as the 'initial' treatment (before multi‐agent therapy) for low‐risk GTN, achieving a cure in approximately 85% of cases (Goldstein 2012). Furthermore, one small phase II study found that, when methotrexate was the primary treatment and pulsed dactinomycin was used as salvage therapy, a cure rate of 94% was achieved (Covens 2006).
In RCTs comparing first‐line MA for low‐risk GTN, salvage therapy is often the comparison intervention (e.g. Lertkhachonsuk 2009; Yarandi 2008). However, the optimal order of the single‐agent sequence remains unclear. Since there may be additional benefits to administering bi‐weekly pulsed dactinomycin as the primary treatment (followed by methotrexate as initial salvage therapy), not only with regard to efficacy and toxicity, but particularly with regard to cost and convenience, these sequential treatment options need further evaluation in a multicentre RCT.
If sequential single‐agent therapy fails, multi‐agent chemotherapy must be used to achieve a cure; this is necessary in 6% to 15% of cases (Covens 2006; Goldstein 2012). The multi‐agent therapy used most frequently at Charing Cross (one of two treatment centres in the UK) is EMA/CO. The New England Trophoblastic Disease Center (NETDC, USA) prefers to use MAC before EMA/CO owing to concerns that etoposide may be associated with an increased risk of secondary tumours (Goldstein 2012); this treatment strategy, with or without hysterectomy, has resulted in a 100% cure rate in low‐risk GTN at NETDC between 1965 and 2010.
High‐risk GTN
EMA/CO is the most widely used primary chemotherapy for high‐risk GTN and is considered to have the best effectiveness to toxicity ratio. The less toxic MAC regimen is considered to be substantially less effective than EMA/CO in high‐risk disease and is therefore not recommended (May 2011). 5‐FU combination regimens (e.g. FA) are favoured in China, with excellent primary remission rates reported and FA resistance occurring mainly in cases with widespread metastases (Zhao 2009). In two studies of EMA/EP as first‐line chemotherapy for high‐risk GTN (Ghaemmaghami 2004) and very high‐risk GTN (risk scores of 12 or more) (Cyriac 2011), EMA/EP was considered to compare favourably with EMA/CO, with remission rates of 88% and 67%, respectively. However, a high proportion of all high‐risk patients will fail first‐line therapy or will relapse after remission. Although high‐risk GTN is less frequent than low‐risk GTN, drug resistance and relapse in high‐risk GTN is inherently much more difficult to treat.
Lurain 2005 studied various combinations of drugs for salvage therapy and concluded that a platinum‐etoposide component was essential. In a subsequent study, 36 out of 40 patients (90%) with high‐risk metastatic disease who were treated initially with EMA/CO, followed by salvage therapy with a platinum‐etoposide combination if necessary, survived; the four patients who died all had risk scores of 12 or more (Lurain 2010b). Currently, the most commonly used salvage regimen in North America and the UK for the treatment of resistant or recurrent high‐risk GTN is EMA/EP (May 2011) whereas BEP and 5‐FU combination regimens appear to be favoured in China (Feng 2011; Zhao 2009). TP/TE may be better tolerated than EMA/EP (Wang 2008) and it is understood that the ISSTD has an RCT planned, comparing these two salvage regimens. Comparisons of BEP versus EMA/EP would also be helpful. In addition, given that there is a wide discrepancy in chemotherapeutic practice between Western and Asian GTN treatment centres, comparisons between the commonly used regimens in these regions is desirable.
To our knowledge, there is currently no comparative data on the relative cost, convenience and QoL relating to any of the regimens in use.
Study flow diagram of search results.
| Stage I | Disease confined to the uterus |
| Stage II | GTN extends outside of the uterus, but is limited to the genital structures (adnexa, vagina, broad ligament) |
| Stage III | GTN extends to the lungs with or without known genital tract involvement |
| Stage IV | All other metastatic sites |
| Scores | 0 | 1 | 2 | 4 |
| Age (years) | < 40 | ≥ 40 | – | – |
| Antecedent pregnancy | mole | abortion | term | – |
| Interval months from index pregnancy | < 4 | 4 to 6 | 7 to 12 | > 12 |
| Pre‐treatment serum hCG (IU/L) | < 103 | 103–104 | 104 to 105 | > 105 |
| Largest tumour size (including uterus) | < 3 | 3 to 4 cm | ≥ 5 cm | – |
| Site of metastases | lung | spleen, kidney | gastrointestinal | liver, brain |
| Number of metastases | – | 1 to 4 | 5 to 8 | > 8 |
| Previous failed chemotherapy | – | – | single drug | ≥ 2 drugs |
| To stage and allot a risk factor score, a patient's diagnosis is allocated to a stage as represented by a Roman numeral I, II, III and IV. This is then separated by a colon from the sum of all the actual risk factor scores expressed in Arabic numerals, i.e. stage II:4, stage IV:9. This stage and score will be allotted for each patient (FIGO 2009). A score ≤ 6 indicates low risk; > 6 indicates high risk. | ||||
| Study | Dates | Participants | Characteristics | Primary treatment | Salvage treatment | Complete response | Severe adverse effects (≥ G3) | Investigators' conclusions |
| 1977 to 1985 | 22 women | Drug‐resistant high‐risk GTN (14 women; WHO scores ≥ 8). Also included 8 women who underwent primary treatment for high‐risk GTN | Methotrexate/vinca alkaloid with or without sequential dactinomycin (12/14 women) | EP with dactinomycin (APE; 8) or without (EP; 6) every 4 weeks | CR = 13/14 (93%) and 11/14 were cured (79%; defined as CR sustained for 12 months). 1 woman died | Data for the drug‐resistant group could not be separated. Leukopenia 11/22 (50%); thrombocytopenia 8/22 (36%); alopecia 22/22 (100%); sepsis 3/22 (14%); renal 4/22 (18%); nausea and vomiting 6/22 (27%). SAEs were more likely to occur with the APE than with the EP regimen | APE/PE regimens compare favourably with other regimens such as MAC and EMA/CO | |
| 1977 to 1985 | 8 women | Drug resistant high‐risk GTN (WHO score > 11) | Methotrexate/vincristine alternated with vincristine/dactinomycin weekly (6/8 women) | PVB (every 21 days) | CR = 6/8 (75%; including 2 woman who had a partial response initially but a CR following hysterectomy). 1 woman relapsed and 5/8 were cured | All toxicities were grade 1/2 | PVB is a well‐tolerated regimen. Hysterectomy plays an important role in the treatment of drug resistant GTN | |
| 1984 to 1992 | 7 women | Median WHO score = 16 (range 10 to 20). Heavily pre‐treated women | Not reported in detail. Various regimens of which 6/7 included etoposide | EP (days 1 to 5; 14 to 21 day cycles) | CR = 6/7 (86%) but only 3/7 had sustained remissions, and 4 died within 18 months | Neutropenia = 5/7 (71%); neutropenic sepsis = 4/7 (57%); thrombocytopenia = 2/7 (29%); renal toxicity = 2/7 (29%) | EP therapy is an active salvage regimen for GTN but has significant haematological and renal toxicity | |
| 1980 to 1997 | 42 women | 34/42 women had relapsed/resistant high‐risk GTN; 8 women had PSTT. 22/34 relapsed/resistant women had hCG levels approaching normal | EMA/CO | EMA/EP | The 22 women with low levels of hCG could not be assessed for response. Of the remaining 12 relapsed/resistant women, CR = 9/12 (75%). OS = 30/34 (88%) | Neutropenia (68%); anaemia (21%); thrombocytopenia (40%). (These data may include data from women with PSTT.) Myelosuppression caused delays in chemotherapy in 88% of patients and dose reductions in 38% | EMA/EP is an effective regimen for relapsed/resistant high‐risk GTN (with surgery in selected cases) but toxicity is significant | |
| 1985 to 2001 | 10 women | 7 women had resistant high‐risk GTN and 3 women had relapsed after treatment | EMA/CO (2) and MEA (8) | FA | OS = 8/10 (80%). Mean follow‐up of 11.5 years. 2 patients died of multidrug resistance and 2 relapsed subsequently and were treated successfully with MEA | Neutropenia (6.4% of cycles) and thrombocytopenia (3.8% of cycles) | FA is an effective and well‐tolerated salvage therapy | |
| Unclear | 15 women | 12 women had resistant high‐risk GTN and 3 had PSTT | Unclear | EMA/EP | CR = 11/15 (73.3%) | Myelosuppression and gastrointestinal SAEs | EMA/EP is an effective salvage therapy for chemo‐refractory GTN | |
| 1980 to 2001 | 26 women | Relapsed or resistant high‐risk GTN | EMA/CO (10). MA‐based without E (16) | All salvage treatment contained E + P. BEP (19), EMA/EP (3), VIP/ICE (3), PVB. Repeated every 21 days | CR = 73%; OS = 61.5% | Not reported | BEP is first choice for high‐risk patients with drug resistance or relapse following treatment with EMA/CO and EMA/EP. This regimen resulted in a 74% CR and 58% OS in this study | |
| 1992 to 2003 | 26 women | 9 women had relapsed or resistant high‐risk GTN. Also included 17 women undergoing primary treatment. Risk score range was 7 to 12 | MA (4); MEA (2); MAC (1); EMA/CO (2) | MEF | CR = 7/9 (78%); OS = 8/9 (96%) at mean follow‐up of 37 months (range 14 to 124 months) | 1 death occurred owing to multi‐drug resistant GTN. Toxicity data could not be separated (reported as % of 167 cycles): neutropenia (26.4%); nausea/vomiting (39%); thrombocytopenia (5.6%). G‐CSF given as necessary | MEF is a well‐tolerated, less‐toxic regimen that is effective as salvage therapy | |
| 1999 to 2005 | 18 women | 11 women had resistant high‐risk GTN and 7 women had relapsed after treatment | EMA/CO | EMA/EP | CR = 12/18 (66.6%) including 9/11 (82%) resistant patients and 3/7 (43%) relapsed patients | Neutropenia (28% of cycles); nausea/vomiting 15% of cycles). Myelosuppression and hepatotoxicity led to dose reductions and delays in 43% of cycles despite the use of G‐CSF as necessary | EMA/EP was more effective in patients with drug resistance than those who have relapsed after treatment with EMA/CO. Toxicity caused treatment delays that might have been prevented with prophylactic G‐CSF | |
| 2001 to 2004 | 11 women | Resistant high‐risk GTN with median risk score of 9 (range 7 to 13) | Various | FAEV | CR = 7/11 (63.6%) | Myelosuppression was treated with G‐CSF in 98.4% of courses | FAEV could be an effective treatment for drug‐resistant GTN | |
| 1996 to 2005 | 13 women | 10 woman had resistant high‐risk GTN and 3 women had relapsed after treatment | EMA/CO | EMA/EP | CR = 11/13 (84.6%); 5 patients had adjuvant surgery/brain irradiation | Not reported | EMA/EP is a highly effective salvage therapy for those patients failing EMA/CO treatment | |
| 1999 to 2006 | 24 women | Group A: 16 women with relapsed/resistant GTN (9 high‐risk, 5 low‐risk and 2 PSTT) Group B: 8 women switched owing to toxicity on previous regimen (4 high‐risk, 1 low‐risk and 3 PSTT). 10/24 women (42%) had received 2 or more previous chemotherapy regimens | Group A: EMA/CO or EMA/EP, or both (5) or BEP (1) Group B: EMA/EP (5), EMA/CO (2), EMA/EP + EMA/CO (1) | TP/TE | Group A: CR = 3/16 (19%); OS = 7/16 (44%; median follow up of 25 months) Group B: CR = 2/4 assessable (50%); OS = 6/8 (75%; at median of 19 months follow up) | Neutropenia = 10/24 (42%); neuropathy = 1/24 (4%); thrombocytopenia = 3/24 (13%). Treatment discontinued in 1 patient owing to neuropathy (grade 2). No dose reductions or delays | TP/TE was more likely to fail if previous chemotherapy had included a platinum agent. Out of 10 patients who had not previously received EMA/EP, 7/10 survived (70%). TP/TE is relatively less toxic than EMA/EP | |
| 1995 to 2007 | 12 women | High‐risk drug‐resistant GTN | FA | BEP | CR = 10/12 (83%) | Not reported | BEP is more convenient than EMA/CO and is well tolerated | |
| 2005 to 2008 | 91 women | 80/91 women had relapsed or resistant high‐risk GTN; 11/91 had relapsed or resistant low‐risk GTN. 63/91 women (69.1%) had received 2 or more previous chemotherapy regimens | Mainly FAV (60), EMA/CO (29) and 5‐FU (22) but several other regimens administered | FAEV | CR = 55/91 (60.4%); NR = 29/91 (31.9%) OS at 3 years = 74.9% | Neutropenia 24/91 (26.4%); febrile neutropenia 6/91 (6.6%); thrombocytopenia 3/91 (3.3%). 7/91 (7.7%) discontinued FAEV owing to toxicity. No neutropenic sepsis or treatment‐related deaths | FAEV is an effective salvage regimen in this cohort of heavily pre‐treated patients. It is more convenient (21‐day cycle) and less toxic than other regimens | |
| 2009 to 2011 | 5 women | Heavily pre‐treated high‐risk women (≥ 3 previous regimens; risk scores of 9, 10, 17, 17 and 18) | Various including EMA, EMA/CO, ICE, VAC, EMA/EP, TP/TE, PT, PI | FA | CR = 1/5 (20%) | Neutropenia 3/12 cycles (25%); diarrhoea 1/12 cycles (8%); mucositis 8/12 cycles (67%) | FA had modest efficacy with tolerable side effects in this group of heavily pre‐treated patients | |
| 5‐FU: 5‐fluorouracil; APE: etoposide, cisplatin, dactinomycin; BEP: bleomycin, etoposide, cisplatin; CR: complete response; E: etoposide; EMA: etoposide, methotrexate, dactinomycin; EMA/CO: etoposide, methotrexate, dactinomycin/cyclophosphamide, vincristine; EMA/EP: etoposide, methotrexate, dactinomycin/ etoposide, cisplatin; EP: etoposide, cisplatin; FA: 5‐fluorouracil, dactinomycin; FAEV: floxuridine, dactinomycin, etoposide, vincristine; FAV: 5‐fluorouracil, dactinomycin, vincristine; G‐CSF: granulocyte colony stimulating factor; GTN: gestational trophoblastic neoplasia; hCG: human chorionic gonadotrophin; MA: methotrexate, dactinomycin; MAC: methotrexate, dactinomycin, cyclophosphamide; MEA: methotrexate, etoposide, dactinomycin; MEF: methotrexate, etoposide, 5‐fluorouracil; NR: no response; OS: overall survival; PI: cisplatin, ifosfamide; PSTT: placental site trophoblastic tumour; PT: carboplatin, paclitaxel; PVB: cisplatin, vinblastine, bleomycin; SAE: severe adverse effects; TP/TE: paclitaxel, cisplatin/paclitaxel, etoposide; VAC: vincristine, actinomycin, cyclophosphamide; VIP/ICE: ifosfamide, etoposide, cisplatin; WHO: World Health Organization. | ||||||||
