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내성이 있거나 또는 재발성 임신성 융모성 종양 치료를 위한 화학요법

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배경

임신성 융모성 종양 (GTN)은 임신과 관련된 종양 중 치료 가능성이 높다; 그러나, GTN 종양의 약 25%는 1차 화학요법 치료 후 내성이 생기거나 또는 재발한다. 이러한 내성과 재발 병변에는 수술을 하는 구조 화학요법 또는 수술하지 않는 구조 화학요법이 필요하다. 세계적으로 여러 가지 구조 요법이 쓰이고 있다. 어떤 치료가 가장 효과적이고 독성이 가장 적은지는 분명하지 않다.

목적

어떤 화학요법이 내성이 있거나 재발하는 GTN에 가장 효과적이고 가장 독성이 적은지를 결정한다.

검색 전략

우리는 2011년 10월 까지 the Cochrane Gynaecological Cancer Group Specialised Register, the Cochrane Central Register of controlled Trials (CENTRAL, 제 4호), MEDLINE과 EMBASE를 검색했다. 또, 관련 학계의 회의록과 연구 참고 문헌 목록을 일일이 검색했다. 개정본 업데이트를 위해 2015년 11월 16일까지 MEDLINE, EMBASE, CENTRAL, Specialised Register를 검색하였다. 따라서 진행중인 연구를 찾았다.

선정 기준

무작위 대조 시험만을 포함시켰다.

자료 수집 및 분석

메타 분석을 위해 데이터 추출 양식을 설계하여 Review Manager 5.1의 무작위‐효과 방법을 사용하기로 했다.

주요 결과

무작위 대조 시험을 확인하지 못 했다; 따라서 메타 분석을 진행할 수 없었다.

연구진 결론

GTN이 prevalence가 낮고 화학요법에 매우 민감한 성질이 있기 때문에 이에 관한 무작위 대조 시험은 거의 없다. 화학요법 치료제는 실제 부작용과 관계가 있을 수 있기 때문에, 이상적인 치료 방법은 부작용이 가장 적으면서 최대의 효과를 보아야 한다. 메토트렉세이트에 내성이 있거나 저 위험 GTN이 재발하는 경우, 추가로 구조 요법이 필요하면 보통 5일간 순차적으로 닥티노마이신을 복용한 후 MAC (메토트렉세이트, 닥티노마이신, 시클로포스파미드) 또는 EMA/CO (에토포시드, 메토트렉세이트, 닥티노마이신, 시클로포스파미드, 빈블라스틴)를 사용하는 방법을 사용한다. 그러나, 5일간 닥티노마이신을 복용하면 pulsed 닥티노마이신보다 부작용이 많아서 1차 메토트렉세이트 치료 실패라는 점에서 두 가지 치료 방법의 상대적 효능과 안전성을 비교하는 무작위 대조 시험이 필요하다.

고 위험 GTN에는, 구조요법으로 선호되는 백금‐에토포시드, 특히 EMA/EP (에토포시드, 메토트렉세이트, 닥티노마이신/에토포시드, 시스플라틴)과 함께 EMA/CO가 1차 치료로 가장 많이 사용된다. TP/TE (파클리탁셀, 시스플라틴/파클리탁셀, 에토포시드), BEP (블레오마이신, 에토포시드, 시스플라틴), FAEV (플록스리딘, 닥티노마이신, 에토포시드, 빈크리스틴)과 FA (5‐플루오로우라실 (5‐FU), 닥티노마이신)과 같은 다른 방법들이 EMA/EP 만큼 효과적일 수 있으며 부작용도 적을 수 있다; 그러나, 현재의 근거만으로는 확실하지 않으며 잘 설계된 무작위 대조 시험에서 테스트를 받아야 한다. 영국에서는, 이 계획에 맞는 환자 수가 적기 때문에 내성이 있고/재발성 GTN의 중재를 비교하는 무작위 대조 시험은 대단히 어렵다. 따라서, 저/고 위험 질환에서 어떤 구조 요법이 가장 우수한 효과‐독성 비율을 가지고 있는지를 결정하기 위한 질 높은 근거를 제공하기 위해 국제적으로 여러 의료기관의 협력이 필요하다. 추가 연구에는 2차 종양에 관한 경제적 평가와 장기적 감시가 포함되어야 한다.

PICOs

Population
Intervention
Comparison
Outcome

The PICO model is widely used and taught in evidence-based health care as a strategy for formulating questions and search strategies and for characterizing clinical studies or meta-analyses. PICO stands for four different potential components of a clinical question: Patient, Population or Problem; Intervention; Comparison; Outcome.

See more on using PICO in the Cochrane Handbook.

1차 치료에 반응하지 않거나 재발하는 임신성 융모성 종양 (GTN) 항암제 치료

본 연구는 1차 치료에 반응하지 않거나 재발하는 GTN 여성 환자의 항암제 치료에 관한 것 이다. GTN은 주로 기태 임신 후 태반 조직에서 발생하는 암 형태를 말한다. 기태 임신은 자궁 내 태반 조직이 비 정상적으로 커진 것 이다. 대부분 자궁 이탈 (D&C)로 치료가 되나, 사례의 20%는 악성으로 진전된다. GTN은 보통 항암제 (화학요법)에 반응을 잘 하나, 이 약들이 독성이 있을 수 있어서 치료 목적은 부작용을 최소화하여 치료하는 것 이다. 의사들이 GTN 여성 환자들에게 가장 적합한 치료를 선택하는 것에 도움을 준다면, 이 질환은 특정 위험 요인에 따라 저 위험 또는 고 위험으로 분류된다.

저 위험 GTN 치료를 위한 화학요법에서는 보통 한 가지 약을 사용하지만, 고 위험 종양은 여러 가지 약을 병용하여 치료한다. 5가지 약을 사용하는 가장 많이 사용하는 조합은 줄여서 EMA/CO라고 한다. 의사들은 혈액 내의 임신 호르몬 (hCG) 수준을 확인하여 치료에 대한 반응을 평가한다. 화학요법이 효과가 없을 것으로 보이면 대체 (또는 구조) 요법을 시작해야 한다. 사례의 약 25%에서 이러한 것이 필요하며 여러 가지 약의 조합이 사용되고 있다.

우리는 여러 가지 구조 조합 중 어느 것이 가장 효과적이며 독성이 적은지가 확실하지 않기 때문에 본 연구를 진행했다. 적합한 연구를 확인하기 위해 2011년 11월 까지의 문헌을 검색했다. 불행히도, 여러 가지 구조 치료 방법을 비교한 양질의 연구를 확인할 수 없었다. 이는 이 질환이 몇 가지 화학요법 조합 방법으로 치료가 잘 되기 때문인 점이 부분적인 이유이나, 이 질환이 드문 질환이어서 대규모 연구를 위한 환자들을 모으기가 어렵기 때문이기도 하다. 따라서, 우리는 효능과 안전성 측면에서 약들을 조합하는 방법에 대해 결론을 낼 수 없었으며, 이 분야의 연구자들이 협력하여 중요한 근거를 제공할 것을 촉구한다.

Authors' conclusions

Implications for practice

Limited evidence from retrospective case series suggest that EMA/EP, BEP, TP/TE, FAEV and other combinations may all be effective as salvage therapy for recurrent or resistant GTN. However, reported efficacies and toxicities vary, as do patient characteristics in the various studies. Since no randomised comparative studies have been conducted, it is not possible to draw any conclusions with regard to these important outcomes, based on the available evidence. Current treatment protocols in use in various UK and US GTD treatment centres can be found in Seckl 2010 and Goldstein 2012, respectively.

Implications for research

Multicentre collaboration with centres in Asia, Latin America and Africa that experience a higher prevalence of this disease is required to produce the high‐quality evidence needed in this field.

For low‐risk GTN, NCT01535053 is currently underway to determine whether the pulsed dactinomycin or five‐ or eight‐day methotrexate regimen is the best primary treatment (see Alazzam 2012a). Trials such as these would benefit from a cross‐over design, whereby, in the event of treatment failure, the alternative intervention is administered, with pre‐specified outcomes. Furthermore, an RCT of pulsed dactinomycin versus five‐day dactinomycin would be helpful to determine whether the more toxic five‐day treatment is warranted in women with low‐risk GTN that is resistant to methotrexate treatment.

For high‐risk GTN, much work is needed to optimise treatment for these women. It is hoped that the proposed trial of EMA/PE versus TP/TE for salvage therapy is commenced soon and is able to provide the necessary high‐quality evidence to guide clinical practice that is currently lacking in this field. Randomised comparisons of the floxuridine‐ or 5‐FU‐based regimens favoured in China with the EMA/EP regimen, following failed EMA/CO primary treatment, would be interesting.

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.

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Table 1. FIGO anatomical staging *

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

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Table 2. Modified WHO Prognostic Scoring System as adapted by FIGO for GTN

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:

  • single‐agent pulsed dactinomycin (Covens 2006) (where first‐line therapy has been methotrexate);

  • five‐day dactinomycin (McNeish 2002);

  • etoposide and dactinomycin (EA) (Dobson 2000);

  • methotrexate, dactinomycin, cyclophosphamide (MAC) (Goldstein 2012);

  • 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:

  • EMA/CO, as reported in Newlands 1986, whereby EMA and CO are given on alternate weeks, is the most widely used;

  • MEA (methotrexate, etoposide, dactinomycin), is reported to have comparable success rates with relatively reduced toxicity (Dobson 2000; Matsui 2004);

  • MAC or methotrexate, dactinomycin, chlorambucil (Curry 1989; Hammond 1973);

  • FA (5‐FU, dactinomycin) or FAV (5‐FU, dactinomycin, vincristine) are commonly used regimens in China (Feng 2011; Zhao 2009);

  • MEF (methotrexate, etoposide, 5‐FU) (Wang 2006);

  • EMA/EP (etoposide, methotrexate, dactinomycin/etoposide, cisplatin) whereby EMA and EP are alternated weekly (Cyriac 2011; Ghaemmaghami 2004);

  • 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:

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Table 3. Retrospective studies of salvage chemotherapy for resistant or recurrent GTN

Study

Dates

Participants

Characteristics

Primary treatment

Salvage treatment

Complete response

Severe adverse effects (≥ G3)

Investigators' conclusions

Theodore 1989

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

Azab 1989

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

Soper 1995

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

Newlands 2000

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

Matsui 2002

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

Xiang 2004

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

Lurain 2005

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

Wang 2006

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

Mao 2007

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

Wan 2007

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

Lu 2008

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

Wang 2008

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

Zhao 2009

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

Feng 2011

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

Manopunya 2012

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.

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:

  1. pulsed dactinomycin versus five‐day dactinomycin;

  2. dactinomycin (pulsed or five‐day) versus EA;

  3. EA versus MAC or EMA/CO;

  4. dactinomycin (pulsed or five‐day) versus MAC or EMA/CO.

Possible intervention comparisons for resistant or recurrent high‐risk GTN would include:

  1. EMA/EP versus TP/TE;

  2. EMA/EP verses BEP.

Types of outcome measures

Primary outcomes

  • Remission/complete response (CR) rate.

  • Treatment failure.

  • Overall survival (OS).

Secondary outcomes

  • 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).

  • Mean number of courses (time) to cure.

  • Mean number of courses (time) to failure.

  • QoL.

  • 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:

  • study methodology: description of randomisation, blinding, number of study centres, study duration, length of follow‐up and number of study withdrawals;

  • participants: number, mean age, mean risk score;

  • intervention: type of intervention; dose and schedule;

  • outcomes:

    • data will be extracted to allow intention‐to‐treat (ITT) analysis where possible;

    • 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);

    • 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);

    • 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).

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:

  1. selection bias: random sequence generation and allocation concealment;

  2. performance bias: blinding of participants and personnel (patients and treatment providers);

  3. detection bias: blinding of outcome assessment;

  4. attrition bias: incomplete outcome data;

  5. reporting bias: selective reporting of outcomes;

  6. 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.

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.
Figures and Tables -
Figure 1

Study flow diagram of search results.

Table 1. FIGO anatomical staging *

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

Figures and Tables -
Table 1. FIGO anatomical staging *
Table 2. Modified WHO Prognostic Scoring System as adapted by FIGO for GTN

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.

Figures and Tables -
Table 2. Modified WHO Prognostic Scoring System as adapted by FIGO for GTN
Table 3. Retrospective studies of salvage chemotherapy for resistant or recurrent GTN

Study

Dates

Participants

Characteristics

Primary treatment

Salvage treatment

Complete response

Severe adverse effects (≥ G3)

Investigators' conclusions

Theodore 1989

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

Azab 1989

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

Soper 1995

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

Newlands 2000

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

Matsui 2002

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

Xiang 2004

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

Lurain 2005

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

Wang 2006

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

Mao 2007

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

Wan 2007

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

Lu 2008

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

Wang 2008

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

Zhao 2009

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

Feng 2011

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

Manopunya 2012

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.

Figures and Tables -
Table 3. Retrospective studies of salvage chemotherapy for resistant or recurrent GTN