| 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 |
