Case Conference July 31st 2019

31-Jul-2019, Divisi Ginekologi Onkologi RSCM

Mrs. LR, 19 yo, G2P0A1, MR 4302598

Pregnancy rate after Methotrexate administration for reproductive age patient

PPDS: Elizabeth Dian Novita (T3B, Oncology Rotation)

Supervisor: dr. Kartiwa Hadi Nuryanto, OBGYN(C)

 

CASE DESCRIPTION

Mrs LR, 19 years old, had received suction curretage of her first pregnancy due to hydatidiform mole at Adjidarmo Rangkasbitung in October 2018 with blood beta HCG level: 49899 mIU/ml and PA result: partial hydatidiform mole. Patient then came to Jakarta and had vaginal bleeding in December 2018. Patient was admitted in Budi Kemuliaan Hospital for blood transfusion due to anemia ec vaginal bleeding (Hb 7,9 g/dl). We found fundal height ½ symphysis – umbilical from the physical examination. Patient was referred to RSCM for further management.

 

In RSCM, ultrasound examination indicated vesicular mass sized 17x10 mm at anterior corpus and 22x12 mm at posterior corpus with unclear margin correspons to gestational trophoblastic disease and uterus sized 10,7x6.85x7.18 cm. Laboratorium results were blood beta HCG level 30536 mIU/ml, TSH 1.8 and FT4 0.75. Patient had normal thorax x-ray. SO patient had FIGO score: 4 (low risk). Patient was planned to have MTX chemotheraphy dose 0.4 mg/kg (20 mg) intramuscularly for 5 days every 2 weeks. Patient didn’t have any menstrual period during chemotherapy. Patient had the last chemotherapy on April 12^th, 2019 and then patient had 2 times menstrual periods before getting pregnant. The patient’s LMP was May 28, 2019 and her blood beta HCG level: 4457 mIU/ml. Ultrasound examination on June 25, 2019 indicated intrauterine singleton pregnancy of 4 gestational weeks. Patient was neither using nor given education of contraception method.

 

Table of Patient’s timeline

 

 

Past illness

Patient already performed curettage due to molar pregnancy and had MTX chemotheraphy

General state

Within normal limit

Gyne exams:

I : v/u within normal limit

Io : Smooth portio, closed external ostium, flour (-), fluxus (-)

Supporting data

1.             Hystopathology result (Oct 30^th 2018) : partial hydatidiform mole

2.             Thorax x-ray within normal limit

3.             US exam (08/01/2019)

Uterus was anteflexed, normal shape, enlarged. Vesicular masses, unregular margin, sized 17x10 mm and 22x12 mm at anterior and posterior corpus correspond to gestational trophoblastic disease mass.

No abnormal mass in uterine cavity.

Basalis stratum endometrium was regular, thickness: 4 mm.

Endoserviks and portio within normal limit.

Both of ovaries within normal limit. Right ovary consist of lutein corpus.

No abnormal adnexa mass.

Liver and kidneys were normal. No ascites.

Conclusion : Gestational trophoblastic disease mass (as same size as the last US exam)

 

 

  

 

 

 

4.             US exam (25/06/2019)

Uterus was anteflexed. Uterine cavity was filled by gestational sac which there wasn’t found fetal echo inside, correspond to 4 weeks gestational age. There wasn’t found active extracavity mass. Endoserviks and portio within normal limit. Both of ovaries within normal limit. There wasn’t found parailiac lymphadenopathy enlargement. Liver and kidneys were normal.

Conclusion : Pregnancy of 4 weeks gestational age. There wasn’t found active extracavity mass.

 

 

 

5.             US exam (09/07/2019)

Uterus was enlarged, homogen myometrium. Uterine cavity was filled by gestational sac which there was fetal inside with CRL 9,3 mm and YS 4,5 mm, correspond to 7 weeks gestational age. Fetal heart rate positive. Endoserviks and portio within normal limit. Both of ovaries within normal limit. There wasn’t found abnormal adnexa mass.

Conclusion : Pregnancy of  7 weeks gestational age.

 

            

 

 

 

 

 

INTRODUCTION

Gestational trophoblastic disease is a group of placental disorders that include hydatidiform mole, invasive mole, choriocarcinoma, placental site trophoblastic tumor and epithelioid trophoblastic tumor. Hydatidiform mole is the most common form of trophoblastic disease, and is considered a benign condition that may develop into other malignant forms, referred indistinctly as gestational trophoblastic neoplasia. ¹  The incidence of hydatidiform mole varies in different populations, affecting 1:1,000 pregnancies in Europe and the United States, while in Asian countries the incidence may reach up to two cases in every 1,000 pregnancies. ² Incidence is higher at both ends of the reproductive spectrum, ie, in women younger than 15 and older than 45.³

Chemotherapy is the treatment of choice for gestational trophoblastic neoplasia and the option between single- and multiple-agent chemotherapy is based on the International Federation of Gynecology and Obstetrics (FIGO) prognostic score.  Women scoring <7 are classified as low-risk and are generally treated with single-agent chemotherapy, usually methotrexate or actinomycin-D, with an overall cure rate of nearly 100%. High-risk disease is usually treated with a chemotherapy regimen comprising etoposide, methotrexate, actinomycin-D, cyclophosphamide, and vincristine. For resistant or relapsing disease, secondline chemotherapy consisting of paclitaxel/etoposide alternating with paclitaxel/cisplatin or bleomycin has been used. More than 90% of patients with trophoblastic neoplasia undergo successful treatment with chemotherapy. Thus, an additional concern is related to their reproductive future,  a high proportion of women express the desire to conceive post-chemotherapy. ⁴

 

CLINICAL QUESTION

 

What question did the study ask?	PICO Analysis
Patients	Reproductive age patient
Intervention	methotrexate
Comparison	Gestational trophoblastic neoplasia management
Outcome	Pregnancy

 

METHODS

Search strategy

The search was conducted on Pubmed and Science Direct on July 27^th, 2019 and keywords were used: ‘reproductive age’, ‘methotrexate’, ‘gestational trophoblastic neoplasia’, ‘pregnancy’.

Search results were filtered by the engine according to the following criteria: articles published in five years and English language with human population, and  the inclusion criteria consisted of the following: reproductive age patient got methotrexate; studies on comparison with patient who got gestational trophoblastic management; reported data concerning pregnancy rate.

 

Figure 1. Flowchart of search strategy

 

 

SELECTION

The titles of the filtered results from Pubmed, and science direct host were screened using the inclusion criteria. A second screening was conducted by reading the abstract, and read for one full text article.

 

 

CRITICAL APPRAISAL

	Questions	Remark
Validity	·      Is the study relevant to the needs of the Project? ·      Does the paper address a clearly focused issue? ·       Have the authors reflected the current state of knowledge according to an unbiased review of the literature? ·      Is the choice of study method appropriate? ·      Is the population studied appropriate? ·      Is confounding and bias considered? ·      Was Follow up for long enough?	Yes   Yes   Yes       Yes   Yes   Yes      Yes
Importancy	What were the results?	In the first study, A total of 27 studies were included in the analysis. The median age ranged between 25.5 and 33.1 years. The pregnancy rateamong women with a desire to conceive, comprising a total of 1329 women and 1192 pregnancies, was 86.7% (95% CI 80.8% to 91.6%). In the second study,  In group A, 57.1% became pregnant; in group B, 36.4% did (P  = 0.060). Instead, pregnancy rate was 52.2% among high-risk patients not undergoing hysterectomy (57.1% vs 52.2%, P  = 0.449).  In a multivariate analysis that included age, International Federation of Gynecology and Obstetrics score, chemotherapy type, previous pregnancies, and pregnancy desire, only age (P  = 0.006) and pregnancy desire (P  = 0.002) had a significant impact on the probability to have subsequent pregnancies.
Applicability	Will the results help me in caring for my patient?	Yes

 

 

 

 

 

DISCUSSION

In first study, assessed the pregnancy rate after chemotherapy, accounting for 3764 women and 3846 pregnancies. The pooled proportion was 67.42% (95% CI 48.2% to 83.9%) with substantial inter-study heterogeneity. (I2=99.25%, p<0.0001; online supplementary Figure 1A). The pooled proportion from six studies assessing the pregnancy rate among women with a desire to conceive, comprising a total of 1329 women and 1192 pregnancies, was 86.7% (95% CI 80.8% to 91.6%) with high inter-study heterogeneity (I2=82.62%, p<0.0001). ⁵

 

We demonstrated that nearly seven out of 10 women will conceive following chemotherapy treatment for gestational trophoblastic neoplasia. Notably, nearly nine out of 10 women with a desire for childbearing will get pregnant. The loss of primordial follicles caused by chemotherapy may theoretically result in decreased ovarian reserve. A proportion of women may thus experience a period of anovulation. Nonetheless, the vast majority of patients maintain a normal menstrual cycle through treatment or recover normal menstrual function without fertility compromise. Of note, the recent MITO-9 study demonstrated a non-significant difference in pregnancy rate between the single- and multi-agent chemotherapy groups in women with a desire for pregnancy. ⁵

 

 

In the entire population, 36 (48%) of 75 patients had 1 or more pregnancies after the completion of chemotherapy and follow-up. Pregnancy rates in patients wishing to conceive were 76.7% in group A and 64.7% in group B (P  = 0.500). Patients with a diagnosis of nonmolar GTN did not have aworse pregnancy rate compared with patients with a molar GTN (7/18 [38.9%] vs 29/57 [50.9%], P  = 0.269). The pregnancy rate of the entire population was 48%. Among patients who actually wished to conceive, pregnancy rate was 75.5%. This result underlines the importance of including a supportive care component in the clinical management of these women: this would help patients develop a more positive mental representation of illness and avoid quality of life and relationship disruption.  Multivariate analysis showed that the desire for pregnancy had a significant impact on the probability to attain future pregnancies (P  = 0.002). Age had a relevant impact too, as expected (P  = 0.006). The FIGO score, type of chemotherapy, and presence of previous pregnancies had no impact on pregnancy probability. ⁶

 

 

 

CONCLUSION

Nearly 90% of patients desiring future fertility after chemotherapy for gestational trophoblastic disease were able to conceive. A non-significant difference in pregnancy rate between the single- and multi-agent chemotherapy groups in women with a desire for pregnancy. ⁵ It showed that the desire for pregnancy and age had a relevant impact  on the probability to attain future pregnancies. The FIGO score, type of chemotherapy and presence of previous pregnancies had no impact on pregnancy probability. ⁶

REFERENCES

1. Berkowitz RS, Goldstein DP, Horowitz NS. Initial management of low risk gestational trophoblastic neoplasia. http://www.uptodate.com 2019
2. Goldstein DP, Berkowitz RS. Current management of gestational trophoblastic neoplasia. Hematol Oncol Clin N Am 2012; 26: 111-131

3.      New Zealand Gynaecologic Cancer Group Guidelines. Gestational Trophoblastic Disease. NZGTD 2018:1-13

4. Lazzam M,  Tidy J,  Hancock BW, et al. Subsequent pregnancy outcomes after complete and partial molar pregnancy, recurrent molar pregnancy, and gestational trophoblastic neoplasia An Update from the New England trophoblastic disease center. The Journal of Reproductive Medicine 2014;59 (5): 188-194

5.      Tranoulis A, Georgiou D, Sayasneh A, Tidy J. Gestational trophoblastic neoplasia: a meta-analysis evaluating reproductive and obstetrical outcomes after administration of chemotherapy. International Journal of Gynecology Cancer 2019; 29: 1021-1031

6. Cioffi R, Bergamini A, Gadducci A, Cormio G, et al. Reproductive outcomes after gestational trophoblastic neoplasia. A comparison between single-agent and multiagent chemotherapy Retrospective analysis from the MITO-9 Group. International Journal of Gynecological Cancer 2018;00:1021-1031

 

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