Treatment of non-metastatic gestational trophoblastic disease

13 TREATMENT OF NON-METASTATIC GESTATIONAL TROPHOBLASTIC DISEASE Howard D. Homesley

13.1

INTRODUCTION

Non-metastatic gestational trophoblastic disease (GTD) in most women can be successfully diagnosed and treated with preservation of normal reproductive potential. It is critical to manage hydatidiform mole properly to minimize acute complications, identify malignant sequelae and initiate therapy promptly. However, it is necessary to individualize therapy for women with malignant GTD based upon risk factor characterization, with patients at low risk receiving less toxic therapy and aggressive multi-agent therapy reserved for patients with high-risk disease. Even though GTD embraces varied neoplasms of the placenta, hydatidiform mole ordinarily can be managed by molar evacuation and expectant surveillance of quantitative serum human chorionic gonadotropin (hCG) levels. Approximately 80% of complete moles and more than 90-95 of partial moles go into complete remission without chemotherapy [1]. More recently needless therapy of presumed malignant disease in women with false-positive human chorionic gonadotropin concentrations has been emphasized by a number of reports [2-9]. Laboratory assays for beta-human chorionic gonadotropin (hCG) may yield false positive results. False positive results have been reported as high as 800 mIU/ml. False positive results are explained by antimouse antibodies (HAMA), heterophile antibodies, and nonspecific protein interference in addition to other causes. False positive assays have been verified from different assay kits (platforms) from many manufacturers. Unusual clinical situations that are difficult to explain or the unexpected absence of response to therapy may now be possibly considered to be discordant on the basis of phantom hCG results. The presumptive diagnosis of either ectopic pregnancy or gestational trophoblastic disease can lead to unnecessary treatments. It is advisable where only the abnormal hCG may lead to surgical intervention or chemotherapy that the reliability of the serum hCG should be questioned. Multiple assays may report similar false positive results. Urinary hCG should be used as a confirmatory test since the interfering substances do not appear to be excreted in their interfering form into the urine.

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While performing the urinary assay for hCG is the simplest method to resolve a false positive assay, the local clinical laboratory could be requested to confirm the reliability of the assay by sending the serum of the patient in question to an hCG reference laboratory. Malignant GTD can occur after any type of pregnancy. Again, there must be guard against over diagnosis of GTD in early tubal ectopic pregnancy even though extremely rare. At the University of Sheffield Medical School from 1986 to 1996 of the 4261 women referred to the Trophoblastic Centre, 25 (0.6%) had suspected tubal ectopic hydatidiform mole. [10] Using histopathologic review and DNA flow cytometric analysis 17/20 showed no evidence of hydatidiform mole (circumferential trophoblastic proliferation, hydrops. scalloped villi, and stromal karyorrhexis). Polar trophoblastic proliferation and hydropic villi are features of early placentation and of hydropic abortion. Sheets of extravillous trophoblast may be particularly prominent in tubal ectopic gestation. In the absence of circumferential trophoblastic proliferation combined with hydropic change, a diagnosis of gestational trophoblastic disease should be avoided. The prognosis of GTD is determined by several clinical risk factors including anatomical site of disease, duration of disease, hCG level and type of antecedent pregnancy. Patients with non-metastatic and lowrisk metastatic (metastasis to lungs and/or vagina) GTD have an excellent outcome when treated with single-agent chemotherapy [11]. Non-metastatic GTD (NMGTD) is most amenable to single-agent therapy where patients have an antecedent molar pregnancy with a plateau, an elevation or a persistent hCG elevation after molar evacuation. For over 30 years, single-agent methotrexate (MTX) (2025 mg intramuscularly every day for five days about every two weeks) has been associated with high cure rates for NMGTD [12]. MTX with citrovorum factor (CVF) rescue has a similar high remission rate with decreased toxicity [1215]. 13.2 GYNECOLOGIC ONCOLOGY GROUP

The Gynecologic Oncology Group (GOG) conducted clinical studies in patients with NMGTD with the intent to discover more convenient, less expensive and hopefully equally efficacious singleagent regimens [16 19]. 13.2.1 DEFINITION OF NON-METASTATIC GESTATIONAL TROPHOBLASTIC DISEASE The GOG criteria for inclusion of patients in the NMGTD trials are listed in Table 13.1.

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Table 13.1 GOG Definition for NMGTD Factor hCG level Serial hCG levels Percentage elevation Duration of elevation Confirmation of elevation required Persistent elevation above normal Finding No limit 3 10% 3 weeks Yes repeat once 16 weeks

Table 13.2 GOG Criteria for Progression Criterion Metastasis Decrease in hCG level One log hCG level decrease Finding Yes <10%, over 2 weeks Required over 6 weeks

Pelvic ultrasound to exclude intrauterine pregnancy was recommended for all patients treated more than two weeks after passage of a molar pregnancy. Computed tomography (CT) of the brain and liver was not mandatory in patients who strictly met the definition of nonmetastatic, post-molar GTD without previous chemotherapy. In the USA patients seldom undergo pretreatment uterine curettage. Nearly all patients were placed on oral contraceptives after molar evacuation. 13.2.2 TREATMENT FAILURE In a clinical trial, the definition of progression or failure has to be inflexible for there to be standardized assessment of response to chemotherapy (Table 13.2). Individualized therapy where one has the discretion to follow hCG levels that regress in a desultory manner over a prolonged interval is not practical. Thus, in the GOG collaborative trial, treatment flexibility was not possible and may have resulted in technically higher failure rates than where patients may be followed for longer periods of observation, especially at near-normal hCG levels Validation of serum hCG levels with urinary levels may have been manifested in a higher success rate as many patients failed weekly methotrexate at persistent low hCG levels. 13.2.3 PROGNOSTIC FACTORS Identification of various prognostic factors at the start of chemotherapy allows patients with GTT to be categorized into low295

Treatment of non-metastatic gestational trophoblastic disease

and high-risk groups so that they can be given the minimal treatment necessary to achieve the highest efficacy. Persistent GTD patients had twice as high (85.9 versus 48.3 U/ml) CA-125 levels prior to suction of molar evacuation [20]. These CA125 level measurements may help predict which molar patients will develop persistent disease. Likewise higher progesterone at molar evacuation and continued levels higher than 5 ng/ml predict persistent mole [21]. In 2000, the International Federation of Gynecology and Obstetrics (FIGO) staging for trophoblastic disease tumor combined anatomical and risk factor considerations in staging the non-metastatic patients (Tables 13.3, 13.4) [22]. The NMGTD patients would be those in stage I: 6 or a less score. Each stage is subcategorized by FIGO 2000 scoring system with a low risk group of a score of 6 or less. A Roman numeral expresses the stage and the risk score separated by a colon. It is noteworthy that for the GOG clinical trials there was no restriction for entry by hCG level. Analysis of hCG level in many studies reveals this to be a significant prognostic factor. The pretreatment hCG level in the GOG studies was found subsequently not to be prognostically significant and the hCG level was not found to relate to response [23]. The hCG regression curve serves as a reliable guide for the administration of chemotherapy, but also can be a means to identify patients who are going to develop a persistent mole [24]. A consecutive series of 454 women treated between 1968 and 1992 were analyzed by multivariant analysis pretherapy HCG levels were not significantly associated with survival [25]. Prior therapy, type of antecedent pregnancy, number of metastatic sites and duration of disease were identified as independent prognostic factors. In comparing the available GTD staging and classification systems, all are able to identify low- and high-risk subsets of patients with similar efficiency[26]. The combination of FIGO staging and risk factors enhances discrimination between prognostic groups. Others prefer a non-anatomical scoring system that predicts drug resistance and offers more specific therapy [27].

Table 13.3 FIGO staging for trophoblastic tumor Stage I Disease confined to uterus Stage II Metastasis limited to genital structures Stage III Metastasis to lungs Stage IV All other metastatic sites

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Table 13.4 FIGO 2000 Scoring System

0 FIGO SCORING Age Antecedent pregnancy Interval months from index pregnancy Pre-treatment serum hCG (IU/L) Largest tumor size (including uterus) cm Site of metastases Number of metastases Previous failed chemotherapy < 40 Mole <4 40 Abortion 4 <7 Term 7 <13 13 1 2 4

<103

103 <104

104 <105

105

<3

3 <5

Lung -

Spleen, Kidney 14 -

Gastro-intestinal 58 Single drug

Liver, Brain >8 2 or more drugs

It is unclear whether or not chemoprophylaxis reduces the incidence of persistent trophoblastic disease in patients at high risk [28]. Following chemoprophylaxis to prevent persistent molar disease, more courses (2.5 versus 1.4) of chemotherapy were required until remission was complete in the group who received prophylactic therapy compared to the untreated group. Although partial and complete hydatidiform moles are distinct clinicopathological entities that can be distinguished histologically, it does not appear that clinical management of partial mole should be any different from complete mole [29]. 13.3 SONOGRAPHY

A number of investigators have assessed the reliability of transvaginal ultrasonography in the detection of uterine involvement in patients with GTT to determine the role of this procedure in management [3037]. Uterine localization of disease can be detected appearing as hypoechoic areas and myometrial nodules. Favorable response to chemotherapy can be imaged by regressions of nodules noted by
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Treatment of non-metastatic gestational trophoblastic disease

transvaginal ultrasonography. The transvaginal color flow Doppler sonography has also been noted to correlate with prognosis and hCG levels [33,35,36]. Color flow Doppler can be a non-invasive, reproducible, useful and highly reliable diagnostic approach for the diagnosis and management of patients suffering from uterine GTD. 13.4 METHOTREXATE WITH FOLINIC ACID RESCUE In the NMGTD patient, MTX with folinic acid rescue is often preferred [38]. There is a high complete remission rate (90.2%) and often (81.5%) this can be obtained following only one course of chemotherapy. Between 1964 and 1986, 487 patients with gestational trophoblastic tumor were treated with MTX and folinic acid. From 1974, all patients were stratified into prognostic groups on admission. Of the true low-risk patients, 347 of 348 (99.7%) survived. Of 13 patients under-scored and treated as low risk when they should have been treated as medium risk, 12 (92%) were alive, but nine (69%,) needed to change treatment because of drug resistance. Although the survival in these patients was excellent, 69 of 348 (20%) low-risk patients had to change treatment because of the development of drug resistance, and a further 23 (6%) needed to change treatment because of drug-induced toxicity. The 20% first-line failure rate is similar to that found with weekly intramuscular MTX, which has negligible toxicity. Others have concluded that high-dose MTX does not appear to offer any clinical advantage over conventional-dose MTX in lowrisk patients [39]. 13.5 GOG NMGTD CLINICAL TRIALS In the two GOG intramuscular MTX trials, 125 patients were evaluable for response [15, 16]. There was no correlation noted between response and age, performance status or initial hCG values. With the weekly MTX, the time to response was a median of seven weeks with a range of 319 weeks no different from the nonresponders. In the initial study, using lower MTX levels, there was an 81% complete response rate in 53 patients. In the second study, with rapid escalation to 50 mg/m2, the complete response rate was 74%. In both studies there were no delays in therapy related to myelotoxicity. No patients required hysterectomy during treatment. In the single-dose actinomycin D (ACTD) GOG study of NMGTD, the same criteria for entry were used except no patient had an hCG titer >40 000 U/l [18]. ACTD was given intravenously at a dose of 1.25 mg/m2 every 14 days. The response rate using the same GOG criteria was 94%. The two patients who failed to respond to pulse therapy were changed to five-day ACTD, one patient responded, and the other was switched to MTX followed by hysterectomy. The
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specimen contained a focus of choriocarcinoma, and the patient received combination chemotherapy. 13.6 LOW-RISK METASTATIC TROPHOBLASTIC DISEASE Virtually all patients with non-metastatic and low-risk metastatic disease can be cured using single-agent MTX or ACTD. Review of the clinical course of 48 patients with low-risk metastatic GTT treated with primary single-agent chemotherapy revealed that although all patients achieved sustained remission, 25 (51%) required a second single-agent regimen, and seven (14%) needed combination chemotherapy [40]. An average of 3.4 courses of chemotherapy was necessary to achieve remission, and six patients (12%) underwent resection of resistant tumor foci. Primary single-agent chemotherapy is a reasonable treatment option in patients with low-risk metastatic disease, although a higher first-line failure rate should be anticipated. In patients with vaginal metastases, the prognosis depends mainly on the extent of the disease [41]. A favorable response to chemotherapy was observed in low-risk patients with vaginal metastases. 13.7 SUMMARY

The GOG clinical trials indicate that intramuscular weekly MTX and single-dose ACTD in NMGTD patients are effective, safe, inexpensive and convenient. An ongoing randomized GOG trial is in progress to assess the GOG findings prospectively and compare toxicity between weekly intramuscular MTX and single dose ACTD. Traditional therapy consists of ACTD administered intravenously at 1012 mg/kg per day for five days or MTX administered intramuscularly or intravenously at 0.4 mg/kg per day for five days. The cycle is repeated after a rest of seven days. A mean of three courses, or approximately six weeks, is required to reach a normal hCG level with either single-dose or five-day ACTD. Eighty-one per cent of patients treated with single-dose ACTD experienced toxicity, although <10% had severe symptoms of nausea and vomiting which were the most common adverse effects. High-dose MTXCVF rescue, which usually consists of 1 mg/kg MTX every day for four doses alternating with CVF rescue, has a remission rate of >90% and lack of significant toxicity [14]. However, a later study had an MTXCVF failure rate of 28%[42]. There is some question about the pharmacological effect of CVF rescue on MTX since low drug levels were noted prior to the CVF dose; the decrease in toxicity may be an effect of the schedule rather than the CVF rescue [43].
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A comparison in cost between pulse ACTD, five day ACTD, intramuscular MTX, five-day MTX and eight-day MTXCVF indicates that single-dose ACTD or intramuscular MTX greatly reduces cost [16, 17]. Single-dose ACTD is comparable to conventional alternatives. Because of the efficacy and toxicity profile, pulsed ACTD appears superior to current standard therapy in terms of convenience and cost effectiveness. Weekly MTX may be superior to pulsed ACTD because of less gastrointestinal toxicity. Others have used single-agent intravenous 5-fluorouracil infusion and oral etoposide, which have similar complete response rates to those of MTX regimens [44, 45]. Five-day MTX has a high incidence of toxicity (21%)[25]. Intramuscular MTX has minimal hematological (grades 1 and 2) and gastrointestinal toxicity (grades 1 and 2). Five-day fluorouracil infusion has the most severe toxicity. Oral etoposide is associated with alopecia and amenorrhea along with significant hematological and gastrointestinal toxicity. Although survival is excellent when MTX and folinic acid are used, in one large report 20% of low-risk patients had to change treatment because of the development of drug resistance, and 6% needed to change treatment because of drug-induced toxicity [46]. At another institution, patients were treated with either weekly MTX or MTX and folinic acid [47]. Weekly MTX was equally effective and less toxic than the eight-day MTXfolinic acid regimen. Efforts should continue to identify new chemotherapy protocols that maximize remission rates and minimize toxicity and hospitalization. Alternating five-day chemotherapy with MTX and ACTD as primary treatment for non-metastatic gestational disease was studied in nine patients with a 100% complete response [48]. Stomatitis was universal and mild to moderate. Thirty-seven patients with NMGTD were treated with one or more cycles of oral MTX following intramuscular MTX as part of induction therapy, with remission in 31 patients (84%), indicating that this is safe, easily administered and effective [49]. None of the regimens may approach the ideal; yet, single-agent therapy has much to offer when appropriately given to the patient with low-risk trophoblastic disease.

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