Gestational trophoblastic neoplasia after achieving a nondetectable serum human chorionic gonadotrophin level

Authors


  • Linked article: This article is commented on by Seckl M, pp. 1420 in this issue.

Abstract

Objective

To determine the risk of recurrent trophoblastic disease after normalisation of human chorionic gonadotrophin (hCG) levels in women with hydatidiform mole.

Design

A retrospective review of data from a national gestational trophoblastic disease centre.

Setting

The Trophoblastic Disease Unit, Dakar, Senegal.

Sample

Women with pregnancies affected by hydatidiform mole registered between 2006 and 2012.

Methods

The women were followed up in accordance with the hospital protocol ‘Score de Dakar’. For women who progressed to gestational trophoblastic neoplasia (GTN) the time to onset of GTN, treatment and evolution were evaluated. The rate of evolution to GTN after normalisation of hCG was determined.

Main outcome measures

Rate of occurrence of GTN after chemotherapy for hydatidiform mole.

Results

Five hundred and thirty-one women were diagnosed to have molar pregnancies. According to the hospital's protocol, 107 (20.2%) of these had chemotherapy and 224 (42.2%) had prophylactic chemotherapy. Five hundred and thirteen women (96.4%; 95% confidence interval [95% CI] 95.05–98.14%) achieved remission. Eighteen women (3.4%; 95% CI 1.86–4.94%) developed GTN (11 before remission and seven after remission). Seven women out of the 18 developed GTN after hCG normalisation (1.3%). Five of these seven were diagnosed beyond the recommended period of follow up. The mean interval to diagnosis of GTN was 18.7 months. These seven women underwent combination chemotherapy: five achieved complete remission whereas two died from GTN.

Conclusions

Cytotoxic therapy for hydatidiform mole does not prevent GTN, it delays its diagnosis and promotes GTN after normalisation of hCG.

Introduction

Gestational trophoblastic disease encompasses a spectrum of pregnancy-related disorders that includes benign, premalignant disorders (complete and partial hydatidiform mole) and persistent, malignant disorders (invasive mole, choriocarcinoma, placental site trophoblastic tumour and epithelial trophoblastic tumour). Gestational trophoblastic neoplasia (GTN) is a term used for the persistent/malignant disorders.[1]

The risk of GTN after molar pregnancy has been associated with older maternal age,[2] theca lutein cysts >6 cm in size on presentation and a previous history of hydatidiform mole.[3] Additionally, risk of malignant disease after hydatidiform mole has been associated with the use of oral contraceptives.[4]

In 1986, Bagshawe et al.[5] found that GTN could recur after spontaneous normalisation of human chorionic gonadotrophin (hCG) levels—therefore a follow-up protocol is used worldwide after hCG normalisation. Follow-up guidelines include at least 6 months of monitoring after normalisation of hCG levels. In 2004, Wolfberg et al.[6] reported two cases (0.2%) of GTN in a large retrospective study of 876 women with complete hydatidiform mole after normalisation of their hCG. The aim of this study was to determine the risk for recurrent trophoblastic disease after normalisation of hCG levels in women with hydatidiform mole.

Methods

This study was performed at the Gynaecologic and Obstetric Clinic of Dakar Teaching Hospital, the referral centre for gestational trophoblastic disease in Senegal. All women with molar pregnancies who were treated and followed up at this centre between 1 January 2006 and 31 December 2012 were analysed retrospectively. The women were followed up in accordance with the hospital's protocol ‘Score de Dakar’.[7] This score includes age, parity, area of residence, blood group, income, level of postevacuation hCG, character of vesicles, duration of pregnancy and history of hydatidiform mole. According to this protocol, women were classified into low, medium and high risk of progression to GTN. Low risk was defined by a score ≤7, medium risk by a score between 8 and 15 and high risk by a score >15. Table 1 shows this scoring system. Monitoring of hCG is recommended for women at low risk. For those at medium risk, treatment is with single-agent chemotherapy (Chem-P) (methotrexate 20 mg/m2 once per day from day 1 to day 5). For women at high risk, hysterectomy and chemotherapy (Chem-T) (intramuscular methotrexate, 20 mg/kg, and intravenous cyclophosphamide, 500 mg, on day 1 and day 8 every 3 weeks) are recommended until undetectable serum hCG levels have been achieved. No consolidation courses were administered.

Table 1. The Dakar scoring system[7]
Prognostic factorsPoints awarded in the scoring system
1234
  1. Low risk, score of ≤7; medium risk, score between 8 and 15; high risk, score >15.

Age (years)20–2930–39<20>40
Parity2–34–50–1>5
Area of residenceDakar<100 km from Dakar>100 km from Dakar 
Blood groupABAB 
IncomeMiddleLowNone 
hCG within the 45 days following uterine evacuationPositivePlateauRising
Character of vesiclesVesicles with embryoMacrovesicles (≥1 cm)Microvesicles (<1 cm) 
Pregnancy duration2 months≤3 months>3 months 
History of hydatidiform mole  Yes 

Depot medroxyprogesterone acetate or subdermal implants were used for contraception throughout the follow-up period, which is 2 years in Senegal. Our clinic is also a family planning clinic, so at the end of follow up, some women who preferred to continue contraception were followed in the same service. Any gynaecological symptoms were supported in the gestational trophoblastic disease unit. Women in whom a diagnosis of GTN after normalisation of hCG was made without regular contraception were excluded from the analysis.

For the determination of hCG levels, our laboratory performed a two-site monoclonal antibody immunoradiometric assay, which is considered to be reliable for the management of trophoblastic disease. An hCG level of <5 iu/ml was considered negative. The data for initial postevacuation serum β-hCG levels, number of weeks until serum β-hCG levels became undetectable and number of women with disease relapse following one undetectable serum β-hCG level were analysed. Diagnosis of GTN was made according to the International Federation of Gynecology and Obstetrics (FIGO) Criterion[8] and the rate of evolution to a GTN after normalisation of hCG was determined. For these specific cases of GTN, the diagnostic interval was calculated from date of hCG normalisation. The statistical significance of the data was evaluated using the chi-square test for qualitative data and Fisher's exact test when appropriate. Student's t-test was used for quantitative data. SPSS version 19.0 (SPSS Inc., Chicago, IL, USA) was used for data analysis.

Results

Five hundred and thirty-one women were diagnosed to have molar pregnancies. The mean postevacuation hCG value was 8226.31 iu/l (range 0.5–787.5 iu/l).

According to the hospital's protocol, 224 (42.2%) and 107 (20.2%) women, respectively, had Chem-P and Chem-T treatment. Five hundred and thirteen women (96.4%; 95% confidence interval [95% CI] 95.05–98.14%) achieved remission. The mean time to attain an undetectable hCG level was 4.2 months, and 60.3% of women achieved undetectable levels of hCG within 4 months. The mean time to attain an undetectable hCG level was 5.3 months in the Chem-T group (95% CI 4.96–6.42%, P < 0.00001), 3.7 months in the Chem-P group (95% CI 3.54–4.22, P < 0.00001) and 3.2 months in the simple monitoring group (95% CI 3.41–4.09, P < 0.00001). The demographic and clinical characteristics of the participants are summarised in Table 2.

Table 2. Demographic and clinical characteristics of women
CharacteristicsInitial treatment, n (%)
Chem-PChem-TMonitoringTotal (%)
  1. CHM, complete hydatidiform mole; PHM, partial hydatidiform mole.

Age (years)
≤2021 (19.8)54 (50.9)31 (29.3)106 (100)
21–4059 (16.1)165 (45.1)142 (38.8)366 (100)
≥4127 (45.75 (8.527 (45.859 (100)
Total224 (42.2)107 (20.1)200 (37.7)531 (100)
Histology
CHM88 (44.6)45 (22.8)64 (32.6)197 (100)
PHM19 (38)7 (14)24 (48)50 (100)
Unspecified117 (41.2)55 (19.4)112 (39.4)284 (100)
Total224 (42.2)107 (20.1)200 (37.7)531 (100)
Mean postevacuation hCG level (iu/l) 5910.5923 127.363560.56 

Eighteen women (3.4%; 95% CI 1.86–4.94%) developed GTN (11 before remission and seven after remission). The median time to onset was 9.8 months: 3.5 months in the simple monitoring group (95% CI 2.02–4.94, P = 0.0001), 12.1 months in the Chem-P group (95% CI 1.59–17.9, P = 0.009) and 21.1 months in Chem-P group (95% CI 7.2–33.08, P < 0.00001). The outcomes for women included in the study are summarised in Figure 1.

Figure 1.

Flow chart depicting recruitment and outcomes of study participants.

Six women out of these 18 were considered to be at high risk according to the FIGO scoring system and these women received initial cytotoxic therapy to prevent GTN. A single-agent methotrexate protocol was used for those considered at low risk according to the FIGO scoring system (12/18) and combination chemotherapy for the high-risk group (6/18). This consisted of etoposide–methotrexate–cyclophsphamide–oncovin (actinomycin D is not available in Senegal) and methotrexate–fluorouracil–etoposide according to the protocol of Wang et al.[9]

The overall remission rate after the single-agent methotrexate protocol was 91.6% in the low-risk group. In the high-risk group, two women achieved complete remission, one did not attend follow up and three died from GTN. For those women who achieved remission, two courses of consolidation chemotherapy were given beyond the first negative hCG level.

Seven women developed GTN after hCG normalisation, an overall rate of 1.3%. Five of the seven cases of GTN were diagnosed beyond the recommended period of follow up, which is 2 years in Senegal. The characteristics of these seven women are summarised in Table 3. The mean interval to diagnosis of GTN was 18.7 months (8.4–32.2 months). Five women achieved complete remission (three in the low-risk group and two in the high-risk group) whereas two died from GTN. The median overall survival was 6.2 months.

Table 3. Characteristics of participants (1–7) diagnosed with gestational trophoblastic neoplasia after hCG normalisation
 Age (years)HM typeInitial hCG level (iu/l)Initial managementTime to hCG normalisation after HM (months)Time to GTN after hCG normalisation (months)FIGO group riskDisease progression
  1. HM, hydatidiform mole; CHM, complete hydatidiform mole; PHM, partial hydatidiform mole; HR, high risk; LR, low risk.

130CHM13 098Chem-T11.532.2HRNo
223Unspecified14 144Chem-T9.420.2HRYes
330PHM57 400Chem-T5.0310.7LRYes
440Unspecified23.61Chem-T4.617.4HRNo
530Unspecified274.25Chem-P4.920.1LRNo
620Unspecified16 9964.48.4LRNo
727CHM4816.5Chem-T4.122.2LRNo

Discussion

Main findings

In the present study, the use of cytotoxic therapy does not prevent the development of GTN, it delays diagnosis of GTN and promotes the development of GTN after remission. In addition, administration of cytotoxic therapy at the time of diagnosis of hydatidiform mole increases the FIGO score by two or four points if GTN occurs, resulting in the prescription of combination chemotherapy (high-risk group). Combination (multiple-agent) chemotherapy is expensive and difficult to implement in Senegal, and often progresses to failure because of beaded administration due to significant delays in women collecting the money needed to buy these cytotoxic products. US and French reference centres do not recommend the use of prophylactic chemotherapy because of the risk of resistance to subsequent chemotherapy.[10, 11] Golfier et al.[12] state that there is never an indication for any chemotherapy, even if the initial hCG level is very high.

Strengths and limits

The strengths of this study include a substantial cohort of women and a large diverse sample. All data were collected from patient records and verified by two specialists. The main weakness in the study is the lack of some cytotoxic drugs in Senegal.

Interpretation

The rate of postmolar GTN in our study (1.3%) is higher than what has previously been reported in the literature.

In our centre the use of cytotoxic agents was based on the risk of evolution of hydatidiform mole to GTN. Since 1966, several studies have focused on the primary prevention of postmolar GTN and have evaluated prophylactic chemotherapy with methotrexate or actinomycin D, but their results have been controversial.[13] According to Berkowitz and Goldstein, hydatidiform mole can be divided into low and high risk for persistence based on signs and symptoms of marked trophoblastic proliferation at the time of evacuation, i.e. hCG >100 000 miu/ml, excessive uterine enlargement and theca lutein ovarian cyst >6 cm in diameter. Local invasion and metastases, respectively, developed in 31% and 9% of high-risk women and 3.4% and 0.6% of low-risk women.[14]

In 2012, a Cochrane review concluded that prophylactic chemotherapy may reduce the risk of progression to GTN in women with hydatidiform mole who are at a high risk of malignant transformation; however, current evidence in favour of prophylactic chemotherapy is limited by the poor methodological quality and small size of the included studies. The authors added that as prophylactic chemotherapy may increase drug resistance, delay treatment of GTN and expose women to unnecessary toxic adverse effects, this practice could not be currently recommended.[15]

There are few studies that have evaluated the risk of relapse after achieving a nondetectable serum hCG level. This risk appears to be very low, <1%.[6, 8, 10, 16-22] Because this risk is very low, there are no factors associated with it. Our study demonstrates that cytotoxic treatment at the molar pregnancy stage increases this risk.

Conclusion

Cytotoxic therapy for hydatidiform mole does not prevent GTN and increases the rate of GTN after hCG normalisation. Patients with hydatidiform mole should be followed by hCG monitoring and chemotherapy should only be used in women with confirmed GTN.

Disclosure of interests

We have no conflicts of interest to declare.

Contribution to authorship

MG established the design of the study. MDN, MM, SMK, AAD, MMN and MD collected and analysed the data. MG, MDN and JCM wrote the article. All authors interpreted the data and reference articles.

Details of ethics approval

In Senegal, a retrospective study involving only data taken from patients' files without disclosing identity does not require ethics approval. However, the committee of the hospital gives its approval before publishing such data. That was the case for this study.

Funding

None.

Acknowledgements

We thank all the women whose data were used in the study, the dedicated specialist nurses in the gynaecological clinic, Mrs Aida Mbaye, the staff of the Gynecologic and Obstetric Clinic and the University of Dakar.

Time to stop offering prophylactic chemotherapy after molar pregnancies?

  • M Seckl

  • Imperial College, London, UK

Linked article: This article is a mini commentary on M Gueye et al., pp 1415–19 in this issue. To view this article http://dx.doi.org/10.1111/1471-0528.12742.

Women who have had a complete or partial hydatidiform mole evacuated from their uterus have a 16% and 0.5–1% risk, respectively, of developing malignant change to gestational trophoblastic neoplasia (GTN). This is most easily detected by serial monitoring of human chorionic gonadotrophin (hCG) in serum or urine. A plateaued or rising hCG indicates malignant transformation and the need for chemotherapy. The type of chemotherapy required depends on a number of factors that are used in the International Federation of Obstetricians and Gynecologists (FIGO) scoring system to categorise women as either having a low or high risk of their disease becoming resistant to single-agent therapy with either methotrexate or actinomycin D. Nearly all women on hCG surveillance have their disease caught early, score as low risk and so commence single-agent drug therapy and most will be cured on this simple, relatively nontoxic treatment (Seckl et al. Lancet 2010;376:717–29). Moreover, if this fails, all are subsequently cured with additional therapy. Surveillance therefore spares most women from being unnecessarily exposed to cytotoxic agents and results in a 100% cure rate. However, there may be situations when hCG surveillance is not possible so the question then arises as to whether prophylactic chemotherapy (Chem-P) is effective after uterine evacuation of a molar pregnancy. This could be judged in terms of safety, efficacy and health economics. As far as safety is concerned, single-drug methotrexate or actinomycin D seems safest and is what most investigators have employed, but even this can kill occasional women due to neutropenic sepsis and idiosyncratic reactions such as Stevens–Johnson syndrome or fulminant hepatitis. So does it work? A recent Cochrane review identified only a very limited number of studies, which were of poor quality. The authors concluded that although the risk of malignant change may be reduced there may also be an increased risk of subsequent drug-resistant disease and a delayed start of curative therapy, so Chem-P could not be recommended (Fu et al. Cochrane Database Syst Rev 2012;10:CD007289). In this issue, Gueye et al. describe their experience of Chem-P given to women after molar evacuation. Patients were subdivided into low, medium or high risk of subsequent problems based on their local Dakhar scoring system. The low-risk group underwent surveillance, medium-risk women had single-agent intramuscular methotrexate 20 mg/m2 on days 1 to 5 once (Chem-P) and women at high risk had hysterectomy plus intramuscular methotrexate and cyclophosphamide 500 mg intravenously given on days 1 and 8 every 3 weeks until hCG normalisation (Chem-T). Monitoring was continued for 2 years but the frequency and nature of this are not described. Interestingly, the risk of progression to GTN following hCG normalisation was highest in the Chem-T group at 5% (5/107) compared with just 0.4% (1/224) and 0.5% (1/200) in the Chem-P and surveillance groups, respectively. Moreover, two of the Chem-T women died of multidrug-resistant disease whereas none of the others died. The groups appeared reasonably matched for the proportion of complete versus partial hydatidiform moles, which is the main determinant of GTN risk. This plus other data led the authors to reasonably conclude that neither Chem-P nor Chem-T can safely be recommended. The study lacks clarity in places and has a number of confounding variables but combined with previous data it adds to the body of evidence that prophylactic chemotherapy is not a good idea. A health economic analysis would probably also show that it is not financially effective given the low costs of hCG surveillance. It is time to stop recommending prophylactic chemotherapy for these women.

Disclosure of interests

None to declare. ■

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