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Management of Low-Risk Gestational Trophoblastic Tumors with Etoposide (VP16) in Patients Resistant to Methotrexate
GYNECOLOGIC ONCOLOGY ARTICLE NO.
61, 218–220 (1996)
0128
Management of Low-Risk Gestational Trophoblastic Tumors with Etoposide (VP16) in Patients Resistant to Methotrexate G. MANGILI, M.D., E. GARAVAGLIA, M.D., L. FRIGERIO, M.D., G. CANDOTTI, M.D.,
AND
A. FERRARI, M.D.
Department of Obstetrics and Gynaecology, University of Milan, S. Raffaele Hospital Scientific Institute, Via Olgettina 60, 20132 Milan, Italy Received April 24, 1995
Careful selection and treatment monitoring of patients with gestational trophoblastic tumors (GTT) is critical because 20–50% of patients may develop a resistance and consequently require alternative chemotherapeutic agents. In our study we propose and demonstrate the efficacy of etoposide (VP16) as a second-line drug. An average of 5 courses with VP16 were used to achieve a remission in 12 patients resistant to MTX with low-risk GTT. Toxicity was mild and no resistance to VP16 was observed. A follow-up of 66 months (range, 22–109) has been performed for the patients and all of them are now disease free. Two patients had a pregnancy, respectively, 3 and 4 years after treatment. The others did not desire any pregnancy. q 1996 Academic Press, Inc.
INTRODUCTION
The outlook for patients with low-risk GTT is excellent, with virtually 100% survival in most recent series [1–3]. Although a variety of agents, such as actinomycin D [4] and etoposide [5] have been used with substantial success, a single-agent chemotherapy with methotrexate now appears to be the best initial therapy for patients with low-risk GTT [3, 6–8]. Careful selection and monitoring of treatment are critical: because of resistance about 20–50% of patients may require alternative chemotherapeutic agents in order to achieve remission [9, 6, 10–12]. Furthermore 5% of patients needs to change treatment because of drug-induced toxicity. Etoposide activity in GTT was demonstrated in 1977 and introduced into the chemotherapeutic management for trophoblastic neoplasia by Bagshawe’s group in London [13]. VP16 has become an invaluable component of combination therapy in medium- and high-risk GTT [14]. Despite its apparent contribution in poor prognosis GTT, the singleagent activity of etoposide is documented inadequately. The purpose of our study was to demonstrate the activity of VP16 as a single agent in low-risk patients resistant to MTX. MATERIALS AND METHODS
The medical records of all patients with low-risk GTT and resistant to MTX treated by our group from 1987 to
04-16-96 02:53:30
RESULTS
Because of drug resistance, 12 low-risk GTT patients required a change from the initial treatment with MTX. The mean age was 31.8 (range, 17–48). Before the chemotherapy with MTX, the mean prognostic score was 2.5, with a pretreatment bhCG of 26,241 IU/liter (range, 510–86,000). Lung metastases were present in 4 patients (3 in stage IA and I in stage IIIA) (Table 3). MTX resistance occurred after an average of 3 chemotherapy courses (range, 3–7). Three patients were changed due to a less than 1 log bhCG fall. The mean prognostic score was 5 (range, 3–8) estimated
218
0090-8258/96 $18.00 Copyright q 1996 by Academic Press, Inc. All rights of reproduction in any form reserved.
/ 6d0b$$4263
1993, were reviewed in detail. We analyzed the age of the patients, the mean prognostic score, pretreatment serum human chorionic gonadotrophin (bhCG) levels, site and extention of metastatic disease, the type and toxicity of treatment, the stage, according to the FIGO staging for trophoblastic tumors (Table 1), the mean follow-up, and eventual following pregnancy. The Charing Cross Hospital scoring system for gestational trophoblastic disease modified by Bagshawe in 1983 (Table 2) [12] has been used in choosing the treatment. We administered 1 mg/kg MTX intramuscularly on Days 1, 3, 5, and 7, and 6 mg folinic acid intramuscularly on Days 2, 4, 6, and 8. We repeated the same treatment every 7 days to each patient. The response was evaluated weekly by serum bhCG level. We considered as a response the fall in bhCG concentration following chemotherapy and the absence of bhCG during the 8 weeks after the last cycle of chemotherapy. If bhCG continued to rise on treatment or if levels plateaued or ceased to fall 1 log after a chemotherapy cycle, the tumor was regarded as resistant. The patients resistant to MTX were treated with 100 mg/m2 VP16 iv for 5 consecutive days every 10 days. All patients with lung metastases underwent MTX prophylactic subarachnoid administration. After each chemotherapy, treatment toxicity was monitored with a weekly complete blood cells count (leukocyte, granulocyte and platelet count, hemoglobin), electrolyte, and renal and hepatic function tests.
goa
AP: Gyn Onc
219
VP16 IN LOW-RISK TROPHOBLASTIC TUMOR
TABLE 1 FIGO Staging for Trophoblastic Tumors (Am. J. 1992)
TABLE 3 Characteristics of Patients before Treatment with MTX
Stage I: Disease confined to uterus II: Tumor extending outside uterus but limited to genital structures III: Tumor extending to lungs IV: All other metastatic sites Note. A, with no risk factor; B, with 1 risk factor; C, with 2 risk factors; risk factor, (1) hCG ú100,000 mlU/ml; (2) duration of disease ú 6 months from termination of antecedent pregnancy.
again after the onset of the resistance to MTX in the 12 patients. The mean pretreatment bhCG was 17,400 IU/liter (range, 40–81,000). We performed the treatment about 4 months after the antecedent pregnancy (range, 2–7). The mean number of chemotherapy courses with VP16 to achieve remission was 5 (range, 2–8). Two patients underwent a total abdominal hysterectomy before MTX in another hospital and two before VP16 (Table 4). VP16 toxicity was mild: reversible alopecia, nausea, and emesis (all women); leukopenia of grade 2, õ3000/mm3 (2 patients); leg phlebitis (one patient). No life-threatening toxicity occurred. One case of severe hypersensitivity to etoposide was observed with chest pain, fever, bronchospasm, urticaria, and hypotention requiring intravenous fluids and corticosteroids. This patient was treated with hydroxyurea, MTX, mercaptopurina, and dactinomycin according to the chemotherapic schedule proposed by Bagshawe for middle-risk patients. All women presented amenorrhea for more than 3 months. The follow-up was of 66 months (range, 22–109) and all patients are now disease free. Two patients had a pregnancy, respectively, 3 and 4 years after treatment. The others did not desire any pregnancy.
Patient
Age
Surgery pre-MTX
Pretreatment bhCG
Metastases
Score
Stage
1 2 3 4 5 6 7 8 9 10 11 12
25 27 23 29 47 41 48 17 22 43 30 29
— — — — — Isterectomy Isterectomy — — — — —
610 50,800 3,477 14,400 86,000 3,300 510 55,900 24,100 52,600 2,200 21,000
Lung — — — — Lung — Lung Lung — — —
1 3 4 2 4 2 2 4 3 2 1 2
IIIA IA IA IA IA IIIA IA IIIA IIIA IA IA IA
DISCUSSION
Our study demonstrated the high activity of etoposide in patients with GTT. All of them achieved sustained gonadotropin remission after chemotherapy with VP16. This has been shown recently by other authors such as Bagshawe et al. [12] or Hitchins and Newlands [11]. The last authors found that bhCG fell significantly in 78% of patients (18/23) with established resistance to MTX and no one progressed. Because they did not administer repeated cycles of singleagent etoposide, the speculation of resistance is impossible. Wong et al. [19] reported good results in terms of remission of tumor in a series of 60 patients with GTT treated with oral etoposide therapy. Furthermore, they observed low relapse rate of 5% compared to their experience after MTX alone. In their opinion etoposide should not be reserved only for drug-resistant GTT. Our study showed no case of VP16 resistance. The prognostic score was not helpful in predicting
TABLE 2 Charing Cross Hospital Scoring System for Gestational Trophoblastic Disease (Bagshawe and colleagues, 1983) [6] Score 0
1
2
Age (years) Antecedent pregnancy (AP) Interval from AP (months) hCG (IU/liter) AB0 blood groups (F 1 M)
õ37 Mole õ4 1,000–10,000
Number of metastases Sites of metastases Largest tumor mass (cm) Previous chemotherapy
0 Lung; vagina õ3 —
ú39 Abortion or unknown 4–6 õ1,000 A 1 0; 0 1 A 0/A 1 unknown 1–3 Kidney; spleen 3–5 —
Term delivery 7–12 10,000–100,000 B 1 A (0) AB 1 A (0) 4– 8 GI tract; liver ú5 Single agent
Note. Low risk, õ6; middle risk, 6–9; high risk, ú9.
/ 6d0b$$4263
04-16-96 02:53:30
goa
AP: Gyn Onc
6
ú12 ú100,000
ú8 Brain
2 or more drugs
220
MANGILI ET AL.
TABLE 4 Characteristics of Patients before Treatment with VP16 3. Patient
Surgery post-VP16
bhCG pretreatment
Metastases
Score
1 2 3 4 5 6 7 8 9 10 11 12
— — — — Isterectomy — — — — Isterectomy — —
40 5,300 352 64 81,000 54 129 77,700 120 37,900 310 5,800
Lung Lung — — — — — Lung Lung — — Lung
6 7 5 3 7 5 4 6 3 4 3 8
the drug resistance in patients with low-risk GTT. In contrast, high pretreatment bhCG levels [3] and metastatic disease seem to be risk factors for chemotherapy resistance. They may show the conditions of administering VP16 as initial chemotherapy. Single-agent MTX is not always an appropriate treatment for patients with GTT [11]. Hitchins and Newlands (’88) treated eight low-risk patients with single first-line agent VP16. Seven of them showed a complete remission and one changed therapy because of drug resistance. Gonadal toxicity related to etoposide is a major consideration in females during reproductive life. Choo and Wong [16] reported significant ovarian dysfunction among patients undergoing single-agent etoposide. He noticed that young patients had amenorrhea for a short period, while in older patients may be irreversible. This may be related to the low number of ovarian follicles in older patient. It is known that reproductive function after hydatiform mole and low-risk trophoblastic neoplasia is not compromised [17, 18], even after a chemotherapy with MTX or VP16. Infertility problems are associated with the alkylating agents used in combination therapy for high-risk disease [17]. In our study two patients desiring pregnancy succeeded.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
REFERENCES
17.
1. DuBeshter, B., Berkowitz, R. S., and Goldstein, D. P. Metastatic gestational trophoblastic disease: Experience at the New England Trophoblastic Disease Center, 1965 to 1985, Obstet. Gynecol. 69, 390, (1987).
18.
2. Soper, J. T., Clark-Pearson, D., and Hammond, C. B. Metastatic gesta-
/ 6d0b$$4263
04-16-96 02:53:30
goa
19.
tional trophoblastic disease: Prognostic factors in previously untreated patients, Obstet. Gynecol. 71, 338 (1988). Smith, D. B., Holden, L., Newlands, E. S., and Bagshawe, K. D. Correlation between clinical staging (FIGO) and prognostic groups with gestational trophoblastic disease, Br. J. Obstet. Gynaecol. 100, 157– 160 (1993). Osathanondh, R., Goldstein, D. P., and Pastorfide, G. B. Actinomycin D as the primary agent for gestational trophoblastic disease, Cancer 36, 863 (1975). Wong, L. C., Choo, Y. C., and Ma, H. K. Use of oral VP16-213 as primary chemiotherapeutic agent in treatment of gestational trophoblastic disease, Am. J. Obstet. Gynecol. 150, 924 (1984). Hilgers, R., Newlands, E., Hoffman, R., Mitchell, H., and Bagshawe, K. D. Correlation of plasma methotrexate concentration with human chorionic gonadotropin and therapeutic response to low-dose methotrexate–citrovorum factor in low–medium-risk gestational trophoblastic tumors, Gynecol. Oncol. 41, 117–122 (1991). Ross, G. T., Goldstein, D. P., and Hertz, R. Sequential use of methotrexate and actinomycin D in the treatment of metastatic choriocarcinoma and related trophoblastic disease in women, Am. J. Obstet. Gynecol. 93, 223 (1965). Berkowitz, R. S., Goldstein, D. P., and Bernstein, M. R. Ten years experience with methotrexate and folinic acid as primary therapy for gestational trophoblastic disease, Gynecol. Oncol. 23, 111 (1986). Newlands, E. S. Management of gestational trophoblastic tumors (GTT), Proc. Gynaecol. Oncol. Meeting, London, September (1987). [Abstract] DuBeshter, B., Berkowitz, R., Goldstein, D. P., and Bernstein, M. R. Management of low-risk metastatic gestational trophoblastic tumors, J. Rep. Med. 36, 1 (1991). Hitchins, R. N., and Newlands, E. S. Single agent etoposide in gestational trophoblastic tumours, Eur. J. Cancer Clin. Oncol. 24, 1041– 1046 (1988). Bagshawe, K. D., Dent, J., and Newlands, E. S. The role of lowdose methotrexate and folinic acid in gestational trophoblastic tumours (GTT), Br. J. Obstet. Gynaecol. 96, 735–802 (1989). Newlands, E. S., and Bagshawe, K. D. The role of VP16-213 (etoposide; NSC-141540) in gestational choriocarcinoma, Cancer Chemother. Pharmacol. 7, 211 (1982). Newlands, E. S., Bagshawe, K. D., and Begent, R. H. J. Developments in chemotherapy for medium and high risk patients with gestational trophoblastic tumors, Br. J. Obstet. Gynaecol. 93, 63 (1986). World Health Organization Scientific Group. Gestational trophoblastic disease, Technical Report Series 692. Geneva, Switzerland, WHO, pp. 1–81 (1983). Choo, Y. C., and Wong, L. C. Ovarian dysfunction in patients with gestational trophoblastic tumours, Br. Med. J. 288, 102–106 (1984). Kohorn, E. Single-agent chemotherapy for nonmetastatic gestational trophoblastic neoplasia, J. Reprod. Med. 36, 49–55 (1991). Ayhan, A. Pregnancy after chemotherapy for gestational trophoblastic disease, J. Reprod. Med. 35, 522–525 (1990). Wong, L. C., Frcog, B. S., and Choo, Y. C. Primary oral etoposide therapy in gestational trophoblastic disease, Cancer 58, 14–17 (1986).
AP: Gyn Onc
61, 218–220 (1996)
0128
Management of Low-Risk Gestational Trophoblastic Tumors with Etoposide (VP16) in Patients Resistant to Methotrexate G. MANGILI, M.D., E. GARAVAGLIA, M.D., L. FRIGERIO, M.D., G. CANDOTTI, M.D.,
AND
A. FERRARI, M.D.
Department of Obstetrics and Gynaecology, University of Milan, S. Raffaele Hospital Scientific Institute, Via Olgettina 60, 20132 Milan, Italy Received April 24, 1995
Careful selection and treatment monitoring of patients with gestational trophoblastic tumors (GTT) is critical because 20–50% of patients may develop a resistance and consequently require alternative chemotherapeutic agents. In our study we propose and demonstrate the efficacy of etoposide (VP16) as a second-line drug. An average of 5 courses with VP16 were used to achieve a remission in 12 patients resistant to MTX with low-risk GTT. Toxicity was mild and no resistance to VP16 was observed. A follow-up of 66 months (range, 22–109) has been performed for the patients and all of them are now disease free. Two patients had a pregnancy, respectively, 3 and 4 years after treatment. The others did not desire any pregnancy. q 1996 Academic Press, Inc.
INTRODUCTION
The outlook for patients with low-risk GTT is excellent, with virtually 100% survival in most recent series [1–3]. Although a variety of agents, such as actinomycin D [4] and etoposide [5] have been used with substantial success, a single-agent chemotherapy with methotrexate now appears to be the best initial therapy for patients with low-risk GTT [3, 6–8]. Careful selection and monitoring of treatment are critical: because of resistance about 20–50% of patients may require alternative chemotherapeutic agents in order to achieve remission [9, 6, 10–12]. Furthermore 5% of patients needs to change treatment because of drug-induced toxicity. Etoposide activity in GTT was demonstrated in 1977 and introduced into the chemotherapeutic management for trophoblastic neoplasia by Bagshawe’s group in London [13]. VP16 has become an invaluable component of combination therapy in medium- and high-risk GTT [14]. Despite its apparent contribution in poor prognosis GTT, the singleagent activity of etoposide is documented inadequately. The purpose of our study was to demonstrate the activity of VP16 as a single agent in low-risk patients resistant to MTX. MATERIALS AND METHODS
The medical records of all patients with low-risk GTT and resistant to MTX treated by our group from 1987 to
04-16-96 02:53:30
RESULTS
Because of drug resistance, 12 low-risk GTT patients required a change from the initial treatment with MTX. The mean age was 31.8 (range, 17–48). Before the chemotherapy with MTX, the mean prognostic score was 2.5, with a pretreatment bhCG of 26,241 IU/liter (range, 510–86,000). Lung metastases were present in 4 patients (3 in stage IA and I in stage IIIA) (Table 3). MTX resistance occurred after an average of 3 chemotherapy courses (range, 3–7). Three patients were changed due to a less than 1 log bhCG fall. The mean prognostic score was 5 (range, 3–8) estimated
218
0090-8258/96 $18.00 Copyright q 1996 by Academic Press, Inc. All rights of reproduction in any form reserved.
/ 6d0b$$4263
1993, were reviewed in detail. We analyzed the age of the patients, the mean prognostic score, pretreatment serum human chorionic gonadotrophin (bhCG) levels, site and extention of metastatic disease, the type and toxicity of treatment, the stage, according to the FIGO staging for trophoblastic tumors (Table 1), the mean follow-up, and eventual following pregnancy. The Charing Cross Hospital scoring system for gestational trophoblastic disease modified by Bagshawe in 1983 (Table 2) [12] has been used in choosing the treatment. We administered 1 mg/kg MTX intramuscularly on Days 1, 3, 5, and 7, and 6 mg folinic acid intramuscularly on Days 2, 4, 6, and 8. We repeated the same treatment every 7 days to each patient. The response was evaluated weekly by serum bhCG level. We considered as a response the fall in bhCG concentration following chemotherapy and the absence of bhCG during the 8 weeks after the last cycle of chemotherapy. If bhCG continued to rise on treatment or if levels plateaued or ceased to fall 1 log after a chemotherapy cycle, the tumor was regarded as resistant. The patients resistant to MTX were treated with 100 mg/m2 VP16 iv for 5 consecutive days every 10 days. All patients with lung metastases underwent MTX prophylactic subarachnoid administration. After each chemotherapy, treatment toxicity was monitored with a weekly complete blood cells count (leukocyte, granulocyte and platelet count, hemoglobin), electrolyte, and renal and hepatic function tests.
goa
AP: Gyn Onc
219
VP16 IN LOW-RISK TROPHOBLASTIC TUMOR
TABLE 1 FIGO Staging for Trophoblastic Tumors (Am. J. 1992)
TABLE 3 Characteristics of Patients before Treatment with MTX
Stage I: Disease confined to uterus II: Tumor extending outside uterus but limited to genital structures III: Tumor extending to lungs IV: All other metastatic sites Note. A, with no risk factor; B, with 1 risk factor; C, with 2 risk factors; risk factor, (1) hCG ú100,000 mlU/ml; (2) duration of disease ú 6 months from termination of antecedent pregnancy.
again after the onset of the resistance to MTX in the 12 patients. The mean pretreatment bhCG was 17,400 IU/liter (range, 40–81,000). We performed the treatment about 4 months after the antecedent pregnancy (range, 2–7). The mean number of chemotherapy courses with VP16 to achieve remission was 5 (range, 2–8). Two patients underwent a total abdominal hysterectomy before MTX in another hospital and two before VP16 (Table 4). VP16 toxicity was mild: reversible alopecia, nausea, and emesis (all women); leukopenia of grade 2, õ3000/mm3 (2 patients); leg phlebitis (one patient). No life-threatening toxicity occurred. One case of severe hypersensitivity to etoposide was observed with chest pain, fever, bronchospasm, urticaria, and hypotention requiring intravenous fluids and corticosteroids. This patient was treated with hydroxyurea, MTX, mercaptopurina, and dactinomycin according to the chemotherapic schedule proposed by Bagshawe for middle-risk patients. All women presented amenorrhea for more than 3 months. The follow-up was of 66 months (range, 22–109) and all patients are now disease free. Two patients had a pregnancy, respectively, 3 and 4 years after treatment. The others did not desire any pregnancy.
Patient
Age
Surgery pre-MTX
Pretreatment bhCG
Metastases
Score
Stage
1 2 3 4 5 6 7 8 9 10 11 12
25 27 23 29 47 41 48 17 22 43 30 29
— — — — — Isterectomy Isterectomy — — — — —
610 50,800 3,477 14,400 86,000 3,300 510 55,900 24,100 52,600 2,200 21,000
Lung — — — — Lung — Lung Lung — — —
1 3 4 2 4 2 2 4 3 2 1 2
IIIA IA IA IA IA IIIA IA IIIA IIIA IA IA IA
DISCUSSION
Our study demonstrated the high activity of etoposide in patients with GTT. All of them achieved sustained gonadotropin remission after chemotherapy with VP16. This has been shown recently by other authors such as Bagshawe et al. [12] or Hitchins and Newlands [11]. The last authors found that bhCG fell significantly in 78% of patients (18/23) with established resistance to MTX and no one progressed. Because they did not administer repeated cycles of singleagent etoposide, the speculation of resistance is impossible. Wong et al. [19] reported good results in terms of remission of tumor in a series of 60 patients with GTT treated with oral etoposide therapy. Furthermore, they observed low relapse rate of 5% compared to their experience after MTX alone. In their opinion etoposide should not be reserved only for drug-resistant GTT. Our study showed no case of VP16 resistance. The prognostic score was not helpful in predicting
TABLE 2 Charing Cross Hospital Scoring System for Gestational Trophoblastic Disease (Bagshawe and colleagues, 1983) [6] Score 0
1
2
Age (years) Antecedent pregnancy (AP) Interval from AP (months) hCG (IU/liter) AB0 blood groups (F 1 M)
õ37 Mole õ4 1,000–10,000
Number of metastases Sites of metastases Largest tumor mass (cm) Previous chemotherapy
0 Lung; vagina õ3 —
ú39 Abortion or unknown 4–6 õ1,000 A 1 0; 0 1 A 0/A 1 unknown 1–3 Kidney; spleen 3–5 —
Term delivery 7–12 10,000–100,000 B 1 A (0) AB 1 A (0) 4– 8 GI tract; liver ú5 Single agent
Note. Low risk, õ6; middle risk, 6–9; high risk, ú9.
/ 6d0b$$4263
04-16-96 02:53:30
goa
AP: Gyn Onc
6
ú12 ú100,000
ú8 Brain
2 or more drugs
220
MANGILI ET AL.
TABLE 4 Characteristics of Patients before Treatment with VP16 3. Patient
Surgery post-VP16
bhCG pretreatment
Metastases
Score
1 2 3 4 5 6 7 8 9 10 11 12
— — — — Isterectomy — — — — Isterectomy — —
40 5,300 352 64 81,000 54 129 77,700 120 37,900 310 5,800
Lung Lung — — — — — Lung Lung — — Lung
6 7 5 3 7 5 4 6 3 4 3 8
the drug resistance in patients with low-risk GTT. In contrast, high pretreatment bhCG levels [3] and metastatic disease seem to be risk factors for chemotherapy resistance. They may show the conditions of administering VP16 as initial chemotherapy. Single-agent MTX is not always an appropriate treatment for patients with GTT [11]. Hitchins and Newlands (’88) treated eight low-risk patients with single first-line agent VP16. Seven of them showed a complete remission and one changed therapy because of drug resistance. Gonadal toxicity related to etoposide is a major consideration in females during reproductive life. Choo and Wong [16] reported significant ovarian dysfunction among patients undergoing single-agent etoposide. He noticed that young patients had amenorrhea for a short period, while in older patients may be irreversible. This may be related to the low number of ovarian follicles in older patient. It is known that reproductive function after hydatiform mole and low-risk trophoblastic neoplasia is not compromised [17, 18], even after a chemotherapy with MTX or VP16. Infertility problems are associated with the alkylating agents used in combination therapy for high-risk disease [17]. In our study two patients desiring pregnancy succeeded.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
REFERENCES
17.
1. DuBeshter, B., Berkowitz, R. S., and Goldstein, D. P. Metastatic gestational trophoblastic disease: Experience at the New England Trophoblastic Disease Center, 1965 to 1985, Obstet. Gynecol. 69, 390, (1987).
18.
2. Soper, J. T., Clark-Pearson, D., and Hammond, C. B. Metastatic gesta-
/ 6d0b$$4263
04-16-96 02:53:30
goa
19.
tional trophoblastic disease: Prognostic factors in previously untreated patients, Obstet. Gynecol. 71, 338 (1988). Smith, D. B., Holden, L., Newlands, E. S., and Bagshawe, K. D. Correlation between clinical staging (FIGO) and prognostic groups with gestational trophoblastic disease, Br. J. Obstet. Gynaecol. 100, 157– 160 (1993). Osathanondh, R., Goldstein, D. P., and Pastorfide, G. B. Actinomycin D as the primary agent for gestational trophoblastic disease, Cancer 36, 863 (1975). Wong, L. C., Choo, Y. C., and Ma, H. K. Use of oral VP16-213 as primary chemiotherapeutic agent in treatment of gestational trophoblastic disease, Am. J. Obstet. Gynecol. 150, 924 (1984). Hilgers, R., Newlands, E., Hoffman, R., Mitchell, H., and Bagshawe, K. D. Correlation of plasma methotrexate concentration with human chorionic gonadotropin and therapeutic response to low-dose methotrexate–citrovorum factor in low–medium-risk gestational trophoblastic tumors, Gynecol. Oncol. 41, 117–122 (1991). Ross, G. T., Goldstein, D. P., and Hertz, R. Sequential use of methotrexate and actinomycin D in the treatment of metastatic choriocarcinoma and related trophoblastic disease in women, Am. J. Obstet. Gynecol. 93, 223 (1965). Berkowitz, R. S., Goldstein, D. P., and Bernstein, M. R. Ten years experience with methotrexate and folinic acid as primary therapy for gestational trophoblastic disease, Gynecol. Oncol. 23, 111 (1986). Newlands, E. S. Management of gestational trophoblastic tumors (GTT), Proc. Gynaecol. Oncol. Meeting, London, September (1987). [Abstract] DuBeshter, B., Berkowitz, R., Goldstein, D. P., and Bernstein, M. R. Management of low-risk metastatic gestational trophoblastic tumors, J. Rep. Med. 36, 1 (1991). Hitchins, R. N., and Newlands, E. S. Single agent etoposide in gestational trophoblastic tumours, Eur. J. Cancer Clin. Oncol. 24, 1041– 1046 (1988). Bagshawe, K. D., Dent, J., and Newlands, E. S. The role of lowdose methotrexate and folinic acid in gestational trophoblastic tumours (GTT), Br. J. Obstet. Gynaecol. 96, 735–802 (1989). Newlands, E. S., and Bagshawe, K. D. The role of VP16-213 (etoposide; NSC-141540) in gestational choriocarcinoma, Cancer Chemother. Pharmacol. 7, 211 (1982). Newlands, E. S., Bagshawe, K. D., and Begent, R. H. J. Developments in chemotherapy for medium and high risk patients with gestational trophoblastic tumors, Br. J. Obstet. Gynaecol. 93, 63 (1986). World Health Organization Scientific Group. Gestational trophoblastic disease, Technical Report Series 692. Geneva, Switzerland, WHO, pp. 1–81 (1983). Choo, Y. C., and Wong, L. C. Ovarian dysfunction in patients with gestational trophoblastic tumours, Br. Med. J. 288, 102–106 (1984). Kohorn, E. Single-agent chemotherapy for nonmetastatic gestational trophoblastic neoplasia, J. Reprod. Med. 36, 49–55 (1991). Ayhan, A. Pregnancy after chemotherapy for gestational trophoblastic disease, J. Reprod. Med. 35, 522–525 (1990). Wong, L. C., Frcog, B. S., and Choo, Y. C. Primary oral etoposide therapy in gestational trophoblastic disease, Cancer 58, 14–17 (1986).
AP: Gyn Onc