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Trophoblastic disease: 20 years' experience
355
Int. J. Gynecol. Obstet., 1989,28: 355-360 International Federation of Gynecology and Obstetrics
Trophoblastic
disease: 20 years’ experience
J.C. Remy, M. McGlynn,
J. McGuire
and M. Macasaet
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, State University of New York - Health Science Center at Brooklyn, 450 Clarkson Avenue, Brooklyn, 11203 (U.S.A.) (Received March 23rd, 1988) (Accepted May 5th. 1988)
Abstract A series of I55 women with gestational trophoblastic disease (GTD) was evaluated to determine the effect of age on the severity of the disease. The malignant sequelae of hydatidiform moles were of similar frequency at all ages. However, young women, less than 20 years old, had significantly less malignant GTD and significantly less metastatic malignant GTD than did older women. Keywords: Gestational; Trophoblastic; ignant; Sequelae; Hydatidiform; Mole.
Mal-
Introduction The history of gestational trophoblastic disease (GTD) shows that this entity, which has a propensity for early and distant metastases, has evolved from one of the most fatal cancers in women to the most curable for two key reasons: (1) the discovery of very effective chemotherapeutic agents; (2) the development of the sensitive radioimmune assay for beta-human chorionic gonadotrophin (HCG) which allows us to detect the presence of GTD in the absence of clinical manifestations. Prior to the advent of chemotherapy, the mortality rate was 60% in non-metastatic and 98% in metastatic gestational trophoblastic disease. Today most studies report cure rates 0020-7292/89/$3.50 @ 1989 International Federation of Gynecology and Obstetrics Published and Printed in Ireland
approaching 100% for patients with nonmetastatic and low risk metastatic disease. This is one of the most dramatic successes of chemotherapy in the management of human malignancies even in the presence of widespread metastases. However, even with modern chemotherapy, in high risk metastatic disease the cure rate varies between 50 and 60%. In order to reduce the incidence of malignant sequelae after benign GTD (hydatidiform mole or Hmole), Lewis et al. in 1966 [5] proposed that prophylactic chemotherapy be administered at the time of evacuation of H-mole. However, this concept has not been accepted by the majority of oncologists because evaluation shows that only 10-l 5% of women with H-moles will develop malignant sequelae and severe toxicities though rare may occur. Furthermore standard chemotherapy does not prevent malignant sequelae in all patients. The present study reviews our experience in treating patients with GTD at Kings County Hospital and State University Hospital from 1966 to 1985. The effect of secondary chemotherapy and adjuvant irradiation is also evaluated. Materials and methods From 1966 to 1985, 177 patients with GTD were cared for at Kings County Hospital and State University Hospital. However, only 155 patients had clinico-pathologic records for Clinical and Clinical Research
356
Remy et al.
analysis; 20 (13 o/o) with choriocarcinoma and 135 (87%) with an initial histologic diagnosis of H-mole. The records of all patients were reviewed independently by two reviewers. Patients were grouped by age as less than 20 years, 20-35 years and over 35 years. Patients with a histologic diagnosis of Hmole and no evidence of metastatic disease were evacuated and followed by weekly HCG assays until the titers became negative, and then monthly assays for 6 months and bimonthly assays for a further 6 months. Patients were strongly encouraged to use contraception during the follow-up period. Most favored contraceptive pills. The intrauterine device was discouraged lest abnormal uterine bleeding obscure GTD-related symptoms. Base line chest X-ray, hematologic studies, liver and kidney function tests were requested. Malignant sequelae following H-mole were defined by HCG titers that rose or failed to decline for 3 consecutive weeks, or clinical or radiologic evidence of metastatic disease. Patients with malignant sequelae and choriocarcinoma underwent investigational studies including chest X-ray, liver and spleen scan, brain scan, intravenous pyelogram, blood chemistries, hematologic profiles and HCG determinations. In recent years, computerized tomography of the brain replaced radionucleide scanning. Based on the results of these studies and on physical examination, the patients were categorized as having nonmetastatic or metastatic disease. The latter group was further divided into good prognostic and poor prognostic subgroups based on standard criteria. Patients were classified as poor prognosis if one or more of the following was present: HCG over (1) immediate pretreatment 100,000 IU/l in urine or 40,000 IU/ml in serum; (2) more than 4 months from antecedent pregnancy to treatment; (3) antecedent term gestation; (4) brain and/or liver metastases; Int J Gynecol Obstet 28
(5) prior unsuccessful chemotherapy.
Patients with non-metastatic GTD and patients with metastatic GTD with good prognosis were treated with methotrexate (0.4 mg/ kg per day x 5 days) or with dactinomycin (0.5 mg/day x 5 days) if renal or liver disease contraindicated the use of methotrexate. Courses were given with a 7-lo-day window as toxicity permitted. Patients who did not respond to the single agent were subsequently treated by a combination of methotrexate, dactinomycin and cyclophosphamide (MAC). Patients with poor prognosis metastatic GTD were treated with MAC. Courses were given at IO-1Cday intervals depending on hematologic recovery and toxicity. Treatment was withheld if the white blood cell count was less than 3000/mm3 and the platelet count was below 100,000/mm3. Patients with liver or brain metastases were treated simultaneously with radiation (36004000 rad to brain and 1500-2000 rad to liver) and chemotherapy (MAC). In the latter part of this study, a modified Bagshawe protocol [ 11 was used. During treatment, patients were followed with complete blood and platelet counts every day. Hematologic profiles were done weekly between treatments, while chemistry studies, chest X-rays and physical examinations were performed at 2 or 3-week intervals. Response to treatment was followed by HCG assays, and clinical and radiologic assessments of lesion size. Complete remission was diagnosed when three consecutive weekly HCG titers were within normal range and there was no clinical or radiologic evidence of disease. After remission, HCG titers were obtained every 2 weeks for 6 weeks and then monthly for 6 months and every other month for another 6 months. Patients were encouraged not to get pregnant for 1 year following remission. Regression curves for the decline of HCG titers were obtained by computing the geometric mean of titers for each time period after evacuation.
351
Trophoblastic disease: 20 years’ experience
Results
-
20-35 ??
Of the 155 women in this series, 43 (28%) were less than 20 years of age, 93 (60%) were between 20 and 35 years of age, and 19 (12%) were over 35. In the youngest group, GTD was diagnosed during the first pregnancy in approximately 60% of cases, in contrast to 2% during the fourth pregnancy. In the oldest group, 80% of H-moles occurred during the fourth pregnancy and none during the first pregnancy. Of the 135 women with H-moles, 95 (70%) had a benign course requiring no chemotherapy and 40 (30%) developed malignant sequelae requiring chemotherapy. As shown in Table I, malignant sequelae occurred after the evacuation of H-mole in only 24% of 42 patients under 20 years of age, in 32% of 78 patients aged 20-35 years and in 33% of 15 patients over 35 years of age. The lower proportion of malignant sequelae in the youngest women was not however statistically significant. Malignant sequelae developed in five women over 35 even though hysterectomies were performed after initial evacuation. Regression curves for the decline of serum HCG titers were calculated for benign cases in each age group. Figure 1 shows the HCG regression curve for women aged 2035 years and the upper 95% confidence limit. All values for women under 20 and over 35 fell within the upper confidence limit indicating that HCG regression at the age extremes is similar to that in the middle years. In the older women the decline was somewhat
Table 1. Development hydatidiform mole by age.
Age (years) Less than 20 20-35 More than 35 Total
No. of women
of
malignant
sequelae
after
Malignant no.
Sequelae %
42 78 15
10 25 5
24 32 33
135
40
30
ii
0
1
2
3
4 Weeks
5 after
6
yrs
< 20yrs >35yrr
7 evacuation
Fig. 1. HCG regression curve for women aged 20-35 with benign gestational trophoblastic disease (hydatidiform moles). mean values for 35 women aged 20-35; - - - - - - , -, upper 95% confidence limit of the mean; * , mean values for 17 women aged less than 20.0 , mean values for 7 women aged over 35.
more rapid than in the 20-35-year-old reference group, possibly reflecting the fact that two of the seven women over 35 had initial hysterectomies. Malignant GTD comprised 50% of all GTD in 20 women over 35 years, 43% of all GTD in 93 women aged 20-35 years, but only 26% of all GTD in 43 women under 20 years of age (Table II). The lower proportion in young women was statistically significant. Malignant metastatic GTD comprised 25% of all GTD in women over 35, 16% in women aged 20-35, but only 7% in women under 20. The lower proportion in the youngest women was statistically significant. Among the 38 women with malignant nonmetastatic GTD cure was achieved in all cases (100%) with single chemotherapeutic agent. Among the nine women with malignant metastatic GTD with good prognostic facClinical and Clinical Research
358
Remy et al.
Table II.
Type of gestational trophoblastic disease by age.
GTD Type
Age group
Table III. Poor prognosis malignant metastatic GTD: survival by age and decade.
Total Brain/liver metastases
No. brain liver
< 20 years 20-35 years > 35 years H-mole (benign course)
32
53
10
95
Malignant non-metastatic
8
25
5
38
Malignant metastatic (good prognosis)
1
Malignant metastatic (poor prognosis)
2
Total % Malignant GTD % Malignant metastatic
5
10
3
2
9
14
43 26*
93 43
20 50
136 45
7*
16
25
17
*Significantly lower than the proportion in women aged 20 + (P< 0.05).
tors, cure was achieved with a single agent in eight cases, but even multiagent therapy failed to prevent disease progression in one case. Of the 14 women with poor prognosis malignant metastatic GTD, seven had brain and/or liver metastases (Table III). Six of these women died of disease an average of 44 months after diagnosis and one is alive with persistent disease 38 months after diagnosis. Of the seven women who had other poor prognostic factors, five (7 1o/o)were cured and have survived an average of 46 months free of disease, while two died of disease within 2 years. The majority of women with brain or liver metastases were diagnosed in the first decade, whereas all but one of the seven without brain or liver metastases were diagnosed in the second decade. Int J Gynecol Obstet 28
N Survival Survival N VO months
Survival Survival Vo months
Age group < 20years 20-35years > 35years
1 0 4 25 2 0
41 49 34
1 6 --
100 67
Total
7
14
44
7
71
Time period 1966-1975 5 1976-1985 2
0 50
47 38
1 6
0 83
Total
14
44
7
71
7
12 40
15 39
Discussion According to the literature, there is an increased risk of development of H-mole at the extreme ages of reproductive life. Bandy et al. [3] found a significant increase in the incidence of H-mole in women under 16 years of age or over 39 years of age and a significant decrease in women in the 20-29 years age group. The greatest risk of H-mole occurred in women over 49 years of age. Reports from the U.S. [2-3,8-11,131 indicate that for all age groups, the propor-
Table IV. Reported frequency of malignant sequelae after hydatidiform mole. Author
Total cases
2202 Bandy et al. [3] Berkowitz et al. [4] 858 337 Weed et al. [5] 51 Laurain et al. [6] 121 Schlaerth et al. [7] 127 Morrow et al. [8] 212 Hatch et al. [9] Stone and Bagshawe [lo] 611 Remy et al. 135
VoMalignant sequelae 21.7 18.6 20.2 21.6 26.4 29.1 32.0 lo.? 30.0
Trophoblastic disease: 20 years’ experience
tion of H-moles that develop malignant sequelae ranges from 19% to 32% (Table IV). However, several reports indicate that the risk of malignant sequelae varies with age. Bandy [3] reported 22% malignant sequelae in 2202 patients, with the lowest risk of malignant GTD in women under 16 (14%) and the highest in women aged 50 and above (38%). In contrast, Stone and Bagshawe [lo] reported 10.5% malignant sequelae after H-mole in 15 -19-year-olds, no different from 10% for the whole group of 611 patients. In our series the youngest women had a relatively low proportion (24%) of malignant sequelae compared to older women (33%), but the reach statistical did not difference significance. However, when total malignant GTD was considered, the women under 20 (26%) had a significantly lower proportion of malignant GTD than did the older women (43%). The outcome of women with malignant GTD in this series parallels other reports and reaffirms how chemotherapy has changed the course of this once fatal disease. Among 38 women with malignant non-metastatic GTD, single agent chemotherapy effectively controlled progression, while among nine women with metastatic GTD but good prognostic factors, all but one were cured with multiagent chemotherapy. Although only 43% of with poor prognostic factors women survived, 83% of those without liver or brain metastases were cured, in contrast to a single survivor (with persistent disease) among the seven with brain/liver metastases. These results in the poor prognosis group are consistent with series described by Bagshawe [2], Surwit [12], Weed [13], Lewis [7], Lurain [8] and Berkowitz [4]. All define the poorest risk group as those with brain/liver metastases, but report survival rates of up to 50% when aggesssive multiagent therapy is used. We ascribe the relatively poor outcome in this series to the fact that five of the seven were treated in the early years of the series with single agents or with vincristine, doxorubicin and cyclophosphamide. The sin-
359
gle survivor in this series might have had complete remission, but consistently failed to comply with therapy. It may be significant that in this 20-year study, the frequency of good prognosis metastatic malignant GTD has shifted from 17% in 1966-1975 to 75% in 1976-1985. We suspect that this shift may reflect the widespread availability of HCG testing. In summary, this series makes it clear that although the prognosis of GTD is excellent, especially in young women, control of the disease requires vigilance and monitoring of any women at risk. The critical measures in control are:
(1) the use of HCG testing both for follow-up of H-mole and for investigating abnormal uterine bleeding in premenopausal women. (2) the early and thorough workup of a patient with evidence of GTD before instituting therapy in order to accurately define prognostic factors. (3) the early and aggressive use of multiagent chemotherapy. By applying these three methods rigorously, it should be possible to reduce the risks of GTD even further. References Bagshawe KD: Risk and prognostic factors in trophoblastic neoplasia. Cancer 38: 1373, 1976. Bagshawe KD: Treatment of high risk choriocarcinoma. J Reprod Med 29: 813, 1984. Bandy LC, Clarke-Pearson DL, Hammond CB: Malignant potential of gestational trophoblastic disease at the extreme ages of reproductive life. Obstet Gynecol64: 395, 1984. Berkowitz RK, Goldstein DP, Bernstein MR: Horizons in the management of gestational trophoblxstic neoplasiaanalysis of treatment failure. J Reprod Med 26: 227, 1981. Hatch KD, Shingleton HH, Younger B, Boots LR: Elevated titers of the beta subunit of human chorionic gonadotropin in oophorectomized women being treated for trophoblastic disease. Am J Obstet Gynecol 137: 122, 1980.
Clinical and Clinical Research
360
Remy et al. Lewis JL, Gore H, Herting AT, Goss DA: Treatment of trophoblastic disease. Am J Obstet Gynecol 196: 710, 1966. Lewis JL: Treatment of metastatic gestational trophoblastic neoplasms-a brief review of developments in the years 1968 to 1978. Am J Obstet Gynecol136: 163.1980. Lurain JR, Brewer JI, Torok EE, Halpern B: Gestational trophoblastic disease: treatment results at the Brewer Trophoblastic Disease Center. Obstet Gynecol 60: 354, 1982. Morrow CP, Buckley JD, Driscoll SG, S&man AE, Surti U, Kohern EI, Schlaerth JB, Twiggs LB, Goldstein DP, Hammond CB, O’Brien TJ, Young RH, Scully RE: Symposium on trophoblastic disease. Clin Obstet Gyne~0127: 151, 1984. Schlaerth JB, Morrow CP, Kletzky OA, Nalick RH, D’Ablaing GA: Prognostic characteristics of serum human chronic gonadotropin titer regression following molar pregnancy. Obstet Gynecol58: 478, 1981. Stone M, Bagshawe KD: An analysis of the influence of maternal age, gestational age, contraceptive method and
Int J Gynecol Obstet 28
the mode of primary treatment of patients with hydatidiform moles on the incidence of subsequent chemotherapy. Br J Obstet Gynecol86: 782, 1979. 12 Surwit EA, Alberts DS, Christian CD, Graham VE: Poor prognosis gestational trophoblastic disease-an update. Obstet Gynecol 64: 21, 1984. 13 Weed JC, Barnard DE, Curry JL, Clayton LA, Hammond CB: Chemotherapy with the modified Bagshawe protocol for poor prognosis metastatic trophoblastic disease. Obstet Gynecol599: 377, 1982.
Address for reprints: J.C. Remy Box 24 SUNY-Health Science Center at Brooklyn 450 Clarkson Avenue Brooklyn NY 11203 U.S.A.
Int. J. Gynecol. Obstet., 1989,28: 355-360 International Federation of Gynecology and Obstetrics
Trophoblastic
disease: 20 years’ experience
J.C. Remy, M. McGlynn,
J. McGuire
and M. Macasaet
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, State University of New York - Health Science Center at Brooklyn, 450 Clarkson Avenue, Brooklyn, 11203 (U.S.A.) (Received March 23rd, 1988) (Accepted May 5th. 1988)
Abstract A series of I55 women with gestational trophoblastic disease (GTD) was evaluated to determine the effect of age on the severity of the disease. The malignant sequelae of hydatidiform moles were of similar frequency at all ages. However, young women, less than 20 years old, had significantly less malignant GTD and significantly less metastatic malignant GTD than did older women. Keywords: Gestational; Trophoblastic; ignant; Sequelae; Hydatidiform; Mole.
Mal-
Introduction The history of gestational trophoblastic disease (GTD) shows that this entity, which has a propensity for early and distant metastases, has evolved from one of the most fatal cancers in women to the most curable for two key reasons: (1) the discovery of very effective chemotherapeutic agents; (2) the development of the sensitive radioimmune assay for beta-human chorionic gonadotrophin (HCG) which allows us to detect the presence of GTD in the absence of clinical manifestations. Prior to the advent of chemotherapy, the mortality rate was 60% in non-metastatic and 98% in metastatic gestational trophoblastic disease. Today most studies report cure rates 0020-7292/89/$3.50 @ 1989 International Federation of Gynecology and Obstetrics Published and Printed in Ireland
approaching 100% for patients with nonmetastatic and low risk metastatic disease. This is one of the most dramatic successes of chemotherapy in the management of human malignancies even in the presence of widespread metastases. However, even with modern chemotherapy, in high risk metastatic disease the cure rate varies between 50 and 60%. In order to reduce the incidence of malignant sequelae after benign GTD (hydatidiform mole or Hmole), Lewis et al. in 1966 [5] proposed that prophylactic chemotherapy be administered at the time of evacuation of H-mole. However, this concept has not been accepted by the majority of oncologists because evaluation shows that only 10-l 5% of women with H-moles will develop malignant sequelae and severe toxicities though rare may occur. Furthermore standard chemotherapy does not prevent malignant sequelae in all patients. The present study reviews our experience in treating patients with GTD at Kings County Hospital and State University Hospital from 1966 to 1985. The effect of secondary chemotherapy and adjuvant irradiation is also evaluated. Materials and methods From 1966 to 1985, 177 patients with GTD were cared for at Kings County Hospital and State University Hospital. However, only 155 patients had clinico-pathologic records for Clinical and Clinical Research
356
Remy et al.
analysis; 20 (13 o/o) with choriocarcinoma and 135 (87%) with an initial histologic diagnosis of H-mole. The records of all patients were reviewed independently by two reviewers. Patients were grouped by age as less than 20 years, 20-35 years and over 35 years. Patients with a histologic diagnosis of Hmole and no evidence of metastatic disease were evacuated and followed by weekly HCG assays until the titers became negative, and then monthly assays for 6 months and bimonthly assays for a further 6 months. Patients were strongly encouraged to use contraception during the follow-up period. Most favored contraceptive pills. The intrauterine device was discouraged lest abnormal uterine bleeding obscure GTD-related symptoms. Base line chest X-ray, hematologic studies, liver and kidney function tests were requested. Malignant sequelae following H-mole were defined by HCG titers that rose or failed to decline for 3 consecutive weeks, or clinical or radiologic evidence of metastatic disease. Patients with malignant sequelae and choriocarcinoma underwent investigational studies including chest X-ray, liver and spleen scan, brain scan, intravenous pyelogram, blood chemistries, hematologic profiles and HCG determinations. In recent years, computerized tomography of the brain replaced radionucleide scanning. Based on the results of these studies and on physical examination, the patients were categorized as having nonmetastatic or metastatic disease. The latter group was further divided into good prognostic and poor prognostic subgroups based on standard criteria. Patients were classified as poor prognosis if one or more of the following was present: HCG over (1) immediate pretreatment 100,000 IU/l in urine or 40,000 IU/ml in serum; (2) more than 4 months from antecedent pregnancy to treatment; (3) antecedent term gestation; (4) brain and/or liver metastases; Int J Gynecol Obstet 28
(5) prior unsuccessful chemotherapy.
Patients with non-metastatic GTD and patients with metastatic GTD with good prognosis were treated with methotrexate (0.4 mg/ kg per day x 5 days) or with dactinomycin (0.5 mg/day x 5 days) if renal or liver disease contraindicated the use of methotrexate. Courses were given with a 7-lo-day window as toxicity permitted. Patients who did not respond to the single agent were subsequently treated by a combination of methotrexate, dactinomycin and cyclophosphamide (MAC). Patients with poor prognosis metastatic GTD were treated with MAC. Courses were given at IO-1Cday intervals depending on hematologic recovery and toxicity. Treatment was withheld if the white blood cell count was less than 3000/mm3 and the platelet count was below 100,000/mm3. Patients with liver or brain metastases were treated simultaneously with radiation (36004000 rad to brain and 1500-2000 rad to liver) and chemotherapy (MAC). In the latter part of this study, a modified Bagshawe protocol [ 11 was used. During treatment, patients were followed with complete blood and platelet counts every day. Hematologic profiles were done weekly between treatments, while chemistry studies, chest X-rays and physical examinations were performed at 2 or 3-week intervals. Response to treatment was followed by HCG assays, and clinical and radiologic assessments of lesion size. Complete remission was diagnosed when three consecutive weekly HCG titers were within normal range and there was no clinical or radiologic evidence of disease. After remission, HCG titers were obtained every 2 weeks for 6 weeks and then monthly for 6 months and every other month for another 6 months. Patients were encouraged not to get pregnant for 1 year following remission. Regression curves for the decline of HCG titers were obtained by computing the geometric mean of titers for each time period after evacuation.
351
Trophoblastic disease: 20 years’ experience
Results
-
20-35 ??
Of the 155 women in this series, 43 (28%) were less than 20 years of age, 93 (60%) were between 20 and 35 years of age, and 19 (12%) were over 35. In the youngest group, GTD was diagnosed during the first pregnancy in approximately 60% of cases, in contrast to 2% during the fourth pregnancy. In the oldest group, 80% of H-moles occurred during the fourth pregnancy and none during the first pregnancy. Of the 135 women with H-moles, 95 (70%) had a benign course requiring no chemotherapy and 40 (30%) developed malignant sequelae requiring chemotherapy. As shown in Table I, malignant sequelae occurred after the evacuation of H-mole in only 24% of 42 patients under 20 years of age, in 32% of 78 patients aged 20-35 years and in 33% of 15 patients over 35 years of age. The lower proportion of malignant sequelae in the youngest women was not however statistically significant. Malignant sequelae developed in five women over 35 even though hysterectomies were performed after initial evacuation. Regression curves for the decline of serum HCG titers were calculated for benign cases in each age group. Figure 1 shows the HCG regression curve for women aged 2035 years and the upper 95% confidence limit. All values for women under 20 and over 35 fell within the upper confidence limit indicating that HCG regression at the age extremes is similar to that in the middle years. In the older women the decline was somewhat
Table 1. Development hydatidiform mole by age.
Age (years) Less than 20 20-35 More than 35 Total
No. of women
of
malignant
sequelae
after
Malignant no.
Sequelae %
42 78 15
10 25 5
24 32 33
135
40
30
ii
0
1
2
3
4 Weeks
5 after
6
yrs
< 20yrs >35yrr
7 evacuation
Fig. 1. HCG regression curve for women aged 20-35 with benign gestational trophoblastic disease (hydatidiform moles). mean values for 35 women aged 20-35; - - - - - - , -, upper 95% confidence limit of the mean; * , mean values for 17 women aged less than 20.0 , mean values for 7 women aged over 35.
more rapid than in the 20-35-year-old reference group, possibly reflecting the fact that two of the seven women over 35 had initial hysterectomies. Malignant GTD comprised 50% of all GTD in 20 women over 35 years, 43% of all GTD in 93 women aged 20-35 years, but only 26% of all GTD in 43 women under 20 years of age (Table II). The lower proportion in young women was statistically significant. Malignant metastatic GTD comprised 25% of all GTD in women over 35, 16% in women aged 20-35, but only 7% in women under 20. The lower proportion in the youngest women was statistically significant. Among the 38 women with malignant nonmetastatic GTD cure was achieved in all cases (100%) with single chemotherapeutic agent. Among the nine women with malignant metastatic GTD with good prognostic facClinical and Clinical Research
358
Remy et al.
Table II.
Type of gestational trophoblastic disease by age.
GTD Type
Age group
Table III. Poor prognosis malignant metastatic GTD: survival by age and decade.
Total Brain/liver metastases
No. brain liver
< 20 years 20-35 years > 35 years H-mole (benign course)
32
53
10
95
Malignant non-metastatic
8
25
5
38
Malignant metastatic (good prognosis)
1
Malignant metastatic (poor prognosis)
2
Total % Malignant GTD % Malignant metastatic
5
10
3
2
9
14
43 26*
93 43
20 50
136 45
7*
16
25
17
*Significantly lower than the proportion in women aged 20 + (P< 0.05).
tors, cure was achieved with a single agent in eight cases, but even multiagent therapy failed to prevent disease progression in one case. Of the 14 women with poor prognosis malignant metastatic GTD, seven had brain and/or liver metastases (Table III). Six of these women died of disease an average of 44 months after diagnosis and one is alive with persistent disease 38 months after diagnosis. Of the seven women who had other poor prognostic factors, five (7 1o/o)were cured and have survived an average of 46 months free of disease, while two died of disease within 2 years. The majority of women with brain or liver metastases were diagnosed in the first decade, whereas all but one of the seven without brain or liver metastases were diagnosed in the second decade. Int J Gynecol Obstet 28
N Survival Survival N VO months
Survival Survival Vo months
Age group < 20years 20-35years > 35years
1 0 4 25 2 0
41 49 34
1 6 --
100 67
Total
7
14
44
7
71
Time period 1966-1975 5 1976-1985 2
0 50
47 38
1 6
0 83
Total
14
44
7
71
7
12 40
15 39
Discussion According to the literature, there is an increased risk of development of H-mole at the extreme ages of reproductive life. Bandy et al. [3] found a significant increase in the incidence of H-mole in women under 16 years of age or over 39 years of age and a significant decrease in women in the 20-29 years age group. The greatest risk of H-mole occurred in women over 49 years of age. Reports from the U.S. [2-3,8-11,131 indicate that for all age groups, the propor-
Table IV. Reported frequency of malignant sequelae after hydatidiform mole. Author
Total cases
2202 Bandy et al. [3] Berkowitz et al. [4] 858 337 Weed et al. [5] 51 Laurain et al. [6] 121 Schlaerth et al. [7] 127 Morrow et al. [8] 212 Hatch et al. [9] Stone and Bagshawe [lo] 611 Remy et al. 135
VoMalignant sequelae 21.7 18.6 20.2 21.6 26.4 29.1 32.0 lo.? 30.0
Trophoblastic disease: 20 years’ experience
tion of H-moles that develop malignant sequelae ranges from 19% to 32% (Table IV). However, several reports indicate that the risk of malignant sequelae varies with age. Bandy [3] reported 22% malignant sequelae in 2202 patients, with the lowest risk of malignant GTD in women under 16 (14%) and the highest in women aged 50 and above (38%). In contrast, Stone and Bagshawe [lo] reported 10.5% malignant sequelae after H-mole in 15 -19-year-olds, no different from 10% for the whole group of 611 patients. In our series the youngest women had a relatively low proportion (24%) of malignant sequelae compared to older women (33%), but the reach statistical did not difference significance. However, when total malignant GTD was considered, the women under 20 (26%) had a significantly lower proportion of malignant GTD than did the older women (43%). The outcome of women with malignant GTD in this series parallels other reports and reaffirms how chemotherapy has changed the course of this once fatal disease. Among 38 women with malignant non-metastatic GTD, single agent chemotherapy effectively controlled progression, while among nine women with metastatic GTD but good prognostic factors, all but one were cured with multiagent chemotherapy. Although only 43% of with poor prognostic factors women survived, 83% of those without liver or brain metastases were cured, in contrast to a single survivor (with persistent disease) among the seven with brain/liver metastases. These results in the poor prognosis group are consistent with series described by Bagshawe [2], Surwit [12], Weed [13], Lewis [7], Lurain [8] and Berkowitz [4]. All define the poorest risk group as those with brain/liver metastases, but report survival rates of up to 50% when aggesssive multiagent therapy is used. We ascribe the relatively poor outcome in this series to the fact that five of the seven were treated in the early years of the series with single agents or with vincristine, doxorubicin and cyclophosphamide. The sin-
359
gle survivor in this series might have had complete remission, but consistently failed to comply with therapy. It may be significant that in this 20-year study, the frequency of good prognosis metastatic malignant GTD has shifted from 17% in 1966-1975 to 75% in 1976-1985. We suspect that this shift may reflect the widespread availability of HCG testing. In summary, this series makes it clear that although the prognosis of GTD is excellent, especially in young women, control of the disease requires vigilance and monitoring of any women at risk. The critical measures in control are:
(1) the use of HCG testing both for follow-up of H-mole and for investigating abnormal uterine bleeding in premenopausal women. (2) the early and thorough workup of a patient with evidence of GTD before instituting therapy in order to accurately define prognostic factors. (3) the early and aggressive use of multiagent chemotherapy. By applying these three methods rigorously, it should be possible to reduce the risks of GTD even further. References Bagshawe KD: Risk and prognostic factors in trophoblastic neoplasia. Cancer 38: 1373, 1976. Bagshawe KD: Treatment of high risk choriocarcinoma. J Reprod Med 29: 813, 1984. Bandy LC, Clarke-Pearson DL, Hammond CB: Malignant potential of gestational trophoblastic disease at the extreme ages of reproductive life. Obstet Gynecol64: 395, 1984. Berkowitz RK, Goldstein DP, Bernstein MR: Horizons in the management of gestational trophoblxstic neoplasiaanalysis of treatment failure. J Reprod Med 26: 227, 1981. Hatch KD, Shingleton HH, Younger B, Boots LR: Elevated titers of the beta subunit of human chorionic gonadotropin in oophorectomized women being treated for trophoblastic disease. Am J Obstet Gynecol 137: 122, 1980.
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Remy et al. Lewis JL, Gore H, Herting AT, Goss DA: Treatment of trophoblastic disease. Am J Obstet Gynecol 196: 710, 1966. Lewis JL: Treatment of metastatic gestational trophoblastic neoplasms-a brief review of developments in the years 1968 to 1978. Am J Obstet Gynecol136: 163.1980. Lurain JR, Brewer JI, Torok EE, Halpern B: Gestational trophoblastic disease: treatment results at the Brewer Trophoblastic Disease Center. Obstet Gynecol 60: 354, 1982. Morrow CP, Buckley JD, Driscoll SG, S&man AE, Surti U, Kohern EI, Schlaerth JB, Twiggs LB, Goldstein DP, Hammond CB, O’Brien TJ, Young RH, Scully RE: Symposium on trophoblastic disease. Clin Obstet Gyne~0127: 151, 1984. Schlaerth JB, Morrow CP, Kletzky OA, Nalick RH, D’Ablaing GA: Prognostic characteristics of serum human chronic gonadotropin titer regression following molar pregnancy. Obstet Gynecol58: 478, 1981. Stone M, Bagshawe KD: An analysis of the influence of maternal age, gestational age, contraceptive method and
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the mode of primary treatment of patients with hydatidiform moles on the incidence of subsequent chemotherapy. Br J Obstet Gynecol86: 782, 1979. 12 Surwit EA, Alberts DS, Christian CD, Graham VE: Poor prognosis gestational trophoblastic disease-an update. Obstet Gynecol 64: 21, 1984. 13 Weed JC, Barnard DE, Curry JL, Clayton LA, Hammond CB: Chemotherapy with the modified Bagshawe protocol for poor prognosis metastatic trophoblastic disease. Obstet Gynecol599: 377, 1982.
Address for reprints: J.C. Remy Box 24 SUNY-Health Science Center at Brooklyn 450 Clarkson Avenue Brooklyn NY 11203 U.S.A.