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    -  Edesa WA
    -  Ayad NN
    -  Mounir AM
    -  Haggag MH

 
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ORIGINAL ARTICLE
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Treatment outcome of gestational trophoblastic neoplasia patients in Egypt


 Clinical Oncology Department, Faculty of Medicine, Cairo University, Egypt

Date of Submission17-Jun-2019
Date of Decision16-Jan-2020
Date of Acceptance12-Feb-2020

Correspondence Address:
Wael A Edesa,
Clinical Oncology Department, Faculty of Medicine, Cairo University
Egypt
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijc.IJC_551_19

  Abstract 


Background: Gestational trophoblastic neoplasia (GTN) are a spectrum of tumors that develop from placental tissue. We aimed to evaluate the management and treatment outcome of GTN.
Methods: Patients diagnosed with GTN presented to Kasr Alainy Center of Clinical Oncology between 2008 and 2017 were included in this study. Patients were assigned to low or high-risk according to the World Health Organization (WHO) scoring system. All data were tabulated and statistically studied by descriptive analysis; comparison between the two groups was done using student t-test for continuous data and Chi-square test for categorical data.
Results: A total of 111 patients were studied; the majority of them had WHO low-risk score. In low-risk group, the overall response rate to methotrexate-folinic acid (MTX- FA) or actinomycin D (ActD) was 48.5%, comparable response rate observed between MTX and ActD was 48.2% vs 50%, respectively. Those who received MTX-FA 8-day regimen had higher response rate compared to a weekly schedule, however, no statistical significant difference was observed (51.6% vs 44.4%, respectively, P = 0.586), all low-risk patients who failed MTX or ActD achieved complete remission (CR) with subsequent chemotherapy. Patients with WHO score 5–6 had a significantly lower CR rate compared to patients with scores <5, (28% and 60%, respectively; P = 0.01). Five-years overall survival was significantly lower in high-risk than low-risk patients (79.3% vs 100%, respectively, P = <0.001).
Conclusion: Low-risk patients have a survival rate of 100% even if they did not respond to first-line chemotherapy, MTX-FA 8-day regimen seems to be more effective than MTX weekly regimen.


Keywords: Choriocarcinoma, gestational trophoblastic neoplasia, molar pregnancy
Key Message: Due to varying diagnostic criteria and reporting practices, patients with gestational trophoblastic neoplasia should be treated in high-volume centers to avoid over and under-treatment.



How to cite this URL:
Edesa WA, Ayad NN, Mounir AM, Haggag MH. Treatment outcome of gestational trophoblastic neoplasia patients in Egypt. Indian J Cancer [Epub ahead of print] [cited 2020 Oct 30]. Available from: https://www.indianjcancer.com/preprintarticle.asp?id=297024





  Introduction Top


Gestational trophoblastic disease (GTD) is a group of disorders that arises from the placenta encompassing the premalignant complete and partial hydatidiform moles and the malignant invasive hydatidiform mole, choriocarcinoma, placental site trophoblastic tumor, and epithelioid trophoblastic tumor. The malignant forms of GTD are also collectively known as gestational trophoblastic tumors or neoplasia (GTN).[1] Although GTN is highly metastatic and lethal neoplasia, its natural history was modified in the 1950s, when Hertz et al.[2] introduced methotrexate (MTX) as an effective antineoplastic treatment to promote the systematic cure of women with nonmetastatic disease. Moreover, multi-agent regimens, such as those combining etoposide and cisplatin, were associated with high remission rates, even in disseminated disease cases.[3]

Aim of work

The aim of this study was to evaluate the response to treatment, survival, and the prognostic factors affecting the response.


  Patients and Methods Top


Patients with GTN who presented to Kasr Al Aini Center of Clinical Oncology (NEMROCK), a tertiary cancer center in Egypt, during the period from January 2008 to December 2017 were enrolled in this retrospective analysis. The Institutional Research Advisory Council approved this retrospective study. We accessed NEMROCK database to extract the file numbers of the patients diagnosed with GTD, GTN was identified with certain code of the 10th revision of the International Statistical Classification of Diseases and Related Health Problems (ICD-10) in a local computer-based registry, data were pulled by study staff listed in the protocol, contact with patients, their families, or their physician was permitted to complete a potentially eligible record. The inclusion criteria were patients diagnosed with GTN post-molar, abortion, or full-term pregnancy. Exclusion criteria were cases with the diagnosis of placental site trophoblastic tumor or epithelioid trophoblastic tumor.

We used the following criteria for the diagnosis of GTN: 1- Plateau or rising human chorionic gonadotropin (bHCG) after the uterine evacuation, plateau levels were defined as four or more equivalent values of bHCG over at least three weeks (days 1, 7, 14, 21), rising bHCG was defined as two consecutive rises in bHCG of ≥10% over at least two weeks (days 1, 7, and 14). 2- Histological evidence of choriocarcinoma. 3- Evidence of metastatic disease. 4- Serum bHCG level >20,000 more than four weeks after uterine evacuation. 5- Persistent of bHCG, six months after the molar evacuation.

After a diagnosis of GTN was confirmed, patients had undergone a complete blood picture, kidney, liver function tests, and serum bHCG level, in addition to chest X-ray (CXR), and abdominopelvic ultrasound. Patients diagnosed with lung metastasis by CXR or computerized tomography (CT) chest; abdomen and pelvis as well as CT brain with contrast were requested. The clinical data of patients and disease characteristics, including age, body mass index (BMI) were collected. Antecedent pregnancy, the interval from pregnancy, pretreatment bHCG, largest tumor size, site and number of metastasis, prior failed chemotherapy, and GTN type were described.

Staging and treatment were determined according to the International Federation of Gynecology and Obstetrics (FIGO) anatomic staging and prognostic scoring index.[4] The risk was defined as the risk of developing drug resistance to single-agent chemotherapy MTX or actinomycin D (ActD). In low-risk group (total score ≤6), patients received a single agent, either MTX or ActD. In our department, MTX was given either weekly 50 mg intramuscular (flat dose) or an alternating 8-days MTX/folinic acid regimen (MTX/FA) in which MTX (1 mg/kg) was given IM on days 1, 3, 5, and 7 alternating with folinic acid (0.1 mg/kg) on days 2, 4, 6, and 8 with 1-week interval between cycles. ActD was given as 1.25 mg/m2 intravenous dose (maximum 2 mg) every 2 weeks. Patients who failed first-line MTX or ActD could be switched to second-line ActD or MTX, respectively. In high-risk group (total score >6), patients were started with multi-agent chemotherapy usually EMA-CO regimen (etoposide, methotrexate, ActD, cyclophosphamide, vincristine). Cases who did not respond to EMA-CO were shifted to any of the following salvage chemotherapy regimens; TP/TE (taxane alternating with cisplatin and etoposide), EP-EMA (etoposide, cisplatin, methotrexate, ActD), or BEP (bleomycin, etoposide, cisplatin). During the administration of chemotherapy, serum bHCG level was requested before the next cycle. Chemotherapy was continued until bHCG normalized, then further 2–3 cycles of consolidation chemotherapy were given. After the end of treatment, serum bHCG level was measured monthly for 1 year, patients were referred to gynecology and obstetrics department to start a contraception method that should continue for at least 1 year that could be stopped later, next pregnancy outcome was recorded. Hysterectomy was considered in resistant cases or according to the patient's desire. Relapse was defined when the bHCG level rose after an initial complete remission.

Statistical analysis

All data were tabulated and statistically studied by descriptive analysis as well as survival analysis in relation to different prognostic factors. A comparison between the two groups was done using student t-test for continuous data and Chi-square test for categorical data.

Survival analysis was done according to the Kaplan-Meier method and compared by the log-rank test for significance. Univariate analysis using the Cox regression module was performed to test the power of the relationship between the independent variables and response. Differences were considered significant if the P value was less than 0.05. Overall survival (OS) was calculated as the time elapsed between the date of diagnosis and the date last known to be alive, date of death, or date of study cutoff.

All statistical calculations, data management, and analysis were performed using computer programs Microsoft Excel version 7 (Microsoft Corporation, NY, USA) and SPSS version 20 (Statistical Package for the Social Science; SPSS Inc., Chicago, IL, USA).


  Results Top


A total of 111 patients presented to NEMROCK between January 2008 and December 2017. The median age was 27 years (range 15–55), only 40 patients (36%) had normal weight, the invasive mole was the most common pathology seen in our series (85.6%). In terms of molar pregnancy, 52/80 (65%) patients had complete mole, while 28/80 (35%) had a partial mole. The majority of patients (88.3%) were International Federation of Obstetrics and Gynecology (FIGO) stage 1, only 14 patients (12.6%) presented with distant metastases, with the lung being the most common site. Total risk score ranged from 0 to 17, with median of four, low-risk was documented in 95 patients (85.6%), three patients (2.7%) were at ultra-high risk (total risk score >12), a total of 29 patients (26.1%) had a total risk score of 5–6. The patient's characteristics are summarized in [Table 1].
Table 1: Patients Characteristics

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Out of total 111 patients, 109 (98.2%) patients underwent evacuation; the remaining two patients had resection of brain space-occupying lesion followed by chemotherapy and whole-brain irradiation. Two patients (1.8%) were subjected to hysterotomy due to either delivery or vaginal bleeding. Twenty-three patients (20.7%) underwent hysterectomy; 17 patients (15.3%) underwent a total hysterectomy, while six patients (4.4%) underwent a subtotal hysterectomy. Out of 23 patients, four patients (17.3%) underwent hysterectomy as salvage treatment after chemotherapy failure, three patients were low-risk and one patient was high-risk. On the other hand, eight patients (34.7%) underwent a hysterectomy due to uncontrolled vaginal bleeding. The remaining 11 patients (48%) underwent first-line therapeutic hysterectomy as they didn't desire fertility; however, three patients still required multi-agent chemotherapy due to rising bHCG postoperatively.

In low-risk GTN, 25 patients had incomplete data about treatment and were excluded; therefore, only 70 patients were evaluable for response. Fifty-eight patients (82.8%) received first-line MTX and the remaining 12 (17.2%) received first-line ActD. First-line MTX showed a response rate of 48.2% compared to 50% in first-line ActD (P = 0.913). Of those who received first-line MTX, 31 patients (53.4%) received an 8-day regimen of MTX/FA, and the remaining 27 patients (46.6%) received weekly MTX, the response rate to 8 days and weekly regimen was 51.6% and 44.4%, respectively (P = 0.586). The overall response rate to first-line single-agent chemotherapy was 48.5%.

Out of 70 patients who received first-line single-agent chemotherapy, 34 patients (48.5%) required second-line chemotherapy, 18 patients were given ActD after the failure of MTX with a response rate of 72.2%, 16 patients received second-line EMA-CO (10 patients after failure of MTX and 6 after the failure of ActD). The response rate to second-line EMA-CO was 75%. Only seven low-risk score patients' required third-line chemotherapy, five patients received EMA-CO after the failure of MTX and ActD; the remaining two patients had salvage chemotherapy (BEP and EP-EMA) after the failure of EMA-CO. All of the seven patients showed complete remission to third-line chemotherapy [Figure 1].
Figure 1: Flowchart showing the disposition of the patients MTX: methotrexate; ACT: actinomycin D; EMA-CO: etoposide-methotrexate, actinomycin D, cyclophosphamide, vincristine; TP/TE: taxane alternating with cisplatin and etoposide; EP-EMA: etoposide, cisplatin, methotrexate, Act D; BEP: bleomycin, etoposide, cisplatin; CR: complete remission

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In high-risk GTN, out of 16 patients, only 12 patients (75%) received chemotherapy (as two patients underwent hysterectomy without subsequent bHCG elevation, one patient lost follow-up, and the remaining patient died on the day of presentation). Ten (83.3%) patients received first-line EMA-CO and two patients (16.7%) received EP-EMA, one of the two patients who received EP-EMA was at ultra-high risk with a total score of 17 and died shortly after the start of chemotherapy.

Four patients required salvage second-line multiagent chemotherapy, two patients received TP/TE, while the remaining two patients received paclitaxel/gemcitabine and BEP, respectively, with two patients achieved complete remission, one after TP/TE and the other after paclitaxel/gemcitabine, one patient underwent salvage hysterectomy after failure of second-line TP/TE. Only one patient received third-line TP/TE, unfortunately, this patient did not respond and died from disease progression.

All low and high-risk patients who achieved complete remission after chemotherapy received consolidation. The majority (80%) 60 patients received two cycles while six (8%) and nine (12%) patients received one cycle and three cycles, respectively. With a median follow-up of 30.6 months (range 1.3–103 months), all the patients who achieved complete remission remained event-free (no deaths, relapses nor secondary malignancies) till their last follow-up date.

In our study, factors that adversely affected complete response to first-line chemotherapy in low-risk patients were bHCG ≥10000, presence of metastasis, WHO score 5–6 and FIGO stage III/IV. Univariate analysis of different prognostic variables is listed in [Table 2].
Table 2: Univariate analysis of prognostic factors and the corresponding response rates to first line single agent chemotherapy in low risk patients

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As shown in [Figure 2], the 5-year OS of the total population was 96.9%. According to FIGO staging, the 5-year OS was 100%, 83.3%, and 60% for stages I, III, and IV respectively, [Figure 3]. Low-risk patients had significantly better OS compared to high risk (100% vs 79.3%) respectively (P value <0.001), [Figure 4].
Figure 2: Kaplan-Meier curve of overall survival of whole patients

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Figure 3: Kaplan-Meier curve of overall survival according to International Federation of Gynecology and Obstetrics (FIGO) staging of whole patients

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Figure 4: Kaplan-Meier curve of overall survival according to WHO risk score

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As regards fertility, 67 patients were evaluable for assessment (excluding three dead patients, 23 patients who underwent a hysterectomy and 18 patients with a follow-up interval of less than 1 year), 40 patients (60%) delivered healthy babies. There were no abnormal pregnancies or any unhealthy babies.


  Discussion Top


The main objective of our study was to describe the clinical profile, management, and treatment outcome among patients with GTN treated at NEMROCK during the period from 2008 to 2017. GTN is considered a rare disease, in the present study, a total of 111 patients over a 9-year period were included.

The mean age in our study was 29 years which is slightly lower than those reported by Batti et al.[5] Increased BMI has been associated with poor outcomes compared with normal weight in gynecological malignancies especially ovarian, endometrial, and cervical cancer.[6] In our series, about 60% of patients were overweight/obese, however, with no difference in response, the same findings were observed by Maesta et al.[7] in low-risk GTN patients, therefore, the American Society of Clinical Oncology (ASCO) guidelines recommend that full weight-based cytotoxic chemotherapy doses to be used to treat obese patients with cancer, particularly when the goal of treatment is cure, there is no evidence that short-term or long-term toxicity is increased among obese patients receiving full weight-based doses.[8]

Low-risk GTN is usually treated by single-agent chemotherapy, either MTX-FA or ActD, however, there is no consensus regarding the best single treatment. Some retrospective and non-randomized studies with variation in doses, schedules, and criteria to select patients have shown a 50–90% complete remission (CR) rates. The Cochrane review in 2016 including seven randomized controlled trials that included 667 women concluded that ActD is probably more likely to achieve a primary cure in women with low-risk GTN, and less likely to cause treatment failure compared to MTX regimen. There might be a little or no difference between the pulsed ActD regimen and the MTX regimen as regards to side effects. However, ActD may be associated with a greater risk of severe adverse events than the MTX regimen.[9] In our series, comparable response rate was observed between MTX and ActD (48.2% vs 50%, respectively; P = 0.913). Those who received MTX-FA 8-day regimen had a higher response rate compared to a weekly schedule, however, with no significant difference (51.6% vs 44.4%, respectively; P = 0.586).

Current National Comprehensive Cancer Network (NCCN) guidelines (Version 1.2019) do not recommend weekly MTX due to lesser efficacy.

Patients with low-risk GTN who failed on first-line MTX can switch to ActD and vice versa. Retrospective studies have shown that switch to single-agent ActD after MTX gives a response rate of 76–87%.[1],[10] All patients can achieve CR regardless of whether they need to receive second or sometimes, third-line treatment. In the present study, all low-risk patients who failed MTX or ActD (except three cases who had a hysterectomy) achieved sustained CR with subsequent chemotherapy.

Factors that predict resistance to single-agent chemotherapy in low-risk GTN include high WHO prognostic score, high pretreatment bHCG levels, non-molar antecedent pregnancy, and histopathological diagnosis of choriocarcinoma.[11],[12] In the present study, high bHCG >10.000, prior unsuccessful chemotherapy, and FIGO stages III and IV were significantly had a lower response rate. In addition, patients with WHO score 5–6 had significantly lower CR rate compared to patients with score <5, (28% and 60%, respectively; P = 0.01), these patients represent “gray zone” between low and high-risk score, for whom the single-agent chemotherapy unlikely to achieve a cure,[13] lowering the threshold for the use of multiple-agent chemotherapy in these otherwise low-risk patients can be considered.[14]

With respect to high-risk GTN, Deng et al.[15] conducted a systematic review of chemotherapy and they were unable to draw any firm conclusions about the best primary treatment regimen. However, EMA/CO is the most widely used regimen, despite that 30–40% of patients will develop resistance or relapse after remission and need salvage chemotherapy.[16],[17] Platinum-etoposide combinations, particularly EMA/EP, have been favored as salvage therapy, alternatives, including TP/TE or BEP could be used in view of the absence of randomized trials between those regimens. In the presented study, we observed low numbers of high-risk patients compared to low risk, EMA-CO was the most commonly used chemotherapy regimen and resulted in 70% complete remission rate, 5 years overall survival was significantly lower than low-risk patients (79.3% vs 100%, respectively; P = < 0.001), comparable survival rate was reported in another Egyptian study.[18]

With a median follow-up of 30.6 months (range 1.3–103 months), there was no relapse among the whole group of patients, very low rates of relapse have been reported in the literature.[13],[19]

In our series, no patients developed secondary malignancy; however, further assessment is required to evaluate long-term risks. Late effects of chemotherapy have been remarkably rare; most of this risk appears to occur if combination chemotherapy is continued beyond 6 months. Interestingly, recent data show that when using EMA/CO, there is no overall increased risk of second malignancy, however, there was evidence of an increased risk of leukemia.[20]

Fortunately, apart from EMA/CO hastens menopause by 3 years, fertility is not otherwise compromised, with 83% of women becoming pregnant after either single-agent MTX/FA or multi-agent EMA/CO regimen.[1] In our series, 60% of patients had a subsequent normal pregnancy with healthy babies, only one patient had intrauterine fetal death.

Our results should be interpreted with caution; some limitations to the present study deserve to be mentioned, given a small number of patients, missing information, incomplete documentation which influences proper risk stratification. Also, the retrospective nature of the study makes further generalization very difficult.

Accordingly, we recommend the following:

1- Management of GTN should be performed in centers with experience in treating this kind of disease

2- Multidisciplinary meeting between gynecology and clinical oncology departments for better documentation of incidence of GTN cases, proper selection of cases, accurate risk stratification, rapid referral of those who required chemotherapy and initiation of research projects

3- Appropriate measures to avoid missing data in the patient's files should be undertaken with frequent auditing

4- Psychological support, especially for nullipara patients, is highly recommended for reassuring that further normal pregnancy can safely be achieved after ending chemotherapy

5- Being a rare disease, prospective studies should be done at a multi-institutional level for better determination of the best treatment protocol in our patients.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Seckl MJ, Sebire NJ, Berkowitz RS. Gestational trophoblastic disease. Lancet 2010;376:717-29.  Back to cited text no. 1
    
2.
Hertz R, Li MC, Spencer DB. Effect of methotrexate therapy upon choriocarcinoma and chorioadenoma. Proc Soc Exp Biol Med 1956;93:361-6.  Back to cited text no. 2
    
3.
Newlands ES, Bagshawe KD, Begent RH, Rustin GJ, Holden L. Results with the EMA/CO (etoposide, methotrexate, actinomycin D, cyclophosphamide, vincristine) regimen in high risk gestational trophoblastic tumours, 1979 to 1989. Br J Obstet Gynaecol 1991;98:550-7.  Back to cited text no. 3
    
4.
Ngan HY, Bender H, Benedet JL, Jones H, Montruccoli GC, Pecorelli S. FIGO committee on gynecologic oncology. Gestational trophoblastic neoplasia, FIGO 2000 staging and classification. Int J Gynaecol Obstet 2003;83:175-7.  Back to cited text no. 4
    
5.
Batti R, Mokrani A, Rachdi H, Raies H, Touhami O, Ayadi M, et al. Gestational trophoblastic neoplasia: Experience at Salah Azaiez Institute. Pan Afr Med J 2019;33:121.  Back to cited text no. 5
    
6.
Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med 2003;348:1625-38.  Back to cited text no. 6
    
7.
Maesta I, Horowitz NS, Goldstein DP, Bernstein MR, Ramírez LA, Moulder J, et al. Response to chemotherapy in overweight/obese patients with low-risk gestational trophoblastic neoplasia. Int J Gynecol Cancer 2015;25:734-40.  Back to cited text no. 7
    
8.
Griggs JJ, Mangu PB, Anderson H, Balaban EP, Dignam JJ, Hryniuk WM, et al. Appropriate chemotherapy dosing for obese adult patients with cancer: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol 2012;30:1553-61.  Back to cited text no. 8
    
9.
Lawrie TA, Alazzam M, Tidy J, Hancock BW, Osborne R. First-line chemotherapy in low-risk gestational trophoblastic neoplasia. Cochrane Database Syst Rev 2016:CD007102.   Back to cited text no. 9
    
10.
Prouvot C, Golfier F, Massardier J, You B, Lotz JP, Patrier S, et al. Efficacy and safety of second-line5-day dactinomycin in case of methotrexate failure for gestational trophoblastic neoplasia. Int J Gynecol Cancer 2018;28:1038-44.  Back to cited text no. 10
    
11.
Kwon JS, Elit L, Mazurka J, Moens F, Schmuck ML. Weekly intravenous methotrexate with folinic acid for non-metastatic gestational trophoblastic neoplasia. Gynecol Oncol 2001;82:367-70.  Back to cited text no. 11
    
12.
Taylor F, Short D, Winter MC, Tidy J, Savage PM, Sarwar N, et al. Aretrospective study to evaluate single agent methotrexate treatment in low risk gestational choriocarcinoma in the United Kingdom. Gynecol Oncol 2015;136:258-63.  Back to cited text no. 12
    
13.
Lumsden SA, Short D, Lindsay I, Sebire NJ, Adjogatse D, Seckl MJ, et al. Treatment outcomes for 618 women with gestational trophoblastic tumors following a molar pregnancy at the Charing Cross Hospital, 2000-2009. Br J Cancer 2012;107:1810-4.  Back to cited text no. 13
    
14.
Ngan H, Seckl M, Ross S, Berkowitz RS, Xiang Y, Golfier F, et al. FIGO CANCER REPORT 2018 Update on the diagnosis and management of gestational trophoblastic disease. Int J Gynaecol Obstet 2018;143 Suppl 2:79-85.  Back to cited text no. 14
    
15.
Deng L, Yan X, Zhang J, Wu T. Combination chemotherapy for high-risk gestational trophoblastic tumour. Cochrane Database Syst Rev 2009; CD005196.   Back to cited text no. 15
    
16.
Lurain JR. Gestational trophoblastic disease II: Classification and management of gestational trophoblastic neoplasia. Am J Obstet Gynecol 2011;204:11-8.  Back to cited text no. 16
    
17.
Goldstein DP, Berkowitz RS. Current management of gestational trophoblastic neoplasia. Hematol Oncol Clin North Am 2012;26:111-31.  Back to cited text no. 17
    
18.
El-Lamie IK, El Sayed HM, Badawei AG, Bayomi WA, El-Ghazaly HA, Khalaf-Allah AE, et al. Evolution of treatment of high-risk metastatic gestational trophoblastic tumors: Ain Shams University experience. Int J Gynecol Cancer 2006;16:866-74.  Back to cited text no. 18
    
19.
Ngan HY, Tam KF, Lam KW, Chan KK. Relapsed gestational trophoblastic neoplasia: A 20-year experience. J Reprod Med 2006;51:829-34.  Back to cited text no. 19
    
20.
Savage P, Cooke R, O'Nions J, Krell J, Kwan A, Camarata M, et al. Effects of single-agent and combination chemotherapy for gestational trophoblastic tumors on risks of second malignancy and early menopause. J Clin Oncol 2015;33:472-8.  Back to cited text no. 20
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]
 
 
    Tables

  [Table 1], [Table 2]



 

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