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ORIGINAL RESEARCH |
From the Department of Obstetrics and Gynaecology, University of Hong Kong.
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ABSTRACT |
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 ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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METHODS: Patients who received MBE for GTN between 1985 and 2003 in Queen Mary Hospital were included in this study. Records were reviewed and data were analyzed. Outcomes including response rate, treatment complications, and survival were assessed.
RESULTS: Methotrexate, bleomycin, and etoposide therapy was given as first line to 4 patients with ultra-high-risk GTN. Three responded to the treatment and remained disease free. Methotrexate, bleomycin, and etoposide were given as a second-line therapy to 8 patients who had drug resistance to the initial therapy. Seven responded, and 6 remained disease free at 5 years. Methotrexate, bleomycin, and etoposide were given as a second-line therapy to 8 patients who relapsed 2–18 months after their initial therapy. Seven patients responded, and 4 remained disease-free at 5 years, 2 defaulted, and one died of carcinoma of the colon. Of the 20 patients who received MBE, 12 developed grade 3/4 neutropenia, and 4 developed grade 3/4 thrombocytopenia. The overall response rate for MBE was 85%.
CONCLUSION: Methotrexate, bleomycin, and etoposide should be considered as a second-line therapy in patients who have drug-resistant or recurrent GTN.
LEVEL OF EVIDENCE: III
The treatment for high-risk GTN has improved greatly since the introduction of effective multiple-agent chemotherapy such as the 7-drug combination chemotherapy (CHAMOMA) and the EMA-CO regimens.4,5 The EMA-CO protocol formulated by the Charing Cross Hospital-London group is currently the most commonly used chemotherapy regimen for high-risk GTN.6 Newlands et al7 originally reported an 80% complete response rate in 76 patients who had not received prior chemotherapy, as well as a 79% complete response rate in 72 patients who had received prior chemotherapy. Since then, response rates and long-term survival rates of over 80% have been reported by several groups.1,8–11 However, approximately 25% of these high-risk patients will fail first-line therapy with EMA-CO or relapse from remission and will require salvage chemotherapy.12 In 2003, Escobar et al13 reported their experience in salvage therapy using a cisplatin-based regimen, along with surgical intervention when indicated, which resulted in a 92% survival rate.
In 1986, our unit reported the initial experience between 1976 and 1984 with the modified Bagshawe's regimen (CHAMOCA: hydroxyurea, vincristine, methotrexate with folinic acid, dactinomycin, cyclophosphamide, and doxorubicin) in high-risk GTN when we treated 50 patients.14 In that analysis, 82% of the patients achieved sustained biochemical remission. When patients showed resistance to the above regimen or developed a relapse after an initial successful treatment, they would be treated with high-dose methotrexate, bleomycin, and etoposide (MBE) therapy. In that report, MBE showed a high salvage rate for those who failed the CHAMOCA regimen, which resulted in an overall survival rate of 98%.15 Because of the risk of a second malignancy after the use of etoposide,16 CHAMOC has been used as the first-line treatment for high-risk GTN. However, in recent years, MBE was also used as a first line treatment in patients who have liver or brain metastases, which are associated with a high mortality rate17; by using a second-line regimen as first-line therapy, the prognosis may be improved. In this review, we wish to report our experience from 1985 to 2003 of this combination regimen regarding the response to treatment, treatment-related complications, and survival.
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MATERIALS AND METHODS |
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ABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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A total of 20 patients were treated with MBE in the study period. Four had treatment as initial therapies for ultra-high-risk diseases, which were defined as high-risk scores with liver or brain metastases. Eight patients developed primary drug resistance to combination chemotherapy regimens, including methotrexate and dactinomycin and CHAMOC (doxorubicin was removed from the CHAMOCA protocol in 1985), and they were all treated with MBE. Eight patients received MBE for disease relapse after combination therapies. The mean ± standard deviation risk score before MBE administration was 14.9 ± 3.8 (range 8–25). The mean patient age was 33.8 ± 7.9 years, and the median follow-up was 91months (range 21–205 months).
The protocol we employed is shown in Table 1. Pulmonary function tests were performed before the commencement of chemotherapy. Methotrexate, bleomycin, and etoposide therapy was administered every 3 weeks. Chemotherapy was deferred if the absolute neutrophil count was lower than 1.5 x 109/L or the platelet count was lower than 50 x 109/L. Response to chemotherapy was assessed by measuring the serum hCG level at least once every week. Complete blood count and liver and renal function tests were performed during the resting period before another course of chemotherapy. Hepatotoxicity was defined as a 2-fold increase in serum glutamic oxalate transaminase level after the administration of chemotherapy. Patients with hepatotoxicity would receive folinic acid therapy 8 hours instead of 12 hours after the methotrexate infusion. All gastrointestinal, neurological, dermatological, and pulmonary adverse effects were recorded. Chemotherapy was continued for 2–3 more cycles after normalization of hCG. Remission was diagnosed when serum hCG levels remained below the minimum detectable level (5 IU/L). Drug resistance was diagnosed by a plateau or an increase in hCG levels that continued for at least 3 consecutive weeks. Relapse was diagnosed when serum hCG levels increased again 2 months after the cessation of chemotherapy. Patients who had drug resistance received other chemotherapy regimens.
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Statistical analysis was performed by using Kruskal-Wallis and Fisher exact tests to compare the medians and proportions, respectively. P < .05 was considered statistically significant. Analysis was performed with SPSS 11.5 (SPSS Inc, Chicago, IL).
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RESULTS |
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ABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Eight patients were treated for disease relapse after CHAMOC (6 patients), methotrexate and actinomycin-D (1 patient), and methotrexate (1 patient). The median score before starting MBE was 14. Seven of the patients responded to the treatment, and 4 had sustained remission. Two of the responders defaulted follow-up after 21 and 29 months; they were disease free when they were last seen. One of the responders remained in remission but later developed carcinoma of the colon and died of the disease at 25 months. One of the 8 patients had a relapse 5 months after primary treatment by methotrexate. She was then treated with 4 courses of CHAMOC. This was changed to MBE because of poor response. The patient defaulted after one course of MBE. Three years later she had a hysterectomy for choriocarcinoma and was referred back to us. Treatment with MBE was resumed. However, the patient died of sepsis after 2 weeks as a result of pancytopenia.
The overall response rate for MBE was 85% (17 of 20 patients), with a median follow-up of 91 months (range 21–205 months). The response rates were 75.0% for primary treatment, 87.5% as second-line therapy, and 87.5% for relapse. No significant difference in the response rates was identified between the 3 groups of patients. One patient had a surgical intervention, and 7 patients received radiotherapy (6 patients with brain metastases and 1 patient with liver metastasis and intraperitoneal bleeding).
A total of 96 cycles of MBE were administered. Marrow suppression was the most common adverse effect. Eight patients had grade 1 or 2 and 12 had grade 3 or 4 neutropenia. Two patients had drug-related sepsis requiring antibiotic treatment, and one of them received granulocyte-colony stimulating factor (G-CSF) injection. Four had grade 3 or 4 thrombocytopenia, but none of them had bleeding diatheses. Two patients had dose reduction, and one had delay of treatment. Two patients who had widespread massive GTN and pancytopenia died. Other common adverse reactions to MBE regimen were nausea, vomiting, and alopecia. Eight patients had grade 2 stomatitis. No secondary hematological malignancies have developed in patients treated with MBE in the past 20 years in our unit.
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DISCUSSION |
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The use of MBE as a salvage therapy for CHAMOCA-resistant cases was based on the belief that high-dose methotrexate (MTX) could overcome drug resistance by a dose-dependent response. The hypothesis was that high-dose MTX enhanced passive diffusion, acted on nonactively dividing cells, and affected other targets apart from dihydrofolate reductase.22 When combined with etoposide and bleomycin, which were reported to be effective in GTN,23,24 the response of patients with GTN was very encouraging, with the overall survival in patients being 85% between 1985 and 2003. It then became our standard salvage chemotherapy regimen for high-risk GTN.
Platinum-etoposide combinations with high-dose methotrexate and dactinomycin (EMA-EP) is a salvage chemotherapy regimen commonly used after failed primary treatment with EMA-CO. In 2003, Escobar et al13 reported that their experience with this salvage therapy, along with surgical intervention when indicated, resulted in a 92% survival rate. When compared with EMA-EP, MBE has the advantage of being administered once every 3 weeks. The use of bleomycin, a nonmyelosuppressive agent, may reduce the extent of bone marrow suppression resulting from methotrexate and etoposide.25 There has not been any data comparing these 2 regimens. However, for patients in whom bleomycin is contraindicated, EMA-EP is an alternative to be considered.
Methotrexate, bleomycin, and etoposide therapy was administered to 9 patients who did not have prior CHAMOC. None of them were exposed to etoposide before they received the MBE. Methotrexate, bleomycin, and etoposide therapy was administered to 4 patients with ultra-high-risk GTN, which was defined at the time because of high-risk scores and liver or brain metastases. Although 3 out of 4 patients responded to the treatment, because of the small number, we cannot conclude that MBE is the right choice for those "ultra-high-risk" cases. Liver and brain metastases have been reported as poor prognostic factors, with salvage rates of 44–66% and 33%, respectively. A commonly adopted regimen for liver or brain metastases is EMA-CO with or without irradiation. In the United Kingdom, intrathecal methotrexate, instead of irradiation, has been used for brain metastases.17 With the evidence so far, there is no ideal protocol for the treatment of those patients. Therefore, treatment has to be individualized according to patients' conditions and the centers' own experiences.
Five patients had MBE as a second-line therapy for drug resistance or relapse of disease after non-CHAMOC chemotherapy regimens (Table 2). Four responded to treatment and remain disease-free on long-term follow-up. The only death in this group was due to pancytopenia and sepsis in a patient who presented with massive disease on relapse. The overall survival for patients treated with MBE (with or without prior CHAMOC), as a second-line therapy for either drug resistance or disease relapse, was 87.5%.
In this study cohort, 60% of the patients had grade 3 or 4 neutropenia, and 20% had grade 3 or 4 thrombocytopenia, which is similar to that reported 20 years ago.15 Although a significant proportion of the patients had severe marrow suppression, the episodes were short-lived and only infrequently led to a delay of treatment or dose reduction. Therefore, we do not routinely use G-CSF in neutropenic patients. The only patient in this review who received G-CSF injection was a patient who had a drug-related sepsis. As soon as the neutrophil count was above 1.5 x 109/L and the platelet count was above 50 x 109/L, the treatment was continued with the realization that patients were at risk of complications arising from neutropenia and thrombocytopenia. And, at the same time, back-up facilities were available to deal with those complications if they occurred. Methotrexate, bleomycin, and etoposide therapy could be considered as a second-line salvage therapy in GTN for drug resistance and disease relapse.
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Footnotes |
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Corresponding author: Prof. Hextan Y. S. Ngan, Department of Obstetrics and Gynaecology, Queen Mary Hospital, 102 Pokfulam Road, Hong Kong; e-mail: hysngan{at}hkucc.hku.hk.
doi:10.1097/01.AOG.0000207577.67765.8e
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REFERENCES |
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