Gestational trophoblastic disease

Reviews in Gynaecological Practice 3 (2003) 142–147

Gestational trophoblastic disease H.Y.S. Ngan∗ Department of Obstetrics and Gynaecology, Room 609, Professorial Block, Queen Mary Hospital, University of Hong Kong, Pokfulam Road, Hong Kong, SAR, China Received 4 April 2003; accepted 14 April 2003

Abstract Gestational trophoblastic disease composed of a spectrum of abnormal trophoblastic proliferation. The benign end is molar pregnancy. Changes in the incidence, clinical presentation and criteria for ultrasonic diagnosis were observed over the years. With the help of cytogenetics, differentiation of hydropic degeneration, partial and complete mole is possible but still confined to research setting. Suction evacuation remained the main stay of treatment. Serum human chorionic gonadotrophin (hCG) monitor has to be performed in all post-molar pregnancy and the right choice of assay kit is mandatory to avoid false negative or positive results. The criteria for diagnosing persistent gestational trophoblastic neoplasia (GTN) has been agreed and reported in the FIGO 2000 Gynecologic Oncology Committee Report. Investigative tools were also recommended in the same report. The revised FIGO 2000 staging and classification in GTN has incorporated both anatomical staging and risk score classification modified from WHO. A cutoff of six inclusive was recommended to allocate patients into low and high risk groups. Appropriate treatment using single agent such as methotrexate in low risk group and multiple agents such as EMA-CO in high risk group usually resulted in a high cure rate. In drug resistant disease, multiple agents chemotherapy with and without adjuvant surgery or radiotherapy can salvage over 80% of patients. However, patients with both liver and brain metastasis stands a lower chance of survival. To achieve the best outcome for patients with gestational trophoblastic disease, patients should be managed in centers with experience. © 2003 Elsevier Science B.V. All rights reserved. Keywords: Gestational trophoblastic disease; Gestational trophoblastic neoplasia; Mole; hCG; Surgery; Radiotherapy; Chemotherapy

1. Introduction

2. Molar pregnancy

Gestational trophoblastic disease composed of a spectrum of abnormal trophoblastic proliferation. The benign end is molar pregnancy including partial and complete mole. The malignant end is the choriocarcinoma. Placental site trophoblastic tumor is a separate entity with tumor arising from intermediate trophoblasts instead of cytotrophoblast or syntiotrophoblast where mole and choriocarcinoma arises from. The persistent proliferation of these trophoblastic diseases could be detected by monitoring the serum human chorionic gonadotrophin (hCG) level. Gestational trophoblastic neoplasia (GTN) is disease entity with a persistently elevated serum hCG in the absence of a normal pregnancy and with a history of either normal or abnormal antecedent pregnancy. Treatment is usually by chemotherapy with good outcome.

2.1. The changing scene of molar pregnancy

∗ Tel.:

+852-28554518; fax: +852-28550947. E-mail address: [email protected] (H.Y.S. Ngan).

2.1.1. Incidence Molar pregnancy is more common in South–East Asia. However, a decrease in the incidence was observed in recent years in Japan [1] and a similar decreasing trend in GTT was also observed in Korea and Japan [2]. This could be due to lower parity or better economic status. Early ultrasonographic (USS) diagnosis of non-viable fetus leading to early termination of pregnancy might have remove some early molar pregnancy preventing their progression to a full-blown mole. 2.1.2. Presentations Early diagnosis of mole also lead to the uncommon presentation of severe pre-eclampsia, pulmonary embolism, severe anemia and large lutein cysts which tend to be associated with a late gestation mole and hence was common presentations in the old days. Currently, the most common

1471-7697/$ – see front matter © 2003 Elsevier Science B.V. All rights reserved. doi:10.1016/S1471-7697(03)00047-9

H.Y.S. Ngan / Reviews in Gynaecological Practice 3 (2003) 142–147

143

presentation is abnormal bleeding complicating an early pregnancy [3]. Uterine size can be greater, same or smaller than date. Occasionally, subclinical hyperthyroidism or hyperemesis are still observed.

would enable early diagnosis of GTN. The criteria for a diagnosis of GTN will be discussed below. Subsequent monitoring after hCG has returned to normal could be spaced to once every 2 weeks then 4 weeks for 6–12 months.

2.1.3. Diagnostic investigation Diagnosis of molar pregnancy still relies on ultrasonogram. However, the classical snow-storm appearance may not be seen till at later gestation. At early gestation, molar pregnancy may be diagnosed as missed miscarriage. Recent study reported in a typical sonographic appearance of a first trimester complete mole which was described as a complex, echogenic, intra-uterine mass containing many small cystic spaces [4]. A retrospective review showed that 16 and 70% of complete and partial hydatidiform moles, respectively could be missed on USS [5]. In cases of uncertainty, histological examination would be helpful in making the diagnosis.

2.3.1. Serum hCG The choice of assay method for serum hCG affects the accuracy of the measurement [8]. In patients with GTN, nicked hCG, hCG missing the beta-subunit C-terminal segment, hyperglycosylated hCG, and free beta-subunit are produced in addition to intact hCG. If commercial kit is used, kit that measures only the total hCG for pregnancy test may not be suitable to be used for monitoring in GTN because of false negative result leading to inadequate treatment or false sense of security.

2.1.4. Pathology The classical histopathology of molar pregnancy with hydropic villi and trophoblastic proliferation usually posed no difficulty in diagnosis. However, difficulty may arise in differentiating mole from partial mole and partial mole from hydropic degeneration of villi in miscarriages [6]. Cyto-molecular study can differentiate a diploid mole with both sex chromosomes coming from the father or a triploid partial mole from a diploid miscarriage. However, the more practical approach in clinical setting is to monitor the serum hCG level for at least 6 months in cases of uncertainty. Where hysterectomy is rarely indicated and vaginal biopsy of suspected trophoblastic lesion should be avoided because of risk of uncontrollable hemorrhage, histological diagnosis of invasive or metastatic mole is uncommon. However, clinical diagnosis of invasive or metastatic mole could be made with the help of imaging techniques such as USS, MRI or CT scans.

2.3.2. False positive serum hCG Reports on raised serum hCG level in the absence of GTN reviewed the phenomenon called “phantom hCG” [9]. Heterophilic antibodies in sera giving rise to a false positive hCG assay. This could be differentiated by examining the urine for hCG which should not be detectable because the heterophilic antibodies does not excrete into urine or by serial dilution assay where the level did not followed the dilution factor. 2.4. Central registry To facilitate uniformity of hCG assay, close monitoring and management, patients with molar pregnancy should be registered with a central registry. Since molar pregnancy is not a common disease, pooling of resources and expertise in its management would ensure the best quality care to patients. GTN is a curable disease if appropriate treatment is offered.

2.2. Management of molar pregnancy

2.5. Contraception after molar pregnancy

The standard treatment is suction evacuation of the uterus. Adequate preparation including blood matching, venous access with wide-bore catheter, experienced anesthetist and gynecologist minimizes chance of complication. Molar evacuation can be complicated by heavy bleeding, perforation of the soft uterus, incomplete emptying and rarely pulmonary embolism. Oxytocics is recommended after cervical os dilation and before suction to reduce bleeding. However, a second evacuation 1 week later is not recommended unless there is clinical indication such as persistent bleeding. Termination of pregnancy using medical methods increased the chance of GTN [7].

The reason for contraception after termination of pregnancy is to enable monitoring of serum hCG without the interference of a normal pregnancy. A reliable contraceptive method is preferred. The use of OC is save. Previous publication supports the use of OC immediately after termination of mole. However, in the guidelines for “The management of trophoblastic diseases” of the Royal College of Obstetrics and Gynecology, OC should better be started after the serum hCG has returned to normal (April 1999). The fear was an increase in GTN if OC was started too early. If woman got pregnant within the 6 months surveillance period, no increase in bad obstetric outcome or persistent GTN was observed [10]. The possibility of delaying a diagnosis of GTN should be explained to the women and the woman should take part in the decision on whether the pregnancy should be kept.

2.3. hCG monitoring Serial serum hCG monitoring is important immediate after evacuation. A weekly monitor till level returns to normal

144

H.Y.S. Ngan / Reviews in Gynaecological Practice 3 (2003) 142–147

2.6. Recurrent molar pregnancy There is a 1% chance of having another molar pregnancy in subsequent pregnancy. A recent study in over 5000 complete and partial molar pregnancies showed that the risk of repeat mole in a subsequent pregnancy is about 1 in 60 and is of the same type of mole as the preceding pregnancy [11]. However, women should be reassured that majority had normal pregnancy and delivery following a molar pregnancy. The risk of persistent GTN is higher in patients after two molar pregnancies than after one [12]. 2.7. Mole with co-existing normal twin A complete mole rarely co-exist with a normal twin pregnancy. Diagnosis was usually made incidentally on ultrasonogram. In the presence of an uncomplicated pregnancy, normal karyotype, and a normal sonogram, it is reasonable to allow the pregnancy to continue. They have a high risk of spontaneous abortion, but about 40% result in live births, without significantly increasing the risk of GTN [13].

3. Gestational trophoblastic neoplasia (GTN) 3.1. Diagnosis After years of discussion and negotiation, criteria for the diagnosis of GTN following molar pregnancy has been agreed and was published in the FIGO Gynecology Oncology Report for 2000 [14]. For years, different countries used different criteria in diagnosing GTN leading to discrepancy in the incidence of GTN ranging from 8% in UK to 20% in USA. The following is the criteria agreed by international bodies in the diagnosis of GTN: 1. GTN may be diagnosed when the plateau of human chorionic gonadotrophin lasts for four measurements over a period of 3 weeks or longer, that is for days 1, 7, 14 and 21. 2. GTN may be diagnosed when there is a rise of hCG of three weekly consecutive measurements or longer, over a period of at least 2 weeks or more, on days 1, 7 and 14. 3. GTN is diagnosed when there is histologic diagnosis of choriocarcinoma. 4. GTN is diagnosed when the hCG level remains elevated for 6 months or more. The use of a common definition would be helpful in comparing the incidence and outcome of treatment and in the understanding of the natural course of the disease.

sessment of the level of serum hCG, the size, the number and site of uterine and metastatic tumors. In the FIGO Gynecology Oncology Committee report 2000, tools for investigations were agreed upon by international bodies to look for tumor metastasis. 1. Chest X-ray is appropriate to diagnose lung metastases and it is chest X-ray that is used for counting the number of lung metastases to evaluate the risk score. Lung CT may be used. 2. Liver metastases may be diagnosed by ultrasound or CT scanning. 3. Brain metastases may be diagnosed by MRI or CT scanning. The impact of different investigative tools in staging needs to be assessed after universal acceptance of the diagnostic criteria, staging and treatment. 3.3. Staging of GTN Similar to diagnostic criteria for GTN, different countries and centers used different staging or classification of GTN. Any reasonable comparison amongst centers was impossible. The revised staging and classification of GTN proposed by international bodies was accepted at FIGO 2000 and was published in 2002. A significant change from previous staging is the replacement of the substages with a prognostic score modified from the WHO risk scoring system (Appendix A). Recommendation was made to separate GTN into low and high risk group only at the cutoff score of six inclusive. Comparison of the FIGO 1992 staging, WHO scoring system and the FIGO 2000 staging showed comparable results though fewer patients were categorized in the high risk group [15]. 3.4. Treatment 3.4.1. Low and medium risks GTN The FIGO 2000 GTN staging recommended allocation of GTN into low and high risk groups only using the cutoff point of six inclusive. This differs from the WHO recommendations into three groups, low, medium and high risk using cutoff of three and six inclusive. The two risk groups approach had been used by some researchers and some would include the medium risk into low and some into the high risk group. These made comparison of treatment results rather difficult if not impossible. The universal acceptance of an agreed risk grouping is mandatory for formulating the best treatment and in evaluating the treatment outcome.

3.2. Investigations The purpose of investigations is to assess the extent of the disease and to stage the disease. The new FIGO staging which incorporated the WHO risk scoring required the as-

3.4.2. Low risk GTN Methotrexate with or without folinic acid rescue remains the most effective single agent in the treatment of low risk GTN. In case of drug sensitivity, actinomycin D is an

H.Y.S. Ngan / Reviews in Gynaecological Practice 3 (2003) 142–147

effective alternative. Other single agents that have been shown to be effective includes etoposide and 5-fluorouracil. In patients resistant to methotrexate, a change of chemotherapy would be able to salvage almost all patients. A recent study used the level of serum hCG at the time of resistance to decide on the second line regimen. Serum level below 100 IU/l responded well to actinomycin D. For those above 100 IU/l, combination regimen, EMA-CO (etoposide, methotrexate, actinomycin–cyclophosphamide and vincristine) was used [16]. Other centers used other combination regimens such as MAC (methotrexate, actinomycin D and cyclophosphamide) or CHAMOC (cyclophosamide, hydroxyurea, actinomycin D, methotrexate, vincristine, citrovorum factor). The overall survival rate of low risk GTN if managed appropriately approaches 100%. 3.4.3. High risk GTN The treatment of high risk GTN is multiple chemotherapy. EMA-CO has been used widely with 86% 5 years survival [17]. Some centers still used MAC or the modified CHAMOC regimens. The response rate is over 80%. Experience from Charing-Cross showed that EMA-CO has acceptable toxicities and allows weekly administration of drug in out-patient setting. Recent study showed that MEA (methotrexate, etoposide and actinomycin) has similar response rate as EMA-CO but less toxicity [18]. 3.4.4. Ultra-high risk GTN and resistant disease GTN, in general, responded well to chemotherapy [19]. In patients with multiple sites of metastasis, metastasis to brain and liver carried a higher risk of treatment failure. Prognosis in solitary liver or brain metastasis is better than when metastasis was found in both site with a 5 years survival of only 10% [20]. Second line chemotherapy for drug resistance like EP-EMA regimens can salvage over 70% of patients [21]. Other regimen like MBE (methotrexate, bleomycin, etoposide) has also been used. However, the use of high dose chemotherapy with autologous bone marrow transplant does not seem to be effective. New drugs are continually being explored and drugs like taxol, germcitabine showed some activities in cell lines. 3.5. Adjunctive treatment to chemotherapy 3.5.1. Surgery Surgery is indicated when there is a life-threatening complication amenable to surgical management or when solitary resistant tumor is identified. In patients with torrential bleeding from invasive mole or choriocarcinoma, hysterectomy is the treatment of choice in patients who had completed their family. In young women who wish to conserve the uterus, embolization of the iliac vessels or partial resection of the tumor [22] when feasible

145

could be considered. Successful pregnancy has been reported after embolization treatment [23]. In patients who presented with cerebral symptoms due to a bleeding GTN, craniotomy to control the bleeding may be life-saving. Occasionally, bleeding from internal organs may be controlled by surgery or embolization. In patients with resistant GTN, hysterectomy or pulmonary lobectomy may be used to remove the solitary identifiable tumor and resulted in remission. 3.5.2. Radiotherapy Radiotherapy has limited role in GTN. The main purpose is to decrease tumor size and vascularity and hence decrease the chance of complications. In cerebral metastasis, brain irradiation more than 2200 Gy can control the brain metastasis and improve survival [24]. Similarly, irradiation of large hepatic metastasis may decrease the chance of spontaneous hepatic rupture and bleeding [25]. 3.6. Follow-up after treatment Serum hCG should be monitored closely within 1 year after treatment where the chance of relapse is higher. Patients should be advised to practice reliable contraception and the principle should follow similar to that after molar evacuation. Patients should refrain from getting pregnant for at least 1 year to avoid delaying a diagnosis of relapse. However, if patients got pregnant within the 12 months surveillance [26], it is save to allow the pregnancy to carry on and no significant adverse outcome was found. However, one study showed an increase incidence of spontaneous abortion, still birth and repeat mole in women conceived within 6 months after treatment [27]. It would be advisable to monitor any clinical signs suggestive of relapse during pregnancy where hCG lost its marker function. The chance of relapse was not found to be increased in these patients compared to those who were not pregnant during the 12 months surveillance [26]. The reproductive performance and outcome of the offspring after treatment of GTN showed no difference from normal population [28]. Appendix A The modified WHO risk scoring system is shown in Table A.1. Practice points: • the commonest presentation of molar pregnancy is abnormal vaginal bleeding; • a high index of suspicion for mole in abnormal first trimester ultrasound where typical snow-storm appearance is absent (in case of doubt, histological examination of evacuate should be performed); • appropriate serum hCG assay kit should be chosen for monitoring of hCG in trophoblastic disease;

146

H.Y.S. Ngan / Reviews in Gynaecological Practice 3 (2003) 142–147

Table A.1 FIGO 2000 gestational trophoblastic neoplasia staging and classification FIGO anatomical staging Stage I Stage II Stage III Stage IV

Disease confined to the uterus GTN extends outside of the uterus, but is limited to the genital structures (adnexa, vagina, broad ligament) GTN extends to the lungs, with or without known genital tract involvement All other metastatic sites

Modified WHO prognostic scoring system as adapted by FIGO Scores Age Antecedent pregnancy Interval months from index pregnancy Pretreatment serum hCG (IU/l) Largest tumor size (including uterus) Site of metastases Number of metastases Previous failed chemotherapy

0 <40 Mole <4 <103 – Lung – –

1 ≥40 Abortion 4 to <7 103 to <104 3 to <5 cm Spleen, kidney 1 to 4 –

2 – Term 7 to <13 104 to <105 ≥5 cm Gastrointestinal 5 to 8 Single drug

4 – – ≥13 ≥105 – Liver, brain >8 2 or more drugs

Format for reporting to FIGO Annual Report In order to stage and allot a risk factor score, a patient’s diagnosis is allocated to a stage as represented by a Roman numeral I, II, III, and IV. This is then separated by a colon from the sum of all the actual risk factor scores expressed in Arabic numerals, e.g. stage II: 4, stage IV: 9. This stage and score will be allotted for each patient.

• patients with molar pregnancy should be registered in a trophoblastic disease center for close monitoring and management; • the criteria for diagnosis of GTN recommended by FIGO allowed unification of diagnostic criteria; • investigative tools recommended by FIGO allowed uniform reporting of extent of disease and hence comparable data; • the revised FIGO 2000 staging and classification included both anatomical and risk scoring as well as allocation to low and high risk groups; • appropriate treatment according to the risk groups ensures best outcome; • high risk and drug resistant GTN should be referred to a trophoblastic disease center for better management; • both surgery and radiotherapy have an adjuvant role in the management of GTN.

[2] [3]

[4]

[5] [6]

[7]

[8]

Research agenda: • with the unified diagnostic criteria, investigative tools and staging, randomized controlled study on drug therapy should be considered; • the role and place of new imaging techniques such as PET scan on the assessment and impact on prognosis of GTN need to be explored by randomized study; • though GTN in general is a disease with good response to chemotherapy, further study on new drug or regimen is required to treat drug resistant disease. References [1] Matsui H, Iitsuka Y, Yamazawa K, Tanaka N, Seki K, Sekiya S. Changes in the incidence of molar pregnancies. A population-based

[9] [10]

[11]

[12]

[13]

[14]

study in Chiba Prefecture and Japan between 1974 and 2000. Hum Reprod 2003;18:172–5. Martin BH, Kim JH. Changes in gestational trophoblastic tumors over four decades, a Korean experience. J Reprod Med 1998;43:60–8. Soto-Wright V, Bernstein M, Goldstein DP, Berkowitz RS. The changing clinical presentation of complete molar pregnancy. Obstet Gynecol 1995;86:775–9. Benson CB, Genest DR, Bernstein MR, Soto-Wright V, Goldstein DP, Berkowitz RS. Sonographic appearance of first trimester complete hydatidiform moles. Ultrasound Obstet Gynecol 2000;16:188–91. Lindholm H, Flam F. The diagnosis of molar pregnancy by sonography and gross morphology. Acta Obstet Gynecol Scand 1999;78:6–9. Paradinas FJ, Browne P, Fisher RA, Foskett M, Bagshawe KD, Newlands E. A clinical of 149 complete moles, 146 partial moles and 107 non-molar hydropic abortions. Histopathology 1996;28:101–10. Tidy JA, Gillespie AM, Bright N, Radstone CR, Coleman RE, Hancock BW. Gestational trophoblastic disease: a study of mode of evacuation and subsequent need for treatment with chemotherapy. Gynecol Oncol 2000;78:309–12. Cole LA, Butler S. Detection of hCG in trophoblastic disease. The USA hCG reference service experience. J Reprod Med 2002;47:433– 44. Cole LA. Phantom hCG and phantom choriocarcinoma. Gynecol Oncol 1998;71:325–9. Garner EI, Lipson E, Bernstein MR, Goldstein DP, Berkowitz RS. Subsequent pregnancy experience in patients with molar pregnancy and gestational trophoblastic tumor. J Reprod Med 2002;47:380–6. Sebire NJ, Fisher RA, Foskett M, Rees H, Seckl MJ, Newlands ES. Risk of recurrent hydatidiform mole and subsequent pregnancy outcome following complete or partial hydatidiform molar pregnancy. BJOG 2003;110:22–6. Parazzini F, Mangili G, Belloni C, La Vecchia C, Liati P, Marabini R. The problem of identification of prognostic factors for persistent trophoblastic disease. Gynecol Oncol 1988;30:57–62. Sebire NJ, Foskett M, Paradinas FJ, Fisher RA, Francis RJ, Short D, et al. Outcome of twin pregnancies with complete hydatidiform mole and healthy co-twin. Lancet 2002;359:2165–6. FIGO staging for gestational trophoblastic neoplasia 2000. FIGO Oncology Committee. Int J Gynaecol Obstet 2002;77:285–7.

H.Y.S. Ngan / Reviews in Gynaecological Practice 3 (2003) 142–147 [15] Hancock BW, Welch EM, Gillespie AM, Newlands ES. A retrospective comparison of current and proposed staging and scoring systems for persistent gestational trophoblastic disease. Int J Gynecol Cancer 2000;10:318–22. [16] McNeish IA, Strickland S, Holden L, Rustin GJ, Foskett M, Seckl MJ, et al. Low-risk persistent gestational trophoblastic disease: outcome after initial treatment with low-dose methotrexate and folinic acid from 1992 to 2000. J Clin Oncol 2002;20:1838–44. [17] Bower M, Newlands ES, Holden L, Short D, Brock C, Rustin GJ, et al. EMA/CO for high-risk gestational trophoblastic tumors: results from a cohort of 272 patients. J Clin Oncol 1997;15:2636–43. [18] Dobson LS, Lorigan PC, Coleman RE, Hancock BW. Persistent gestational trophoblastic disease: results of MEA (methotrexate, etoposide and dactinomycin) as first-line chemotherapy in high risk disease and EA (etoposide and dactinomycin) as second-line therapy for low risk disease. Br J Cancer 2000;82:1547–52. [19] Kendall A, Gillmore R, Newlands E. Chemotherapy for trophoblastic disease: current standards. Exp Rev Anticancer Ther 2003;3:48–54. [20] Crawford RA, Newlands E, Rustin GJ, Holden L, A’Hern R, Bagshawe KD. Gestational trophoblastic disease with liver metastases: the Charing Cross experience. Br J Obstet Gynaecol 1997;104:105–9. [21] Newlands ES, Mulholland PJ, Holden L, Seckl MJ, Rustin GJ. Etoposide and cisplatin/etoposide, methotrexate, and actinomycin D (EMA) chemotherapy for patients with high-risk gestational trophoblastic tumors refractory to EMA/cyclophosphamide and vin-

[22]

[23]

[24]

[25]

[26]

[27]

[28]

147

cristine chemotherapy and patients presenting with metastatic placental site trophoblastic tumors. J Clin Oncol 2000;18:854–9. Kanazawa K, Sasagawa M, Suzuki T, Takeuchi S. Clinical evaluation of focal excision of myometrial lesion for treatment of invasive hydatidiform mole. Acta Obstet Gynecol Scand 1988;67:487– 92. Garner EI, Meyerovitz M, Goldstein DP, Berkowitz RS. Successful term pregnancy after selective arterial embolization of symptomatic arteriovenous malformation in the setting of gestational trophoblastic tumor. Gynecol Oncol 2003;88:69–72. Schechter NR, Mychalczak B, Jones W, Spriggs D. Prognosis of patients treated with whole-brain radiation therapy for metastatic gestational trophoblastic disease. Gynecol Oncol 1998;68:183–92. Barnard DE, Woodward KT, Yancy SG, Weed Jr JC, Hammond CB. Hepatic metastases of choriocarcinoma: a report of 15 patients. Gynecol Oncol 1986;25:73–83. Blagden SP, Foskett MA, Fisher RA, Short D, Fuller S, Newlands ES, et al. The effect of early pregnancy following chemotherapy on disease relapse and foetal outcome in women treated for gestational trophoblastic tumours. Br J Cancer 2002;86:26–30. Matsui H, Iitsuka Y, Suzuka K, Yamazawa K, Tanaka N, Seki K, et al. Risk of abnormal pregnancy completing chemotherapy for gestational trophoblastic tumor. Gynecol Oncol 2003;88:104–7. Woolas RP, Bower M, Newlands ES, Seckl M, Short D, Holden L. Influence of chemotherapy for gestational trophoblastic disease on subsequent pregnancy outcome. Br J Obstet Gynaecol 1998;105:1032–5.