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© 2002 American Society for Clinical Oncology Low-Risk Persistent Gestational Trophoblastic Disease: Outcome After Initial Treatment With Low-Dose Methotrexate and Folinic Acid From 1992 to 2000ByFrom the Department of Medical Oncology, Trophoblastic Tumour Screening and Treatment Center, Charing Cross Hospital, London, and Mount Vernon Hospital, Northwood, Middlesex, United Kingdom. Address reprint requests to E.S. Newlands, PhD, FRCP, Department of Medical Oncology, Trophoblastic Tumour Screening and Treatment Centre, Charing Cross Hospital, London W6 8RF, United Kingdom; email: e.newlands{at}ic.ac.uk
PURPOSE: We have simplified the treatment of gestational trophoblastic disease (GTD) in order to reduce the number of patients exposed to potentially carcinogenic chemotherapy. Patients who score 0 to 8 on the Charing Cross scoring system are classified as low-risk and receive methotrexate (MTX) and folinic acid (FA), whereas those who score higher than 8 are classified as high-risk and receive the etoposide, methotrexate, and dactinomycin (EMA)/cyclophosphamide and vincristine (CO) regimen.
PATIENTS AND METHODS: Between 1992 and 2000, 485 women with GTD were commenced on MTX/FA at Charing Cross Hospital, London, United Kingdom. If patients developed MTX resistance or toxicity, treatment was altered according to the level of beta human chorionic gonadotropin (hCG). If serum hCG was RESULTS: The median duration of follow-up was 4.7 years. Overall survival was 100% and the relapse rate was 3.3% (16 of 485 patients). hCG values normalized in 324 (66.8%) of 485 patients with MTX alone, whereas 161 (33.2%) of 485 patients required a change in treatment, 11 because of MTX toxicity and 150 because of MTX resistance. Sixty-seven patients changed to dactinomycin, of whom 58 achieved normal hCG values, and nine required third-line chemotherapy with EMA/CO. hCG values normalized in 93 (98.9%) of 94 patients who changed directly to EMA/CO from MTX. CONCLUSION: Single-agent dactinomycin has activity in patients with low-risk GTD who develop MTX resistance and whose hCG is low. Simplifying the stratification of GTD into two classes (low- and high-risk) does not compromise overall outcome and may reduce the risk of second tumors.
GESTATIONAL trophoblastic disease (GTD) consists of a group of diseases ranging from hydatidiform mole to choriocarcinoma. All patients in the United Kingdom diagnosed with GTD are referred to one of three centers for beta human chorionic gonadotropin (hCG) monitoring and, if necessary, to one of the two centers for treatment. In our center, patients who require treatment (criteria: serum hCG > 20,000 IU/L > 4 weeks after uterine evacuation, static or rising hCG after uterine evacuation, persistent hemorrhage, presence of metastatic disease, diagnosis of choriocarcinoma) are stratified according to the Charing Cross scoring system (Table 1). This scoring system was devised as a way of stratifying patients into treatment groups according to known adverse prognostic factors rather than by strict anatomic definitions. Previously, three prognostic categories were used, namely, high (score > 9), medium (score of 6 to 9), or low risk (score of 0 to 5). Initial treatment for those with low-risk disease was methotrexate (MTX) (50 mg intramuscularly on days 1, 3, 5, and 7 with folinic acid [FA] 7.5 mg orally on days 2, 4, 6, and 8, repeated every 2 weeks),1 whereas for those with medium-risk disease, the chemotherapy regimen consisted of MTX as above, plus oral hydroxyurea 1 g on day 1, oral mercaptopurine 75 mg on the same day as the FA, alternating with courses of either intravenous etoposide 250 mg/m2 on days 1 and 3, or courses of intravenous dactinomycin 0.5 mg daily for 5 days.2 Treatment for high-risk disease was infusional chemotherapy according to the etoposide, methotrexate, and dactinomycin (EMA)/cyclophosphamide and vincristine (CO) regimen3 (Table 2).
The cure rate for GTD is high; therefore, reducing both long- and short-term toxicity, without compromising outcome, has been a priority. We have previously demonstrated that exposure to combination, but not single-agent, chemotherapy is associated with an increased incidence of second tumors, especially myeloid leukemia and colon cancer.4 In addition, combination chemotherapy, more than single-agent methotrexate, increases the risk of an early menopause.5 In an attempt both to simplify treatment and to reduce immediate and delayed toxicity, we have altered our initial management (Fig 1). Patients are now classified as either low risk (Charing Cross score of 0 to 8) or high risk (score > 8) (Table 1), a change that parallels the new proposed combined World Health Organization (WHO)/International Federation of Gynecology and Obstetrics (FIGO) scoring system,6 which also has only two risk categories (low-risk score of 0 to 6, high-risk score > 6; a Charing Cross score of 8 corresponds to a WHO/FIGO score of 6). A recent retrospective analysis of patients treated at one center indicated that the new scoring system resulted in more patients being categorized as low risk, but without compromising outcome.7
Low-risk patients receive single-agent MTX as first-line treatment whereas, as before, EMA/CO is used for the high-risk group. We have previously shown that MTX can cure approximately 30% of patients in the old medium-risk group (score of 6 to 9), whereas the remaining 70% can be salvaged effectively with combination treatment.1 In addition, there is clear evidence that treating low- and medium-risk patients until methotrexate resistance is evident does not reduce the ability of salvage chemotherapy (usually with EMA/CO) to cure patients.8 There has also been a slight change in management for those patients who develop MTX resistance or toxicity, which depends on the serum hCG value at that time. If the serum hCG is low (< approximately 100 IU/L), patients change to single-agent dactinomycin (0.5 mg intravenously daily for 5 days, repeated every 2 weeks). Single-agent dactinomycin has significant activity in GTD and is used regularly in the United States for women with FIGO stage I disease in order to preserve fertility.9 For those whose hCG is greater than approximately 100 IU/L at the time of developing MTX resistance or toxicity, EMA/CO treatment is used as before. Here we present the outcome of a cohort of 485 patients treated according to these new protocols at Charing Cross Hospital since 1992.
Between February 1992 and December 2000, 598 women were treated at Charing Cross Hospital for GTD. All patients were assessed with chest x-ray, pelvic ultrasound, serum hCG, and a review of the histologic findings from the referring hospital. On the basis of this assessment, patients were given a prognostic score according to the modified Charing Cross scoring system (Table 1). Four hundred eighty-five patients who scored  8 were commenced on intramuscular methotrexate (50 mg intramuscularly on days 1, 3, 5, and 7 with FA 7.5 mg orally on days 2, 4, 6, and 8, repeated every 2 weeks; since September 2000, all patients have received 15 mg FA to reduce the incidence of oral mucositis). All patients with pulmonary metastases evident on chest x-ray also had a computed tomographic scan of the chest, abdomen, and pelvis, and a cranial magnetic resonance imaging scan and lumbar puncture performed to exclude CNS disease. Those patients with pulmonary metastases who had no evidence of CNS disease received prophylaxis with intrathecal methotrexate (12.5 mg) every 2 weeks for three doses,8 although the need for CNS prophylaxis has recently been questioned.10 One patient included in this analysis had no histologic findings available, despite several uterine evacuations, but was treated presumptively on the basis of history and raised serum and urine hCG levels (see Results and Discussion). In all patients, hCG values were measured twice weekly during treatment, and any patient who had two static or rising hCG values during treatment was defined as having drug-resistant disease. Those patients who developed resistance to MTX changed treatment according to the hCG level, which is known to correlate with the amount of remaining disease. Consequently, those patients with an hCG level of less than approximately 100 IU/L received single-agent dactinomycin, whereas those with a level greater than 100 IU/L were given EMA/CO (Table 2 lists details of the dactinomycin and EMA/CO regimens). Any patient who developed resistance to second-line dactinomycin (as before, defined as two static or rising hCG values during treatment) was changed to EMA/CO. Patients who developed MTX-induced mucositis were initially treated by increasing the dose of folinic acid or bringing forward the time of rescue from 30 hours to 24 hours after MTX. If this was insufficient, treatment was also changed according to hCG value. Patients who developed toxicity to dactinomycin were changed to EMA/CO. The potential treatment pathways are presented in Fig 1.
Treatment was continued in all cases until the serum hCG values had been normal (< 5 IU/L) for 6 weeks, after which lifelong hCG monitoring commenced. Patients were classified as having relapsed disease if, in the absence of a confirmed pregnancy, the serum hCG value started to rise after it had been within the normal range for
Four hundred eighty-five patients with low-risk gestational trophoblastic disease commenced treatment with methotrexate alone, and the median follow-up period is 4.7 years (range, 2 months to 9.2 years). Their median age at the start of treatment was 30 years (range, 16 to 57 years). One hundred fifty (30.9%) of 485 patients have required a change of treatment because of MTX resistance. An additional 11 patients (2.3%) have required a change in treatment because of methotrexate toxicity, usually mucositis, despite increased folinic acid rescue. The relapse rate after completion of treatment was 3.3% (16 of 485 patients), and the overall survival for all 485 patients was 100%. The outcomes of all patients are summarized in Table 3.
Of the 324 patients whose hCG values normalized with MTX alone, 11 (3.4%) have relapsed at a median interval of 6.3 months (range, 0.3 to 35 months), and all 11 were treated successfully with EMA/CO. One patient relapsed for a second time, but has been disease-free for 43 months after a hysterectomy and further chemotherapy (see below). For those whose serum hCG was approximately 100 IU/mL (median, 40 IU/mL; range, 7 to 476 IU/mL) at the time of developing either MTX resistance (n = 59) or toxicity (n = 8), treatment was changed to dactinomycin. Fifty-eight (86.6%) of 67 required no additional treatment to normalize their serum hCG values, whereas nine (13.4%) of 67 developed resistance to dactinomycin and required infusional chemotherapy with EMA/CO. Of the 67 patients treated with dactinomycin, four (6.0%) relapsed at a median interval after chemotherapy of 11.2 months (range, 4 to 30 months). All four of these had changed treatment because of MTX resistance rather than toxicity. Therefore, the relapse rate among the MTX-resistant group that changed to dactinomycin was 6.8% (four of 59 patients). None of the nine patients who developed resistance to dactinomycin and subsequently changed to EMA/CO chemotherapy has relapsed. Fourteen patients who changed to dactinomycin had hCG values higher than 100 IU/L at the time of starting second-line chemotherapy. The reason for treatment change was MTX toxicity in two cases and MTX resistance in the remainder. In the majority of cases, the hCG had been close to or below 100 IU/L when the decision was made to change treatment, but rose before the patient was able to receive the first dose. The median hCG value of the 14 patients at the time decision was made to change treatment was 110 IU/L. Two (14.3%) of 14 patients developed dactinomycin resistance and one (7.1%) of 14 relapsed after completion of dactinomycin treatment, and these rates do not differ significantly from the resistance and relapse rates for the whole dactinomycin cohort. The four patients who relapsed after dactinomycin treatment were treated with EMA/CO. hCG values returned to normal in three (75%) of four of these patients. The remaining patient originally had a complete hydatidiform mole. She subsequently required a hysterectomy for placental site trophoblastic tumor and received further chemotherapy with paclitaxel and gemcitabine. Her hCG values have now been normal for over 30 months. Ninety-four patients changed directly from MTX to EMA/CO chemotherapy, 91 because of MTX resistance and three because of MTX toxicity. hCG values returned to normal in 93 (98.9%) of 94 of these patients. The one patient who required additional treatment (paclitaxel/cisplatin/etoposide chemotherapy as well as high-dose chemotherapy with peripheral-blood stem cell support) did not have initial histologic findings but, at subsequent hysterectomy, had an unclassifiable trophoblastic tumor that was confirmed to be of gestational origin by molecular genetic analysis. Only one (1.1%) of 94 patients has relapsed after changing directly from MTX to EMA/CO treatment. After additional chemotherapy (EP/EMA: etoposide 150 mg/m2 and cisplatin 75 mg/m2 alternating weekly with EMA)11 and a hysterectomy, hCG values normalized and have remained so for 23 months. Two patients have relapsed twice. One was treated initially with MTX alone, with EMA/CO at first relapse, and with a hysterectomy followed by EP/EMA at second relapse. hCG values have been normal for 43 months since the completion of EP/EMA chemotherapy. The second patient who relapsed twice developed MTX resistance at first treatment and was converted to dactinomycin, which normalized her hCG values. First relapse occurred 25 months after completion of dactinomycin and was treated with a hysterectomy and EMA/CO chemotherapy. Second relapse occurred 4 months after second-line chemotherapy was completed and required a thoracotomy and third-line chemotherapy with EP/EMA. hCG values have been normal for 38 months. The 485 patients have also been analyzed according to their initial score. Patients were subclassified as either original low risk (Charing Cross score of 0 to 5) (n = 434) or new low risk (Charing Cross score of 6 to 8) (n = 51). For those in the original low-risk group, the rate of MTX resistance was 31.3% (136 of 434 patients), and the relapse rate was 3.2% (14 of 434 patients). In keeping with previous results,1 the rate of MTX resistance for those who fell into the new low-risk group was significantly higher (49.0% [25 of 51 patients], P = .018). Also, of the 25 patients in the new low-risk group who developed MTX resistance and thus required second-line therapy, almost all required infusional treatment with EMA/CO (22 of 25 [88.0%]). However, the rate of relapse among the new low-risk group was not different from that of the original low-risk group (3.9% [two of 51 patients] v 3.2% [14 of 434 patients], P = not significant).
Gestational trophoblastic disease is extremely responsive to chemotherapy. Therefore, in addition to achieving long-term cures, minimizing both long- and short-term toxicity must be an important factor in evaluating treatment. We have previously shown that exposure to combination chemotherapy, but not methotrexate and folinic acid, increases the risk of developing second tumors.4 Therefore, in 1992, we changed the initial management of those patients with a Charing Cross score of 6 to 8 from combination chemotherapy to single-agent MTX. We also altered the second-line treatment of all patients treated with MTX whose hCG was low (approximately 100 IU/L) at the time of developing MTX resistance. Rather than receiving EMA/CO combination therapy, patients are now treated with single-agent dactinomycin, a drug used frequently in the United States when preservation of fertility is important.9 Although the criteria for discontinuing single-agent MTX are unchanged (unacceptable toxicity despite increased folinic acid rescue or two static or rising serum hCG values during treatment), the proportion of patients who did change treatment was higher in this series (33.2%) than in a previous report from this center (26%).1 One reason for the apparent increase in MTX resistance is that the majority of patients previously classified as medium risk (Charing Cross score of 6 to 9) are now treated in the same way as those who are low risk. The rate of MTX resistance in medium-risk patients was approximately 70% in the initial report.1 Therefore, our current analysis of low-risk patients includes some who would previously have been classified as medium risk (whom we have called new low-risk patients). The rate of MTX resistance in the new low-risk group is approximately 50% in this cohort. The rates of MTX toxicity, however, are slightly lower in this series than in our previous report (2.4% compared with 6%).1 There were 67 patients who changed to dactinomycin, of whom 58 required no additional treatment, whereas nine required a second change, to EMA/CO. Thus, second-line dactinomycin does have significant activity in GTD and can normalize hCG values in over 85% of patients who develop MTX toxicity or resistance. Perhaps inevitably, single-agent dactinomycin is not as potent as the combination of EMA/CO, where normal hCG values were achieved in all 93 patients who received this as second-line treatment and who had confirmed GTD histologic findings. The greater efficacy of EMA/CO is further reflected in the relapse rates after completion of treatment (6.0% for those who received dactinomycin as second-line therapy compared with 1.1% for those who changed to EMA/CO).
Although the main criterion for changing to dactinomycin as second-line treatment is a serum hCG value of By analyzing patients according to their Charing Cross score at the start of treatment (original low risk, score of 0 to 5; new low risk, score of 6 to 8), we confirm previous findings that patients with higher scores are more likely to develop MTX resistance. However, the relapse rates of the two groups do not differ significantly (3.2% and 3.9%, respectively), and the overall survival for both groups is 100%, confirming that initial treatment with MTX for patients with a Charing Cross score of 6 to 8 does not jeopardize long-term outcome. The main motivating factor behind the introduction of second-line dactinomycin treatment has been to minimize short- and long-term toxicity without compromising outcome. Although we believe that the current strategy achieves this goal, for the nine patients who have had to change treatment twice, first from MTX to dactinomycin and then to EMA/CO, the use of second-line dactinomycin has undoubtedly increased the total duration of their treatment, with potential impacts on quality of life. The possibilities of dactinomycin resistance and the need for a subsequent second change in chemotherapy treatment is explained to patients, and all are given the option to change directly to EMA/CO if they wish. However, the fact that dactinomycin can be given entirely on an outpatient basis (EMA/CO requires one night’s inpatient stay every 14 days) and the reduced likelihood of hair loss are usually powerful motivating factors for this group of patients.
The experience of the second United Kingdom trophoblastic treatment center has recently been published.12 As at Charing Cross, initial treatment for low-risk GTD consists of MTX and folinic acid rescue. However, their management differs in two respects; their definition of low risk is a score of The reported response rate to second-line EA chemotherapy was 97% (34 patients alive and disease-free out of 35). By the same criteria, 160 of the 161 patients presented here who required dactinomycin and/or EMA/CO are alive and disease-free (99.4%): the one patient who still has active disease has an unclassified trophoblastic tumor that is of gestational, genetic origin. Direct comparisons between this cohort of patients and those treated at the New England Trophoblastic Disease Center are difficult for two reasons. First, patients are currently staged according to the FIGO classification system, which is derived from anatomic site of disease. Patients with FIGO stage I disease (confined to the uterus) will generally score low risk, but the correlation is incomplete and is even more so when comparing FIGO stage II/III disease (local extension beyond the uterus and lung metastases, respectively) and the Charing Cross prognostic scoring system.13 Second, primary hysterectomy was used in 6.9% of patients with stage I disease,9 whereas no patients in the Charing Cross cohort were treated with primary surgery after their initial evacuation. Single-agent chemotherapy with either MTX or dactinomycin produced normal hCG values in 91% of those with stage I disease who did not have primary surgery. For those whose disease was resistant to MTX or dactinomycin, combination chemotherapy with either MTX, dactinomycin, and chlorambucil or cyclophosphamide (MAC) or EMA produced normal hCG levels in 88%.9 Patients with stage II/III disease are further classified into low- and high-risk groups according to the WHO prognostic scoring system. Sequential MTX/dactinomycin produced normal hCG values in 84.2% of those with low-risk stage II disease and 83.5% of those with low-risk stage III disease.9 Four groups14-17 have reported outcomes of patients with low-risk stage II and III disease treated with single-agent chemotherapy. The rates at which normal hCG values are produced range from 60% (nine of 15 patients)15 to 87.3% (48 of 55 patients),17 averaging 87.1%. The eventual overall remission rate was 98.6%.
Elsewhere and more recently, other reports of the treatment of low-risk GTD have appeared. In a comparison of single-agent MTX, etoposide, or dactinomycin, the highest rate of primary remission was achieved with etoposide (90.1%) and the lowest with MTX (73.6%).18 However, the long-term risk of second tumors induced by etoposide may reduce its attractiveness as a first-line therapy, although it has also been shown that, in the absence of metastatic disease, hysterectomy can reduce the total amount of etoposide required to produce normal hCG values.19 Finally, infusional MTX (100 mg/m2 bolus followed by 200 mg/m2 over 12 hours) has been used in one small study where folinic acid rescue was only given if serum MTX levels reached a level of In summary, we have presented the outcome of a large cohort of patients with low-risk GTD treated at a single center since 1992. Overall, the rate of survival for all 485 patients is 100%. All patients were initially treated with MTX and folinic acid, which produced normal hCG values in approximately 70% of cases. We have altered the protocols for second-line treatment in an attempt to minimize the exposure to potentially carcinogenic combination chemotherapy that can also induce a premature menopause. The results presented here indicate that single-agent dactinomycin does have significant activity in this disease and can produce complete responses in over 85% of those who are resistant to, or intolerant of, MTX when the serum hCG is relatively low. Moreover, dactinomycin does not compromise the long-term outcome of those who do subsequently require combination chemotherapy. Therefore, we recommend that all patients scoring lower than 9 on the Charing Cross scoring system can be safely treated with MTX and folinic acid as first-line therapy. For those who require a change of treatment, single-agent dactinomycin should be considered if the serum hCG is less than approximately 100 IU/L, whereas EMA/CO should still be used for those with higher hCG values.
1. Bagshawe KD, Dent J, Newlands ES, et al: The role of low-dose methotrexate and folinic acid in gestational trophoblastic tumors (GTT). Br J Obstet Gynaecol 96: 795-802, 1989[Medline] 2. Newlands ES, Bagshawe KD, Begent RH, et al: Developments in chemotherapy for medium- and high-risk patients with gestational trophoblastic tumours (1979-1984). Br J Obstet Gynaecol 93: 63-69, 1986[Medline] 3. Newlands ES, Bagshawe KD, Begent RHJ, et al: Results with the EMA/CO (etoposide, methotrexate, actinomycin-D, cyclophosphamide, vincristine) regimen in high-risk gestational trophoblastic tumors, 1979 to 1989. Br J Obstet Gynaecol 98: 550-557, 1991[Medline]
4.
Rustin GJS, Newlands ES, Lutz JM, et al: Combination but not single-agent methotrexate chemotherapy for gestational trophoblastic tumors increases the incidence of second tumors. J Clin Oncol 14: 2769-2773, 1996 5. Bower M, Rustin GJS, Newlands ES, et al: Chemotherapy for gestational trophoblastic tumours hastens menopause by 3 years. Eur J Cancer 34: 1204-1207, 1998 6. Kohorn EI, Goldstein DP, Hancock BW, et al: Combining the staging system of the International Federation of Gynecology and Obstetrics with the scoring system of the World Heath Organization for Trophoblastic Neoplasia: Report of the Working Committee of the International Society for the Study of Trophoblastic Disease and the International Gynecologic Cancer Society. Int J Gynecol Cancer 10: 84-88, 2000[CrossRef][Medline] 7. Hancock BW, Welch EM, Gillespie AM, et al: A retrospective comparison of current and proposed staging and scoring systems for persistent gestational trophoblastic disease. Int J Gynecol Cancer 10: 318-322, 2000[CrossRef][Medline]
8.
Bower M, Newlands ES, Holden L, et al: EMA/CO for high-risk gestational trophoblastic tumors: Results from a cohort of 272 patients. J Clin Oncol 15: 2636-2643, 1997 9. Berkowitz RS, Goldstein DP: Presentation and management of persistent gestational trophoblastic disease and gestational trophoblastic tumors in the USA, in Hancock BW, Newlands ES, Berkowitz RS (eds): Gestational Trophoblastic Disease. London, United Kingdom, Chapman & Hall, 1997, pp 159-172 10. Gillespie AM, Siddiqui N, Coleman RE, et al: Gestational trophoblastic disease: Does central nervous system chemoprophylaxis have a role? Br J Cancer 79: 1270-1272, 1999[CrossRef][Medline]
11.
Newlands ES, Mulholland PJ, Holden L, et al: Etoposide and cisplatin/etoposide, methotrexate, and actinomycin D (EMA) chemotherapy for patients with high-risk gestational trophoblastic tumors refractory to EMA/cyclophosphamide and vincristine chemotherapy and patients presenting with metastatic placental site trophoblastic tumors. J Clin Oncol 18: 854-859, 2000 12. Dobson LS, Lorigan PC, Coleman RE, et al: Persistent gestational trophoblastic disease: Results of MEA (methotrexate, etoposide and dactinomycin) as first-line chemotherapy in high risk disease and EA (etoposide and dactinomycin) as second-line therapy for low risk disease. Br J Cancer 82: 1547-1552, 2000[CrossRef][Medline] 13. Smith DB, Holden L, Newlands ES, et al: Correlation between clinical staging (FIGO) and prognostic groups with gestational trophoblastic disease. Br J Obstet Gynaecol 100: 157-160, 1993[Medline] 14. Soper JT, Clarkepearson DL, Berchuck A, et al: 5-Day methotrexate for women with metastatic gestational trophoblastic disease. Gynecol Oncol 54: 76-79, 1994[CrossRef][Medline] 15. Ayhan A, Yapar EG, Deren O, et al: Remission rates and significance of prognostic factors in gestational trophoblastic tumors. J Reprod Med 37: 461-465, 1992[Medline] 16. Dubuc-Lissoir J, Sweizig S, Schlaerth JB, et al: Metastatic gestational trophoblastic disease: A comparison of prognostic classification systems. Gynecol Oncol 45: 40-45, 1992[CrossRef][Medline] 17. DuBeshter B, Berkowitz RS, Goldstein DP, et al: Metastatic gestational trophoblastic disease: Experience at the New England Trophoblastic Disease Center from 1965 to 1985. Obstet Gynecol 69: 390-395, 1987[Medline] 18. Matsui H, Iitsuka Y, Seki K, et al: Comparison of chemotherapies with methotrexate, VP-16 and actinomycin-D in low-risk gestational trophoblastic disease. Gynecol Obstet Invest 46: 5-8, 1998[CrossRef][Medline] 19. Suzuka K, Matsui H, Iitsuka Y, et al: Adjuvant hysterectomy in low-risk gestational trophoblastic disease. Obstet Gynecol 97: 431-434, 2001[CrossRef][Medline] 20. Wong LC, Ngan HYS, Cheng DKL, et al: Methotrexate infusion in low-risk gestational trophoblastic disease. Am J Obstet Gynecol 183: 1579-1582, 2000[CrossRef][Medline] Submitted June 27, 2001; accepted December 7, 2001.
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
6 weeks. 
