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1 Gestational trophoblastic neoplasia -Fertility outcomes and survival

3 Abstract

4 Purpose: To investigate the survival and fertility outcomes of the patients treated for gestational
5 trophoblastic neoplasia (GTN).

6 Methods: The clinical records of all the GTN patients registered and treated between January 1,
7 2008, and December 31, 2013, at a regional cancer center (RCC) in Tamil Nadu, India were
8 reviewed. About 35 patients with GTN were identified; 29 patients were included in the study.
9 Methotrexate and the EMACO (Etoposide, Methotrexate, Adriamycin, Cyclophosomide,
10 Vincristine) regimen were administered based on the risk score evaluation, beta human chorionic
11 gonadotropin (HCG) levels were tested during follow ups, and annual ultrasonography and chest
12 radiography were performed.

13 Results: Approximately 15 (51.7%) and 14 (48.3%) patients had low-and high-risk scores
14 respectively. Five patients (17.2%) underwent hysterectomy and 21(72.4%) underwent
15 chemotherapy. Twenty-eight patients (96.6%) survived and only 1 (3.4%) died after treatment
16 because of lung metastasis and pulmonary infections. The overall survival rate in the primary
17 setting was 96.6%. With regard to child-bearing outcomes, 14 patients (48.3%) did not desire a
18 child. Of 15 women who wished to conceive after the treatment, 9 could not conceive, 3 had
19 abortions, and 3 had a normal delivery.

20 Conclusion: The diagnosis made using radiological imaging and beta HCG levels for low- and
21 high-risk patients and the follow-up management was effective in yielding a fertility outcome
22 where patients were able to resume normal reproductive functions. GTN is a highly curable
23 malignancy regardless of the stage and its metastatic nature.

24 Keywords: GTN, survival outcome, fertility outcome, Beta HCG, EMACO, Methotrexate

25
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26 Introduction

27 Gestational trophoblastic neoplasia (GTN) is a rare but curable disease arising in the fetal
28 chorion during pregnancy. GTN encompasses interrelated tumors, namely complete hydatidiform
29 mole, partial hydatidiform mole, invasive mole, choriocarcinoma, and placental site trophoblastic
30 tumor [1].

31 Epidemiological characteristics of gestational trophoblastic disease and GTN are difficult

32 to determine given the rarity of the conditions, inconsistencies in case definitions, and lack of
33 centralized information depositories [2]. The incidences of GTD and GTN are reported to be high
34 in developing countries such as Southeast Asia, Mexico, Philippines, India, Taiwan, and Indonesia
35 in comparison to that in the USA [1-5].

36 Most women with low-risk GTD will be cured by evacuation of the uterus with or without
37 single-agent chemotherapy [6-9]. Surgery and chemotherapy are the commonly adopted treatment
38 strategies with chemotherapy being associated with an overall survival rate of more than 90%even
39 in patients with widespread metastases, followed by dilation and curettage when needed [8-10].
40 However, radiation therapy is administered when the disease has spread to other tissues.
41 Hysterectomy is the last treatment option for patients who have persistent blood loss per vaginam.
42 A review of randomized clinical trials comparing the efficacy of the 2 standard regimens
43 (dactinomycin and methotrexate) for first-line chemotherapy reported that dactinomycin yielded
44 better survival outcomes. However, its toxicity was found to be equivalent to that of methotrexate
45 [11].

46 With improvements in management and follow-up protocols, the overall cure rates of GTN
47 can exceed 98%, with fertility retention and the survival rates ranging from 90.9% to 96% in India,
48 which are equal to those in western countries. The cure rates are 100% in low-risk and 80% to
49 86% in high-risk groups[10,12-15].The efficacy of chemotherapy has allowed for preservation of
50 fertility and improved survival rates of these patients [9,10,16-22].Furthermore, patients treated
51 with fertility-preserving modalities have survival rates comparable to those of patients undergoing
52 hysterectomy[20,21].

53 In the studies performed between 1997 and2006 and between 2001 and2007 in a regional
54 cancer center in Tamil Nadu, India, the survival rates of patients were 71% and 66.7%, respectively
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55 [23,24]. The present study aimed at investigating the survival and fertility outcomes of the patients
56 treated for GTN between January 1, 2008, and December 31, 2013 in the same regional cancer
57 center.

58 Materials and Methods

59 The clinical records of all GTN patients registered and treated between January 1,2008,
60 and December 31, 2013, at the regional cancer center (RCC)were reviewed. The demographic and
61 clinical details of the patients such as age, marital status, nature of pregnancy, parity, diagnosis,
62 and treatment taken outside and at RCC were extracted. In addition, details of the baseline
63 investigations such as blood tests; computed tomography (CT) scans of the chest, brain, abdomen,
64 and pelvis; serum beta HCG levels, and WHO risk scores were recorded. The WHO risk score for
65 GTN was calculated for patients who were admitted before the treatment with the performance
66 status score of ≥2. The inclusion and exclusion criteria for this study are given in table 1.

67 The following treatment strategy was adopted. After complete evaluation of the risk score,
68 patients with low risk were only administered methotrexate. Methotrexate-only treatment is
69 generally adopted in patients with low risk. Methotrexate is injected into a vein or a muscle every
70 day for 5 days, and based on the blood levels of HCG, this is repeated again after a rest period. A
71 large dose of methotrexate once a week may also be given [25]. The EMACO regimen
72 (combination of etoposide, methotrexate/leucovorin, and actinomycin-D) was administered to
73 patients who showed an inadequate response in the low-risk group and to the high-risk patients.

74 The follow-up assessments were carried out as follows. Patients who were completely
75 responsive to the treatment were followed up every 3 monthly. HCG levels were noted during
76 each follow-up session for 36 months. After the 12-month follow-up period, with complete
77 response and cooperation from the patients, annual USG and chest radiography were performed.;
78 Later, follow-up was performed once in 6 months for the next 2 years. Following the successful
79 completion of follow-up sessions for 5 years, the patients were followed up annually, and during
80 each visit, serum beta HCG levels were tested.

81 Results
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82 The age range of the patients was 20-38 years, and the mean age was28.41±5.17years.
83 Most patients (41.4%) belonged to the age group of 31-35 years. The patients’ educational
84 qualifications ranged from primary schooling to post graduation, and most of them (62.1%) had
85 completed high school/higher secondary. Most of the patients (82.8%) were homemakers, whereas
86 the rest were daily wagers, government employees, private job employees, or self-employed.
87 Approximately 58.6% of the patients resided in urban areas, whereas the rest (41.4%) resided in
88 rural areas. Approximately 79.3% of the participants had a non-consanguineous marriage and
89 20.7% were in a consanguineous marriage.

90 The details pertaining to pregnancy of the patients are summarized in Table 1. GTN is
91 affected by the type of pregnancy the patient had at the time of disease or before the disease.
92 hydatidiform moles might progress to choriocarcinoma even after the termination of pregnancy
93 (abortion) and therefore it is important to collect details of the prior pregnancy. Three patients
94 (10.3%) had partial mole, 10 (34.5%) had a hydatidiform complete mole, 9 (31%) had an invasive
95 mole and 7 (24.1%) had choriocarcinoma.

96 Approximately 44.8% of the participants did not have a history of abortion, whereas more
97 than one-third of the patients (27.6%) had an abortion once. Before the onset of the present GTN,
98 18 participants (62.1%) had a complete mole, 1 (3.4%) had partial mole, and 2 (6.8%) had a term
99 pregnancy.

100 Table 2 summarizes the pre-treatment details of the patients. In this study, almost all
101 patients underwent CT scan of the chest, abdomen, and pelvis. Furthermore, 17.2% underwent CT
102 scan of the brain. Approximately 27.6% had lung metastasis and patients had rare presentations in
103 the brain and liver, brain, and lung, and lung and ovary metastases. In more than one-third of the
104 patients ,two third of patients the tumor size was >5 cm, and 17.2% of patients had a tumor <5
105 cm. Almost half of the patients (51.7%) had a low risk score, whereas the rest of them (48.3%)
106 had a high risk score. Nineteen patients (65.5%) had a performance status of 1, and 10 patients
107 (34.5%) had a performance status of 2. The pre-treatment beta-HCG level was in the range of101-
108 500000mIU/mL for most patients (37.9%).

109 Six patients (18.7%) had received upto 2cycles of methotrexate chemotherapy, and 1
110 patient had undergone surgery (TAH-BSO) before admission into the hospital. Eight patients
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111 (25%) had GTN diagnosed elsewhere and were referred to the RCC for further management. A
112 patient with multiple lung metastases and acute respiratory infection/distress was admitted to the
113 ICU for supportive treatment. This patient was deemed unfit for chemotherapy and was not
114 included in the study.

115 The patients who had temporary chemo-induced amenorrhea had resumed menses after the
116 completion of chemotherapy. The average time to resumption of menses after the treatment was 3
117 months. Details of various treatment strategies adopted for the study participants are summarized
118 in Table 3. Most patients (72.4%) received chemotherapy. EMA-CO, methotrexate, EMA-CO +
119 methotrexate, and EP were used for 27.6%, 27.6%,10.3%, and 3.4% of the study participants,
120 respectively. EP chemotherapy was given to the patient who received
121 chemotherapy(EMACO+Methotrexate )elsewhere with persistent disease .

122 A combination that comprised all aforementioned drugs was used in 3.4% of the study
123 participants. Approximately 5 participants (17.2%) underwent hysterectomy; patient who had
124 intact uterus and bilateral fallopian tubes /ovaries fertility was preserved in 24 patients
125 (82.8%).Approximately 29 patients received complete treatment in the form of chemotherapy and
126 surgical management. A patient who belonged to the high-risk group with lung, liver, and brain
127 metastases was treated with chemotherapy (EMACO). Given that the patient had presented with
128 high HCG levels, she was subjected to whole-brain radiotherapy after treatment. But the patient
129 died after 3 months. The remaining 28 patients were healthy and are on regular follow-up leading
130 a normal life.

131 The follow-up reports of this study revealed that28 patients (96.6%) were alive and only 1
132 (3.4%) died after treatment because of lung metastasis and pulmonary infections.

133 With regard to child bearing outcome, 48.3% of the patients did not want to have a child,
134 31% could not conceive, 10.3% had abortions, and 10.3% had a normal delivery after the
135 treatment.

136
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137 Discussion

138 In the present study, the survival rate was 96.6%.In the studies conducted between 1997
139 and 2006 and between 2001 and 2007 in the RCC in South India, the survival rate of patients was
140 71% and 66.7%, respectively [23,24]. Studies show that with sensitive quantitative assays for β-
141 HCG and current approaches to chemotherapy, most women with malignant gestational
142 trophoblastic disease and GTN could be cured, and they can achieve long-term remission and, in
143 most cases, preserve fertility [1,9,10,26,27]. In this study, we found that based on the diagnosis
144 made using radiological imaging and beta HCG levels for low-risk and selected high-risk patients,
145 the reproductive functions resumed to normal after the treatment.

146 In the study by Goto et al., among the 50 patients who underwent fertility-preserving
147 treatment for choriocarcinoma, 23 conceived for a total of 43 pregnancies [20]. We observed that
148 34 children were born without congenital malformations. Patients treated with fertility-preserving
149 modalities had comparable survival rates to those who underwent hysterectomy. In this study,
150 pertaining to fertility outcomes,4 patients who had only received chemotherapy experienced
151 chemo-induced amenorrhea temporarily during the treatment. A meta-analysis of the influence of
152 chemotherapy induced amenorrhea on prognosis demonstrated a significant advantage of survival
153 among patients with amenorrhoea [28]. No differences were apparent between the women who
154 received methotrexate as a single-agent chemotherapy and those who received multi‐agent
155 chemotherapy. Women who had registered a live birth were younger and the duration of follow-
156 up was significantly less among those who did not achieve pregnancy at all. A higher than expected
157 rate of caesarean sections and stillbirths was recorded. The chemotherapy protocols used at this
158 unit have minimal impact on the ability to reproduce after treatment [29].

159 In this study, the patients who were followed up every 3 months were advised not to
160 conceive for a period of 2 years. In a study, about 84.7% patients who underwent hysterectomy
161 for GTN achieved remission. Of patients who underwent hysterectomy to treat chemotherapy-
162 resistant disease, 75.8% subsequently achieved complete remission. Hysterectomy continues to
163 play an important role in the management of selected patients with GTN [30]. Only 5 patients
164 underwent hysterectomy in this study which in turn enhanced the chances of reproduction in most
165 patients included in the study. After the completion of treatment, 4 patients who desired to have a
166 child conceived naturally 2-4 years after the completion of treatment; 3 had normal delivery, and
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167 1 had delivered through a Caesarean section. All the 4 patients had a full-term pregnancy with no
168 congenital malformations in the infants and babies are alive and healthy. The placenta was
169 examined histopathologically, and no abnormalities were detected.

170 The retrospective design of this study was its limitation. During the analysis of case
171 records, few details pertaining to chemotherapy and related toxicity were missing, and therefore,
172 the related information was not included in the study.

173 Conclusion

174 The diagnosis made using radiological imaging and beta HCG levels for low- and high-risk
175 patients and the follow-up management was effective in yielding a fertility outcome where patients
176 were able to resume normal reproductive functions. The EMACO, methotrexate, and EP regimen,
177 separately or in combination, administered to patients based on their low-or high-risk score, was
178 found to be highly effective in improving the survival outcome of patients with GTN.

179
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180 References

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263 Box 1: Inclusion and Exclusion Criteria for sample selection

Inclusion Criteria
All age groups
Molar pregnancy
Received ≥1cycle(s) of chemotherapy
Elevated levels of beta-HCG in the post-treatment period
GTN or molar pregnancy was diagnosed after many years of antecedent delivery
Persistent bleeding after the evacuation of molar pregnancy or during the post-delivery
period
Confirmed biopsy of GTN with lungs, liver, or of multiple-site metastatic disease
Total abdominal hysterectomy with bilateral salpingo-oophorectomy (TAH-BSO)
elsewhere and were found to have GTN
Recurrence after being treated for GTN

Exclusion Criteria
Very poor performance status
Unfit for any type of chemotherapy or surgery
264

265

266 Table 1: Details pertaining to pregnancy of the study participants

Pregnancy details Number (%)

Parity
0 7 24.1
1 10 34.5
2 10 34.5
3 2 6.9
Number of Abortions
0 13 44.8
1 8 27.6
2 5 17.2
3 2 6.9
4 1 3.4
Before the present GTN
Complete mole 18 62.1
Partial Mole 1 3.4
Term pregnancy 2 6.8
267
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269 Table 2: Pre-Treatment details of the study participants

Pre-treatment details Number (%)

CT Scan
Chest, Abdomen, Pelvis 29 100.0
Brain 5 17.2
Metastasis
Brain and Liver 1 3.4
Brain and lung 2 6.9
Lung 8 27.6
Lung and Ovary 1 3.4
WHO risk score
Low 15 51.7
High 14 48.3
Performance status
Score
1 19 65.5
2 10 34.5
Pre-treatment Beta HCG 95548.41±127478.241
level (mIU/mL) (258 – 448090)
<1000 2 6.9
1001 – 10000 9 31.0
10001 – 50000 5 17.2
50001 – 100000 2 6.9
100001 – 500000 6 37.9
270

271 Table 3: Treatment details of the study participants

Treatment details Number (N = 29) %

Chemotherapy
Yes 21 72.4
No 8 27.6
Drugs used
All 1 3.4
EMA-CO 8 27.6
EP 1 3.4
Methotrexate 8 27.6
Methotrexate & EMA-CO 3 10.3
Hysterectomy
Yes 5 17.2
Preservation of fertility(No pelvic surgery) 24 82.8
272