Chemo-resistant gestational trophoblastic neoplasia, 5-years experience of Mansoura University Hospital, Egypt

doi:10.4236/ojog.2011.13029

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Open Journal of Obstetrics and Gynecology, 2011, 1, 153-157

doi:10.4236/ojog.2011.13029 Published Online September 2011 (http://www.SciRP.org/journal/ojog/

OJOG

Published Online September 2011 in SciRes. http://www.scirp.org/journal/OJOG

Chemo-resistant gestational trophoblastic neoplasia, 5-years

experience of Mansoura University Hospital, Egypt

Reda Abd Elhady Hemida 1*, Eman Toson2, Hend Shalaby1, Ehsan Refaie1, Doaa Sharaf Eldin2

1Department of Obstetrics and Gynaecology, Mansoura University Hospital, Mansoura, Egypt.

2Department of Clinical Oncology, Mansoura University Hospital, Mansoura, Egypt.

E-mail: *[email protected]

Received 25 April 2011; revised 23 May 2011; accepted 30 May 2011.

ABSTRACT

Introduction: Gestational trophoblastic neoplasia

(GTN), is recognized as the most curable gynaecolo-

gic malignancy. However, many cases are resistant to

first line chemotherapy. Objective: The aim of the

study is to report our 5 years experience in the ma-

nagement of GTN cases with special stress on the

chemo-resistant cases. Methods: The study was per-

formed through reviewing the records of 51 patients

who were diagnosed as GTN during the period from

1/1/2006 to 31/12/2010 in Mansoura University Hos-

pital, Egypt. Results: Resistance to methotrexate the-

rapy was reported in 15.15% of low risk cases and

received etoposide or cisplatinum/etoposide. Sixty

percent of high risk cases were resistant to MAC

combination and received salvage chemotherapy or

hysterectomy. There was significant correlation be-

tween patient response and initial B-hCG, as well as

WHO risk score (P value = 0.001 in both) but corre-

lations with age, parity, type of antecedent pregnancy,

and histopathology were non significant (p = 0.95,

0.53, 0.47& 0.83 respectively). Conclusion: Low risk

GTN cases who were resistant to methotrexate mono-

therapy received etoposide or cisplatinum/etoposide

as a second-line therapy. High risk GTN cases who

were resistant to MAC combination received second-

line combination chemotherapy and/or hysterectomy.

WHO risk score and initial B-hCG were correlated to

resistance to first line chemotherapy.

Keywords: Gestational Trophoblastic Neoplasia-

Chemotherapy-Resistance

1. INTRODUCTION

Gestational trophoblastic neoplasia (GTN), is the term

now commonly applied to persistent or invasive gesta-

tional trophoblastic disease [1]. GTN is typically diag-

nosed in asymptomatic women undergoing routine hCG

monitoring after evacuation of a complete molar pre-

gnancy. It is recognized today as the most curable gynae-

cologic malignancy [1]. The reported incidence of GTN

is 2/1000 pregnancies in Japan and 0.6 - 1.1/1000 pregn-

ancies in Europe [2]. In Africa, Moodley and colleagues

reported that the incidence of GTN was 0.5 /1000 deli-

veries in South Africa [3].

There are many classifications of GTN, in 1973, Ham-

mond et al. classified GTN into non metastatic and me-

tastatic diseases, the later is further subdivided into good

prognosis metastatic disease and poor prognosis meta-

static disease. In 1976, Bagshawe suggested the use of a

prognostic scoring system. The WHO has adopted a mo-

dification of Bagshawe's scoring system [1].

Patients scored as low risk (score 0 - 6) receive

methotrexate and folinic acid and have a survival rate of

about 100%, but a third require second-line chemo-

therapy, either with single-agent intravenous actinomycin

D or with etoposide, methotrexate, actinomycin D alter-

nating with cyclophosphomide and vincristine (EMA/CO)

[4-6].

Patients scored as high risk (score ≥ 7) receive EMA/

CO as first-line therapy and have a survival rate of 90%

but more than 10% of patients fail this therapy [6,7]. To

salvage women failing EMA/CO, Newlands et al. [8]

have previously shown that the addition of cisplatin to

etoposide (EP) alternating weekly with EMA (1 day only)

with or without surgery salvages a further 75% of cases.

El-lamie et al. [9], recommended incorporation of pacli-

taxel in the third-line treatment of resistant GTN. How-

ever, Deng et al. [10], concluded from a Cochrane syste-

matic review that a MAC regimen was better than other

regimens for high-risk GTN because of lower toxicity.

Furthermore, adjuvant surgical procedures could be

excellent adjuncts to salvage chemotherapy in removing

known foci of chemotherapy-resistant disease in selected

patients with persistent GTN [11].

Zhou et al. [12], classified refractory GTN as chemo-

R. A. E. Hemida et al. / Open Journal of Obstetrics and Gynecology 1 (2011) 153-157

154

resistant GTN group who had never a normal serum beta

subunit of human chorionic gonadotropin (β-hCG) level

during their previous treatment, relapsed GTN group

who had elevated serum β-hCG levels in the absence of

the pregnancy after finished treatment 3 months or more,

and undetermined GTN group who had elevated serum

β-hCG levels in the absence of the pregnancy less than 3

months after completed treatment. They concluded that

comparing with the patients with chemo-resistant GTN,

the outcome of patients with relapsed GTN was better.

Optimization of treatment strategies for patients who

develop drug resistance remains a key challenge. We

tried to clarify factors that were linked to resistance to

first-line chemotherapy and management of the chemo-

resistant cases during the last 5 years in our university

hospital

2. PATIENTS AND METHODS

The study was performed through reviewing the records

of 51 patients who were diagnosed as gestational tropho-

blastic neoplasia during the period from 1/1/2006 to

31/12/2010 in the departments of Gynaecology and Cli-

nical Oncology, Mansoura University Hospital, Egypt.

The cases were diagnosed as GTN after persistent

positive hCG more than 6 months, plateuing, or rising

serum level of B-hCG after evacuation of molar preg-

nancy or after histological diagnosis of choriocarcinoma,

invasive mole, or placental site trophoblastic tumour

(PSTT).

The patients were evaluated with respect to age, parity,

type of antecedent pregnancy, clinical presentation, and

presence of metastasis. The level of serum B-subunit of

hCG at diagnosis, and its level on follow up visits were

studied. Uterine re-curettage and pathological findings

were evaluated. All women were classified as low-risk

or high-risk disease using FIGO and WHO scoring

systems [1].

The first line chemotherapy treatment for these cases

was studied regarding its type (single or multiple agent),

number of courses, and the response rate. Patients needed

second, third lines of combination chemotherapy as well

as performing hysterectomy or other surgical procedures

were also analyzed.

3. STATISTICAL ANALYSIS

The statistical analysis of data done by using excel pro-

gram for figures and SPSS program (SPSS, Inc, Chicago,

USA) statistical package for social science version 16.

To test the normality of data distribution K-S (Kolmo-

gorov-Smirnov) test was done only significant data

revealed to be nonparametric. The description of the data

done in form of mean (+/-) SD for quantitative data and

Frequency & proportion for qualitative data.

The analysis of the data was done to test statistical

significant difference between groups. For quantitative

date student t-test was used to compare between two

groups.

Paired sample t-test was used to compare one group

at different times. Chi square test was used for for quali-

tative data. P is considered significant if less than or

equal to 0.05 at confidence interval 95%.

4. RESULTS

This retrospective study included 51 cases who were

diagnosed as GTN. The mean follow up duration was

28.45 months (range: 3 - 54). Thirty-six cases (70.6%)

were low risk and 15 cases (29.4%) high risk according

to WHO scoring system. The mean age was 28.7 years

(range: 17 - 50 years). The mean parity was 1.29 (range:

0 - 5). Mean B-hCG level on admission was 52705.8

mu/ml (range: 60.0 - 500,000). The mean time since the

last pregnancy was 6.15 months (range: 1 - 72).

The history of the previous pregnancy was shown in

Table 1, as can be seen from the table, 30 cases (58.8%),

followed complete hydatidiform mole.

The initial clinical presentation of the studied cases

was post molar bleeding in 24 cases (47.05%), non-

normalization of hCG after molar evacuation in 10 cases

(19.60%), abnormal vaginal bleeding in 16 cases (31.38%),

and one case (1.97%), was presented to the emergency

unit by internal haemorrhage with elevated hCG (1000

mu/ml) and diagnosed after laparotomy as ruptured he-

patic metastasis of choriocarcinoma .

Dilatation and curettage was done in 36 cases (70.6%),

the histopathology of these cases was shown in Table 2.

There were 8 cases (15.68%) with distant metastases, the

sites of metastasis are shown in Table 3.

Forty-eight patients received first line chemotherapy

for 2 - 15 cycles, 3 low risk cases (5.9%) did not receive

chemotherapy due to spontaneous decline of B-hCG

after uterine re-curettage (a total of 51 cases). Complete

response was achieved in 34 patients (70.83%), while 14

cases were resistant to chemotherapy (29.17%).

Regarding first- line treatment, 33 low-risk cases re-

ceived methotrexate in a dose of 1 mg/kg in days 1, 3, 5,

and 7 alternating with oral folinic acid 0.1 mg/kg in days

2, 4, 6, and 8. Mean number of courses was 5.09 (range:

2 - 15). Twenty-eight cases (84.85%) achieved remission,

while 5 cases (15.15%) needed second line therapy in

the form of etoposide (3 cases) and cisplatinum/etopo-

side (2 cases) with a complete response.

High risk patients (15 cases) received methotrexate -

actinomycin D-cyclophosphamide (MAC) combination

as first-line chemotherapy, 6 cases (40%) responded to

this treatment while 9 cases (60%) were resistant. Ac-

cording to our tumour discussion panel, 6 of the resistant

cases received cisplatinum/etoposide as second-line

R. A. E. Hemida et al. / Open Journal of Obstetrics and Gynecology 1 (2011) 153-157 155

Table 1. The type of antecedent pregnancy.

Count Percentage

Abortion 10 19.6%

Partial mole 9 17.6%

Complete mole 30 58.8%

Term pregnancy 2 3.9%

Total 51 100.0%

Table 2. Histopathology of the studied cases.

Count %

No endometrial biopsy* 15 29.4%

Choriocarcinoma 20 39.2%

Molar tissues 10 19.6%

Invasive mole 3 5.9%

PSTT** 3 5.9%

Total 51 100.0%

*: Diagnosis of GTN was done by non-normalization of B-hCG after

evacuation of hydatidiform mole; PSTT**: Placental site trophoblastic

tumor.

Table 3. Sites of distant metastases.

Percentage Number

62.5% 5 Lungs

12.5% 1 Lungs and brain

12.5% 1 Bone and brain

12.5% 1 Liver

100 % 8 Total

therapy, where 4 of them achieved remission by this

salvage chemotherapy and the other 2 cases did not re-

spond and had hysterectomy. The remaining 3 cases

were not given second line chemotherapy; 2 cases had

hysterectomy as they refused salvage chemotherapy and

they had no distant metastasis while the last case died

during the first line therapy after rapid progress with

lung and brain metastasis.

Radiotherapy was used in two cases (3.92%) with

brain and/or bone metastasis. Surgical treatment was

done in 5 high risk cases (9.8%). Hysterectomy was

done in 4 cases (7.84%); as a second line in 2 cases and

as a third line in 2 further cases. Hepatic resection was

done in one case who presented by internal haemorrhage

due to rupture of hepatic metastasis.

The overall survival of GTN cases in our study was

98.04% and was found to be 100% for low risk patients.

Ta b l e 4 shows the correlation of age, parity, and ini-

tial B-hCG to patient response to first-line chemotherapy.

As can be seen from this table, patient response was not

Table 4. Correlation of age, parity, and initial B-hCG to patient

response to first-line chemotherapy.

ResponseN*Mean S D** P value

Responders37 28.73 7.85

Age Non

responders 14 28.57 9.97

0.953

(NS)***

Responders37 1.38 1.497

Parity Non

esponders 14 1.07 1.73

0.534 (NS)

Responders37 27533.65 46849.297

Initial

hCG Non

responders 14 119232.14 1.40103.5

0.001

(Sig.)****

N*: Number of patients; SD**: Standard deviation; (NS)***: Non signifi-

cant; (Sig.)****: Significant.

significantly correlated to age and parity but there was

significant correlation to initial B- hCG.

Table 5 shows the correlation between type of ante-

cedent pregnancy and patient response to first-line che-

motherapy, P value was 0.74 (non significant).

Table 6 shows the correlation between histopathology

and patient response to first-line chemotherapy, again,

there was no significant correlation. Ta bl e 7 shows the

correlation between WHO risk score and patient re-

sponse to first-line chemotherapy, there was significant

correlation (P value = 0.001).

5. DISCUSSION

Gestational trophoblastic neoplasia is highly responsive

to chemotherapy and prognosis is excellent following

treatment, especially in low-risk patients [13]. However,

resistance to first line chemotherapy was reported to

occur in 33% of low risk cases and about 10% of high

risk cases (4,8). There is a need to find out the factors

that linked to chemo-resistance as well as to reach the

ideal treatment strategies for these patients.

This retrospective study was performed through re-

viewing the records of 51 patients who were diagnosed

as gestational trophoblastic neoplasia during the period

from 1/1/2006 to 31/12/2010 in the departments of Gy-

naecology and Clinical Oncology, Mansoura University

Hospital, Egypt.

The socio-demographic criteria of GTN patients may

differ according to the geographic distribution. The mean

age of our cases was 28.7 years which agreed with find-

ings of other authors [8,12] but did not agree with data

published by Kaye [14], from Uganda who reported that

most of his cases occurred below 20 years or above 35

years. The mean parity of patients in our study was 1.3

which did not agree with Kaye [14] as 68% of his pa-

tients had 5 or more deliveries. This may be explained

by different community criteria.

Most of our GTN cases occurred after complete molar

R. A. E. Hemida et al. / Open Journal of Obstetrics and Gynecology 1 (2011) 153-157

156

Table 5. Correlation of type of antecedent pregnancy to patient

response to first-line chemotherapy.

Response

Responders Non responders Total

Abortion 6 (60%) 4 (40%) 10

Partial mole 8 (88.89%) 1 (11.11%) 9

Complete mole 22 (73.33%)8 (26.66%) 30

Term pregnancy 1 (50%) 1 (50%) 2

Total 37 14 51

P value : 0.47 (non significant).

Table 6. Correlation of histopathology to patient response to

first-line chemotherapy.

Response Total

Responders

Non

res

onders

Endometrial biopsy not done 13 (86.67%) 2 (13.33%)15

Choriocarcinoma 13 (65%) 7 (35%) 20

Molar tissues 9 (90%) 1 (10%) 10

Invasive mole 1 (33.33%) 2 (66.67%)3

PSTT 1 (33.33%) 2 (66.67%)3

Total 37 14 51

P value : 0.083 (non significant).

Table 7. Correlation of WHO risk score to patient response to

first-line chemotherapy.

Response Total

Responders

Non

onders

Low risk (score 0 - 6) 31 (86.11%) 5 (13.99%) 36

High risk (score ≥ 7) 6 (40%) 9 (60%) 15

Total 37 14 51

P value: 0.001 (Significant).

pregnancies (58.8%), as can be seen from Ta bl e 1 , this

was in agree with other authors [15,16]. Ta b l e 2 shows

the histopathology of the cases who had been performed

uterine curettage. Twenty of thirty-six cases (55.56%),

were found to be choriocarcinoma this finding was

agreed with other authors [17,18]. Distant metastases

were shown in Table 3, lung metastasis was the com-

monest, a similar finding was reported by Kumar et al.

[19].

Low risk GTN cases received Methotrexate/folinic

acid but there was 15.15% of patients fail to respond to

this monotherapy. Resistance to methotrexate therapy

was reported also by other authors [5,6].

High risk cases received MAC combination chemo-

therapy, however, 60% of them were resistant to this

protocol. This figure was higher than reports of other

authors [10,12], this can be explained by smaller number

of patients in the current study.

In this study, we tried to determine whether there were

any factors linked to resistance to first line chemothe-

rapy during initial treatment of GTN. Tables 4-7,

showed that there was significant correlation of chemo-

therapy response to initial B-hCG and WHO score (p =

0.001 in both). These findings were supported by other

author [20,21]. No significant correlation of age, parity,

type of antecedent pregnancy, and histopathologic type

(p = 0.95, 0.53, 0.47& 0.83 respectively). This was sup-

ported by the results of Wang et al [22] but did not agree

with Bagshawe [20]. This discrepancy may be as result

of small number of patients who performed endometrial

biopsy (36 cases).

Surgical procedures may be good adjuncts to chemo-

therapy in properly selected cases as the majority of

women with GTN are young and wish to preserve their

fertility. Hysterectomy was done in 4 high-risk cases

who failed to respond to first line chemotherapy as a

second or third line therapy. This findings was also sup-

ported by other authors [12,17,23].

We have to report that this retrospective study re-

presented a single center experience and had relatively

small number of cases. A large multicenter prospective

trial is recommended.

6. CONCLUSIONS

Low risk GTN cases were found to be resistant to meth-

otrexate monotherapy in 15.15%, these cases received

etoposide or cisplatinum/etoposide as a second-line the-

rapy. High risk GTN cases received MAC combination

but 60% were resistant and needed second line com-

bination chemotherapy or hysterectomy. WHO score and

initial B-hCG were significantly correlated to resistance

to first-line chemotherapy.

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