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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