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Adjuvant Hysterectomy in Low-Risk Gestational Trophoblastic Disease

From the Department of Obstetrics and Gynecology, Chiba University School of Medicine, Chiba, Japan.

Address reprint requests to: Hideo Matsui, MD, Department of Obstetrics and Gynecology, Chiba University School of Medicine, Inohana, 1-8-1, Chuo-ku, Chiba, 260-8670, Japan, E-mail: suzukak{at}med.m.chiba-u.ac.jp

	Abstract

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Objective: To evaluate the efficacy of adjuvant hysterectomy with chemotherapy for women with low-risk gestational trophoblastic disease.

Methods: One hundred fifteen consecutive Japanese women (16–52 years old) with low-risk gestational trophoblastic disease (46 with metastatic disease and 69 without) were treated initially with single-agent chemotherapy (etoposide in 85, methotrexate in 27, and actinomycin D in three) with or without adjuvant hysterectomy, and 97 patients (84.3%) achieved primary remission with those treatments. Eight women (9.4%) treated with etoposide required other regimens because of drug resistance or toxicities. The total dose of etoposide given to achieve primary remission was analyzed in 77 women who received etoposide alone or with adjuvant hysterectomy.

Results: In 34 women with metastatic disease, the mean (± standard deviation [SD]) total dose of etoposide was not significantly different with and without adjuvant hysterectomy (2857 ± 842 mg versus 2815 ± 815 mg; P = .957; Mann-Whitney U test). However, in 43 women without metastases, the total dose of etoposide was significantly less in those who had adjuvant hysterectomies than in those who did not (1750 ± 635 mg versus 2545 ± 938 mg; P < .05; Mann-Whitney U test).

Conclusion: Adjuvant hysterectomy decreased the total dose of etoposide given to achieve primary remission in women with nonmetastatic, low-risk gestational trophoblastic disease. If the lesions of gestational trophoblastic disease are confined to the uterus and the woman has no desire to preserve fertility, she should be informed of adjuvant hysterectomy as a treatment option.

Gestational trophoblastic disease is one of the most curable malignancies because of the intrinsic sensitivity of the tumor to certain antineoplastic agents, effective sensitive assays for hCG, and identification of high-risk factors that permit individualized treatment.^1,2 Cure rates for low-risk gestational trophoblastic disease approach 100% even with metastasis, and are estimated to exceed 80% for high-risk gestational trophoblastic disease.^1–5

The excellent results of chemotherapy have diminished the role of operative interventions. Lewis et al⁶ reported that surgery for women with metastatic and nonmetastatic gestational trophoblastic disease is restricted to removal of chemotherapy-resistant foci of gestational trophoblastic disease and control of hemorrhage or infection in emergency cases. Hammond et al⁷ reported that planned surgery significantly reduced the duration of hospitalization and amount of chemotherapy used to achieve remission, regardless of metastasis. The present study attempted to clarify the effect of planned adjuvant hysterectomy in women with low-risk gestational trophoblastic disease.

	Materials and Methods

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From January 1986 through December 1999, we studied 115 consecutive women with low-risk gestational trophoblastic disease (46 with metastasis and 69 without) treated in Chiba University Hospital. The diagnosis of low-risk gestational trophoblastic disease was based on modified Hammond’s criteria⁸ as antecedent molar pregnancy, short duration (under 4 months), no brain or liver metastases, and no treatment history. All women were classified as World Health Organization (WHO) low- or middle-risk groups.

Pretreatment evaluation of each woman included complete history and physical examination, complete blood count, renal and liver function tests, serum hCG level, pelvic and liver ultrasonography, chest x-ray, and computed tomography (CT) of the lungs. Hematologic, renal, and liver function tests, and serum hCG measurement were done before each chemotherapy cycle, then weekly during and after chemotherapy (two or three times).

Before chemotherapy, we explained to the women the effectiveness and drug toxicities of methotrexate, actinomycin D, and etoposide. They each selected one of the three chemotherapy regimens. The choice of etoposide decreased recently, probably because of fear of second malignancies. Patients were initially treated with single-agent chemotherapy; 85 received etoposide (100 mg/day drip infusion for 5 consecutive days), 27 methotrexate (8.5–10 mg/kg and folic acid 85–100 µg/kg IM every other day) and three actinomycin D (8.5–10 µg/kg intravenous injection for 5 consecutive days). Chemotherapy courses were repeated every 2 or 3 weeks until serum hCG levels decreased to normal range (under 1.0 mIU/mL). Chemotherapy was deferred or changed to other regimens if WHO grade 3 or 4 toxicity of any type except alopecia developed. Drug resistance was defined as a plateau (less than a 50% fall in hCG level) or increased in hCG level in three consecutive courses, or appearance of new metastatic disease. Remission was defined when three consecutive weekly hCG levels were within the normal range. After hCG level became undetectable, subjects received one or two additional chemotherapy courses if they had disease without or with metastases, respectively.

When women had no desire to preserve fertility and definite foci of gestational trophoblastic disease were confirmed in their uteri, we recommended adjuvant hysterectomy to reduce the total dose of drugs needed to achieve remission. Cases were not included in which emergency surgery was done or drug-resistant lesions were removed. Adjuvant hysterectomies were done by one of the authors (HM) within 2 weeks after completion of the first chemotherapy course.

Data are reported as mean ± standard deviation (SD) or median and range. Continuous data were examined for skewness and kurtosis using SPSS software package (SPSS Inc., Chicago, IL). Age, pretreatment hCG level, and total dose of etoposide did not fit a Gaussian distribution and were analyzed using Mann-Whitney U test for comparisons between groups. Proportional data were analyzed using Fisher exact test. The level of statistical significance was P < .05.

	Results

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One hundred fifteen Japanese women with low-risk gestational trophoblastic disease were treated primarily with single-agent chemotherapy (etoposide in 85, methotrexate in 27, and actinomycin D in three) and 97 (84.3%) achieved primary remission with or without adjuvant hysterectomy. The other 18 women (15.7%) required change to other chemotherapeutic regimens because of drug resistance or toxicities (Table 1). Adjuvant hysterectomy was done in 37 cases (32.2%), and 78 women were treated with chemotherapy alone (74 desired to retain childbearing capacity, three refused hysterectomy, and one had no definite focus of gestational trophoblastic disease in the uterus). The primary remission rates of initial chemotherapy with and without adjuvant hysterectomy were 86.5% and 83.3%, respectively. Incidence of drug resistance in women with adjuvant hysterectomy (2.7%) tended to be lower compared with those without adjuvant hysterectomy (12.8%), although that difference was not statistically significant (P = .102; Fisher exact test, odds ratio [OR] 0.189, 95% confidence interval [CI] 0.023, 1.535) (Table 1).

	Discussion

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The excellent prognosis of gestational trophoblastic disease has been attained by various kinds of effective systemic chemotherapy,^1,9,10 and surgery has been suggested to be unnecessary in treating gestational trophoblastic disease. It is generally accepted that the most common indications for surgery in women with gestational trophoblastic disease are the removal of chemotherapy-resistant foci and control of hemorrhage or infection in emergency cases.^6,7,11,12 Planned adjuvant hysterectomy in women with low-risk gestational trophoblastic disease is controversial. Lewis et al⁶ reported that hysterectomy was rarely necessary to treat women with nonmetastatic disease. In our previous reports,⁵ 247 women with metastatic and nonmetastatic low-risk gestational trophoblastic disease achieved 100% remissions irrespective of adjuvant hysterectomy. However, Hammond et al⁷ reported that elective initial hysterectomy significantly reduced duration of hospitalization and amount of chemotherapy courses needed to achieve remission, regardless of metastasis. Doses of methotrexate in each course were not constant and methotrexate drug resistance-drug toxicity cases were included in their reports.

In our present study, we evaluated the effect of planned adjuvant hysterectomy for reduced etoposide dose in women with low-risk gestational trophoblastic disease. All women were counseled for effectiveness and short- and long-term drug toxicities with single-agent chemotherapy regimens of methotrexate, actinomycin D, and etoposide. They each selected one of the three chemotherapy regimens. If definite foci of gestational trophoblastic disease were confirmed in the uterus of a woman who had no desire to preserve fertility, she was informed of adjuvant hysterectomy as a treatment option. No emergency surgery was included nor any for removal of drug-resistant lesions.

In all instances, incidence of developing drug resistance was slightly higher (ten of 98, 12.8%) in women who did not have adjuvant hysterectomies compared with those who did (one of 37, 2.7%), but that difference was not statistically significant. Eighty-five women were treated initially with etoposide, whereas three (3.5%) and five (5.9%) needed to change to other regimens because of drug resistance and drug toxicities, respectively. All women recovered from hematologic toxicities of etoposide regimens within 2 weeks and none needed further changes of regimen. Four women had to change chemotherapy regimens because of prolonged elevated liver function tests and one because of mild drug rush. Seventy-seven women completed treatment with etoposide with or without adjuvant hysterectomy. Median ± SD chemotherapy courses were 5.1 ± 1.8 (range two to ten courses). In 43 women with nonmetastatic disease, the total dose of etoposide needed to achieve primary remission was significantly reduced when combined with adjuvant hysterectomy, compared with etoposide alone (P < .05). We did multivariable analysis to correct for the effect of patient age in those 43 women. None of the women aged from 19 to 30 years old had hysterectomies. Excluding them, the interaction between the log (total dose of etoposide) and patient age was not significant (P = .072). The relationship between the log (total dose of etoposide) and hysterectomy was significant (P = .044). However, in 34 women with metastatic disease, adjuvant hysterectomy did not reduce the total dose of etoposide (P = .957).

Recently, second malignancies after etoposide-containing multiagent chemotherapy regimens have been reported.¹³ The risks of myeloid leukemia, colon cancer, and breast cancer were significantly increased. In our study, two women who switched etoposide regimens because of prolonged elevated liver function tests developed rectal and pancreatic cancer. The former woman was treated with etoposide at age 39 and diagnosed as having rectal cancer at age 45. The latter woman was treated at age 42 and was hepatitis virus C positive. At age 51, she was diagnosed with pancreatic cancer. The total cumulative dose of etoposide in both women was 2500 mg. Although the mechanism of second malignancies after sequential or combination chemotherapy with etoposide is unclear, administration of anticancer drugs, especially etoposide, should be kept to a minimum because of the risk of long-term toxicity. Careful follow-up is mandatory for women who receive anticancer agents.

	Footnotes

 
PII S0029-7844(00)01169-8

Received July 14, 2000. Received in revised form October 20, 2000. Accepted November 16, 2000.

	References

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10. Newlands ES, Bagshawe KD, Begent RH, Rustin GJS, Holden L. Results with the EMA/CO (etoposide, methotrexate, actinomycin D, cyclophosphamide, vincristine) regimen in high risk gestational trophoblastic tumours, 1979 to 1989. Br J Obstet Gynaecol 1991;98: 550–7.[Medline]

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