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 Table of Contents  
ORIGINAL ARTICLE
Year : 2022  |  Volume : 46  |  Issue : 4  |  Page : 147-161

Clinical characteristics, management, and outcome of gestational trophoblastic neoplasia patients with brain metastasis: A 10-year experience at the Philippine General Hospital


Division of Trophoblastic Diseases, Department of Obstetrics and Gynecology, Philippine General Hospital, University of the Philippines, Manila, Philippines

Date of Submission10-Mar-2022
Date of Acceptance24-May-2022
Date of Web Publication7-Oct-2022

Correspondence Address:
Gisele V Gonzales-Acantilado
Department of Obstetrics and Gynecology, Philippine General Hospital, University of the Philippines, Taft Avenue, Ermita, Manila 1000
Philippines
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/pjog.pjog_31_22

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  Abstract 


OBJECTIVE: This study aimed to determine the clinical characteristics, management, and outcome of gestational trophoblastic neoplasia (GTN) patients with brain metastasis.
MATERIALS AND METHODS: This was a 10-year descriptive study that included all patients with brain metastasis from GTN. Patients' sociodemographic and clinicopathological profiles were described. Using Kaplan–Meier survival curve, the survival time was determined.
RESULTS: From January 1, 2010, to December 31, 2019, there were 33 GTN patients with brain metastasis. Four were excluded from the study due to incomplete records. Twenty-nine patients were included in the study. Nineteen (65.51%) patients presented with neurologic symptoms upon diagnosis and one (3.44%) during treatment. All received etoposide, methotrexate, actinomycin, oncovin (EMACO) as first-line treatment. Five (17.24%) patients were given induction chemotherapy with low-dose etoposide–cisplatin. Seventeen (58.62%) patients underwent whole-brain radiation and two (6.89%) were given intrathecal methotrexate. Thirteen patients (44.82%) achieved biochemical remission with EMACO chemotherapy. Four patients (13.79%) had resistance to EMACO and were given Etoposide Cisplatin Etoposide Methotrexate Actinomycin (EP EMA). Four patients (13.79%) underwent an adjunctive hysterectomy. Four patients (13.79%) died during treatment. One patient (3.44%) was unable to continue her chemotherapy because she got pregnant before her first consolidation course. There were eight early deaths (<4 weeks of admission) and hence were excluded in the analysis. Three patients who went into biochemical remission relapsed on the 1st, 2nd, and 3rd months after their last consolidation course, respectively. The median follow-up time was 27 months. After excluding early deaths, the survival rate between 3 and 7 years after treatment is at 61.9%. The mean survival time was 5.43 years. Six surviving patients were contacted. Five (17.24%) of them had resumed their everyday life, and one is currently undergoing chemotherapy.
CONCLUSION: The study was able to document brain metastasis from GTN to be 14.28% (29/203) among metastatic high-risk admissions. The biochemical remission rate from first-line treatment was of 61.90% (13/21) and resistance rate was 19.04% (4/21). Lost to follow up after achieving biochemical remission was a challenge encountered.

Keywords: Brain metastasis, gestational trophoblastic neoplasia, intrathecal methotrexate, whole-brain radiation


How to cite this article:
Gonzales-Acantilado GV, Juan FS, Cagayan MS. Clinical characteristics, management, and outcome of gestational trophoblastic neoplasia patients with brain metastasis: A 10-year experience at the Philippine General Hospital. Philipp J Obstet Gynecol 2022;46:147-61

How to cite this URL:
Gonzales-Acantilado GV, Juan FS, Cagayan MS. Clinical characteristics, management, and outcome of gestational trophoblastic neoplasia patients with brain metastasis: A 10-year experience at the Philippine General Hospital. Philipp J Obstet Gynecol [serial online] 2022 [cited 2022 Dec 6];46:147-61. Available from: https://www.pogsjournal.org/text.asp?2022/46/4/147/358077




  Introduction Top


Gestational trophoblastic neoplasia (GTN) is a group of uncommon malignant gynecologic tumors arising from the trophoblast, including invasive mole, choriocarcinoma, and placental site epitheloid trophoblastic tumor.[1] This malignancy group has a remarkable sensitivity to chemotherapy, and the cure rates are almost 100% in the low-risk group and 95% in the high risk with the current chemotherapy regimen.[2],[3] However, some conditions make the prognosis of certain GTN patients poor such as those with the far advanced disease at presentation and long interval time from the time antecedent pregnancy.[4] In addition, brain metastasis is regarded as a poor prognostic factor.[5],[6] Brain metastasis from GTN is rare, with an incidence of 3% to 21.4%.[5] The survival rates of patients with brain metastasis are significantly reduced to 69.8%–71.1%.[7],[8]

Etoposide, methotrexate, actinomycin, oncovin (EMACO) chemotherapy is the first-line treatment for metastatic high-risk GTN patients. In patients with brain metastases, an increase in the methotrexate infusion to 1 g/m2 will help the drug cross the blood-brain barrier. Some centers use intrathecal methotrexate (MTX) 12.5 mg which is given during the CO part when EMACO is used or with the EP part in the.

Etoposide cisplatin, etoposide, methotrexate, actinomycin (EP/EMA) regimen. Some centers may give whole-brain radiotherapy 3000 cGy in 200 cGy daily fractions concurrent with chemotherapy use, stereotactic or gamma knife radiation to treat existing or residual brain metastases after chemotherapy.[9]

Patients with EMACO resistance are mostly salvaged with paclitaxel and Etoposide, alternating with paclitaxel and cisplatin (TE/TP) or with (EP/EMA). In China, the 5 FU-based floxuridine, actinomycin-D, etoposide vincristine (FAEV) regimen is also an effective salvage treatment. For women who have resistance from EP/EMA or TE/TP, options for treatment will include several other standards or high-dose chemotherapy regimens such as etoposide, ifosfamide, and cisplatin or carboplatin, BEP (bleomycin, etoposide, and cisplatin), 5-fluorouracil, actinomycin-D, FAEV high-dose chemotherapy with autologous bone marrow or stem cell transplant and immunotherapy with pembrolizumab can be offered after failure of salvage chemotherapy.[9]

At present, in our institution, high-dose EMACO with concomitant whole-brain radiation is the protocol being followed. Initial reports of the success of treatment in the Philippine General Hospital showed a remission rate of 35% for patients initially presenting with brain metastasis and 15% for patients who developed brain metastasis during or after initial treatment. There are, however, several factors that contribute to the lower survival rate, which include the inability to give systemic chemotherapy on time and lack of surgical intervention.[10]

Among GTN patients with brain metastasis who present with increased intracranial pressure, craniotomy is indicated for central nervous system (CNS) decompression and stabilization. Isolated nodules resistant to drug treatment are excised and this therapeutic regimen results in primary remission of 65% to 80% of and up to 90% cure.[11]

General objective

To determine the clinical outcome of GTN patients with brain metastasis managed at the Philippine General Hospital from January 1, 2010, to December 31, 2019.

Specific objective

  1. To determine the incidence of GTN with brain metastasis patients admitted and managed at the Philippine General Hospital from January 1, 2010 to December 31, 2019
  2. To describe the clinical profile of GTN patients with brain metastasis patients in terms of age, antecedent pregnancy, interval months from the index of pregnancy, pretreatment serum beta human chorionic gonadotropin (hCG) (mIU/mL), largest tumor size, site of several metastasis per site previously failed chemotherapy, histopathology diagnosis if applicable, WHO score, International Federation of Gynecology and Obstetrics (FIGO) stage, neurologic symptoms and size and location ofbrain metastasis
  3. To determine the different treatment modalities used either high-dose methotrexate with concomitant whole-brain radiation or MTX and utilization of induction chemotherapy
  4. To describe the treatment response of the managed patients as to:


    1. Mean number of cycles of the first-line chemotherapy before biochemical remission or resistance
    2. Number of patients who had biochemical remission or resistance to the first-line chemotherapy
    3. Number of patients who had toxicities and adverse reactions encountered during chemotherapy
    4. Number of patients who needed adjunctive procedures
    5. Number of patients who needed salvage chemotherapy
    6. Number of patients who died during and or after treatment
    7. Survival time of the patients included in the study.



  Materials and Methods Top


Study design

This was a descriptive study that was approved by the Institutional Review Board, University of the Philippines Manila Research Ethics Board.

Patient population

Inclusion criteria

This study included all GTN patients who had brain metastasis admitted at the Philippine General Hospital from January 1, 2010 to December 31, 2019.

Exclusion criteria

Patients diagnosed with double primary malignancy, those with a histologic diagnosis of placental site trophoblastic tumor or epithelioid trophoblastic tumor, as well as those with the incomplete clinical record were excluded from the study [Figure 1].
Figure 1: Patient selection, management, and outcome flowchart

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Description of the study procedure

A review of the ward reports of the division of Trophoblastic Diseases of the Department of Obstetrics and Gynecology of the Philippine General Hospital from January 1, 2010, to December 31, 2019, was done to identify GTN patients with brain metastasis. The medical records of eligible patients were retrieved and assessed. Only the data pertinent to the study's specific objectives were abstracted from the medical records and recorded in a patient data form. The following data were extracted:

  1. Age
  2. Antecedent pregnancy
  3. Interval months from the index of pregnancy
  4. Pretreatment serum beta hCG (mIU/mL)
  5. Largest tumor size
  6. Site of number of metastasis
  7. Previously failed chemotherapy
  8. Histopathology diagnosis, if applicable
  9. WHO score
  10. FIGO stage
  11. Neurologic presentation
  12. Administration of high-dose methotrexate with concomitant whole-brain radiation or MTX
  13. Number of cycles of the first-line chemotherapy before biochemical remission or resistance
  14. Biochemical remission or resistance to the first-line chemotherapy
  15. Toxicities and adverse effects encountered during chemotherapy
  16. Administration of induction chemotherapy
  17. Adjunctive surgery done
  18. Need for salvage chemotherapy
  19. Identify the salvage chemotherapy used
  20. Death or who were lost to follow-up
  21. Date of the last consult.


To determine the survival time, date of the diagnosis of the disease, date of first chemotherapy administration and the date of the last recorded consult was obtained. To assess the patient outcome, survivors were contacted through phone or social media in the first half of 2021.

Description of outcome measurements

The primary outcome measure was the survival time which was determined using the Kaplan–Meier survival curve. The biochemical remission rate to first-line chemotherapy was also noted. Biochemical remission is defined as three consecutive normal serum beta hCG levels (≤5 miU/mL). On the other hand, resistance is defined as 2 plateauing values, 1 rising weekly beta hCG titer, or the appearance of new metastasis. Upon completion of chemotherapy, radiographic evidence of residual tumor was not considered evidence of disease as long as the beta hCG level remained <5 mIU/mL. Secondary outcomes included the resistance rate, causes of death, toxicities brought about by administering the various chemotherapeutic regimens, and functional outcomes among patients who have achieved biochemical remission. Toxicities were categorized using the WHO toxicity scoring system [Table 1].
Table 1: WHO common toxicity criteria grading

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Data analysis

Descriptive statistics was used to summarize the demographic and clinical characteristics of the sample population. The survival time was determined using Kaplan–Meier survival curve.


  Results Top


From January 1, 2010, to December 31, 2019, a total of 203 patients with metastatic, high-risk GTN were managed at the division of Trophoblastic Diseases, Department of Obstetrics and Gynecology of the Philippine General Hospital. Of these metastatic high-risk GTN, thirty-three (16.25%) patients had brain metastasis. Among these, four patients were excluded due to incomplete data. There were 29 patients included in the study, 21 of which were managed for at least 1 month, and 8 died in <4 weeks of admission.

Clinical characteristics of gestational trophoblastic neoplasia patients with brain metastasis

Twenty-six patients had a FIGO stage of IV, one patient had a FIGO stage of III who had tumor progression to the brain, and two patients had a FIGO stage of I who had tumor recurrence to the brain. Twenty-six patients had a WHO prognostic score of ≥12, two have ≥7, and one had 3 (A case of tumor recurrence 10 years after remission from her low-risk GTN).

[Table 2] shows the clinical characteristics of the 29 patients included in the study. The patients' age ranged from 17 to 52 years old. 79.31% (23/29) were <40 years old, while 20.68% (6/29) were >40 years old. The hydatidiform mole was the antecedent pregnancy in 58.62% (17/29) patients, 34.48% (10/29) for term pregnancy, and 6.89% (2/29) for abortion. The interval from the index pregnancy to the diagnosis of GTN was more than 12 months in 58.62% (17/29) of patients, seven to 12 months in 10.34% (3/29), 4 to 6 months in 17.24% (5/29), and 13.79% (4/29) in <4 months. The pretreatment serum beta hCG in mIU/mL was ≥100,000 in 66.69% (20/29), 10,000 to <100,000 in 27.58% (8/29), and <1,000 in 3.44% (1/29). The largest tumor size was greater or equal than 5 centimeters in 58.62% (17/29), 3–4 centimeters in 31.03% (9/29), and <3 centimeters in 10.34% (3/29). Lung metastasis was observed in 100% of the patients (29/29), liver metastasis in 24.13% (7/29), vaginal metastasis in 17.24% (5/29), kidney metastasis in 17.24% (5/29), splenic metastasis in 10.34% (3/29), vaginal stump metastasis in 6.89% (2/29), and cervix, adrenal, gastrointestinal, and spine metastasis in 3.44% (1/29). 31.03% (9/29) had a number of metastasis of 1–4, 17.24% (5/29) had 5–8, and 48.27% (14/29) had metastases of more than 8. Previously failed chemotherapy drugs in the form of methotrexate were present in 17.24% (5/29). Nineteen (65.51%) patients had neurological symptoms upon diagnosis, one (3.44%) had neurological symptoms during management, and nine (31.03%) patients had no neurological symptoms.
Table 2: Clinical characteristics of the twenty-nine patients included in the study

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Fifteen (51.72%) patients had single brain metastasis, four (13.79%) had two, three (10.34) had three, one (3.44%) had 5, and four (13.79%) were reported to have multiple lesions. The location for brain metastasis was known in 27 patients, and 2 were not identifiable due to a massive hemorrhage. The location of the brain metastasis was as follows: parietal (n = 6), frontal (n = 4), occiput (n = 3), temporal (n = 1), frontotemporal (n = 1), frontoparietal (n = 1), frontal and parietal (n = 3), cerebral and cerebellar (n = 1), parietal and occipital (n = 2), parietal, posterior, and occiput (n = 1), frontal and medial (n = 1), frontoparietal, frontal, and thalamus (n = 1), parietal and superior sagittal sinus (n = 1), and lateral ventricle (n = 1). The size of brain metastasis ranged from 0.2 cm to 4.0 cm.

Management and outcome of gestational trophoblastic neoplasia patients with brain metastasis

Twenty-one patients were managed for at least 1 month and all received EMACO as first-line chemotherapy [Table 3]. Seventeen (58.62%) patients underwent whole-brain radiation and 2 (6.89%) were given MTX. Five (17.24%) patients were given induction chemotherapy with low-dose etoposide–cisplatin. Thirteen patients (44.82%) achieved biochemical remission. The chemotherapy cycles ranged from 6 to 10 cycles before achieving biochemical remission. The most common toxicities from EMACO chemotherapy [Table 4] were infections of 76.19% (16/21), hypokalemia of 66.66% (14/21), and anemia grade 2–4 of 61.90% (13/21). Nine out of nineteen (47.36%) patients who had with neurological symptoms upon diagnosis achieved biochemical remission. One patient who had neurological symptom during the course of treatment was given palliative care. Four out of nine (44.44%) patients who had no neurological symptoms achieved biochemical remission.
Table 3: Characteristics, treatment, and outcome of twenty-one patients managed for at least 1 month

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Table 4: Toxicities/adverse effects of chemotherapy

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Four patients (19.04%) had resistance to EMACO and were given EP EMA as salvage chemotherapy. EMACO chemotherapy cycles ranged from 5 to 15 prior to resistance. One patient (25%) achieved biochemical remission. Three (75%) patients were offered palliative management secondary to multiple chemotherapy-induced toxicities, chronic tubulointerstitial nephritis with persistent febrile neutropenia MASCC 17–23 and chronic kidney disease Stage 3b. Among these, one patient had chemoresistance to EP EMA, TP TE, and BEP. She had multiple toxicities secondary to her treatment. One patient was administered EP EMA due to tumor relapse and eventually achieved biochemical remission.

Four patients (19.04%) underwent an adjunctive hysterectomy. Two (50%) had the histopathological result of choriocarcinoma, 1 (25%) had an invasive mole, and one did not have results since it was done in another hospital.

Four patients (19.04%) died during treatment. Three of which presented with neurologic symptoms upon diagnosis and all were managed for 2 months. Two patients died of cerebral hemorrhage and two patients died of pulmonary embolism.

One patient (4.76%) was not able to continue her chemotherapy because she got pregnant before her first consolidation course. Her beta hCG level at that time was 1.6 mIU/ml.

There were eight early deaths [Table 5], five among which presented with neurologic symptoms. Among the early deaths, 2 (25%) patients died during the first cycle of chemotherapy, 1 (12.5%) died after two cycles of EP induction chemotherapy and 5 (62.5%) patients died before the institution of chemotherapy. The causes of early deaths were cerebral hemorrhage in seven (87.5%) patients and gastro intestinal hemorrhage in one (1.25%) patient.
Table 5: Clinical characteristics of the eight patients who died in less than 4 weeks of admission

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Patient follow-up after treatment/discharge

One patient was admitted 11 months after biochemical remission due to seizure. Beta hCG, as well as transvaginal ultrasound, were unremarkable. Cranial computed tomography (CT) scan results showed encephalomalic changes in bilateral frontal lobes. The patient was referred to neurology and was managed as a case of acute symptomatic seizure, probably postgliotic. She was discharged improved and remained asymptomatic with normal beta hCG levels up to her last consult.

Among the patients who achieved biochemical remission with EMACO, three relapsed on the first, second, and third months after their last consolidation course [Table 6]. The patient who relapsed on the 1st month after the last consolidation course had residual focus of metastasis documented radiographically as minimally enhancing focus in the subcortical region of the right occipital lobe is measuring 0.5 cm × 0.6 cm × 0.6 cm, pelvic mass adjacent to the bifurcation of the right common iliac vessels measuring approximately 4.8 cm × 1.9 cm × 2.6 cm, splenic mass measuring 1.5 cm × 1.2 cm × 1.2 cm, left adrenal mass measuring 4.4 cm × 1.6 cm × 1.5 cm, and multiple varisized lung nodules with the largest size of 1.7 cm × 1.5 cm × 1.6 cm. She is currently undergoing chemotherapy with EMACO with a 25% reduction of etoposide, methotrexate, and actinomycin and is responding adequately. The patient who relapsed on the 2nd month after the last consolidation course had residual pulmonary mass at the right middle lung field measuring 3.1 cm × 3.0 cm and a sacral focus from S1 to S3. She was given EMACO with high-dose methotrexate. After the treatment, she was lost to follow-up for 5 months. Upon readmission, there was progression to the brain, kidneys, and mediastinum. She was given two cycles of EP induction chemotherapy, EP EMA with high-dose methotrexate with concomitant whole-brain radiation, and ten subsequent EP EMA cycles one among which was a consolidation course. The patient achieved remission. The decision to give only one consolidation course was due to multiple chemotherapy toxicities despite reduced chemotherapy doses and chemotherapy-induced chronic kidney disease. She, however, had a residual pulmonary mass at the right lateral segment of the middle lobe measuring 7 cm × 6.8 cm × 6 cm for which she was advised CT scan guided aspiration biopsy, but was unable to comply. Two months after the last chemotherapy course, the patient's serum beta hCG was 5,318.69 mIU/mL. The patient refused further treatment. Another serum beta hCG was obtained 1 month after and was 28,532.90 mIU/mL. This was the last recorded consult of the patient. Upon contacting the patient's sister, the previously advised CT scan-guided aspiration biopsy of her residual pulmonary mass was not carried out and no further medical intervention was done. The patient died at home 8 months after her last chemotherapy cycle. The patient who relapsed on the 3rd month after the last consolidation course had residual metastasis documented radiographically as a 1 cm × 1.1 cm hyperdense enhancing nodule is seen in the right parietal lobe and a fairly defined lung mass in the anterior segment of the right lower lobe measuring 5.2 cm × 4.5 cm × 5 cm. She was initially given EMACO with high-dose methotrexate and four subsequent cycles of EMACO. She had chemotherapy resistance and was administered five cycles EP EMA, three among which were consolidation courses. She eventually achieved biochemical remission. The patient was lost to follow-up after treatment.
Table 6: Survival time of the twenty-one managed patients

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One of the patients who was given palliative therapy came in as an emergency room death 7 months after administering her last chemotherapy. Upon contacting their relatives, the two other patients who were offered palliative therapy died at home 3 and 9 months respectively after their last chemotherapy cycle.

One patient was unable to continue her chemotherapy because she got pregnant before her first consolidation course. She is currently at her 35–36 weeks age of gestation. Serum beta hCG was obtained in her 32 2/7 weeks and was 3,067 mIU/mL, acceptable for her gestation age.

Six patients were contacted and 5 (83.33%) have resumed their normal everyday life. One delivered 4 months after her last consolidation course. Delivery was unremarkable, and histopathology of her placenta showed no diagnostic abnormality. One patient resumed employment, one is a homemaker, one resumed education and is in senior high school, one is currently undergoing chemotherapy, and the last patient had prenatal consults at the high-risk maternal clinic in the institution.

The median follow-up was 27 months. Mortality was observed within the 1st 3.1 years. No more death occurred after 3.1 years. The analysis showed that the mean survival time was 5.43 years with a lower bound of 3.7 years and an upper bound of 7.3 years. After excluding early deaths, the survival rate between 3 and 7 years after treatment was at 61.9% [Figure 2]. The longest survival time was 8.9 years [Table 7].
Figure 2: Kaplan-Meier survival curve

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Table 7: Survival function using Kaplan–Meier survival curve

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  Discussion Top


The study documented brain metastasis in GTN to be 14.28% (29/203), consistent with that (3%–21.4%) of previous reports in Peking Union Hospital and higher (10.44%) with that of the French Trophoblastic Disease Reference Centre. Brain metastases of GTN are highly vascular lesions, with a propensity for acute intralesional hemorrhage resulting in neurologic deterioration and early death in the course of treatment.[5],[8],[7] Since the study included patients from the recent past 10 years, it was only able to document the proportion of patients surviving between 3 and 7 years after treatment which was at 61.9% large-scale studies on the other hand would document the 5-year survival rate. French Trophoblastic Disease Reference Centre and Peking Union Medical College Hospital have a 5 year survival rate of 69.8% and 71.1% respectively.[7],[8] In a study however conducted at the Charing Cross Hospital 85% of its population were considered long term survivors.[11]

In the study, 47.36% (9/19) of patients who presented with neurologic symptoms upon diagnosis of diseases eventually achieved biochemical remission and 15.78% (3/19) died during treatment. One (5.26%) patient who presented with neurologic symptoms later in the course of treatment was offered palliative care. Four out of nine (44.44%) patients who had no neurological symptoms achieved biochemical remission. A previous study conducted in our institution reported remission in 35% (6/17) among GTN patients who had CNS symptoms on presentation and 15% (2/13) among those who developed lesions during chemotherapy or who had relapsed after initial complete or partial remission.[10] One patient presented with seizure 11 months after chemotherapy and was managed as an acute symptomatic seizure, probably postgliotic. Similarly, in a study including whole-brain radiotherapy interventions, 4 cases of hemianopia, 2 cases of hemiparesis, 2 cases of epilepsy, and an unspecified number of episodes of amnesia, headache, aphasia, and cognitive deficits, were reported.[7]

EMACO was used as the first-line chemotherapy among the patients studied. Thirteen patients achieved biochemical remission with EMACO chemotherapy documenting a biochemical remission rate of 61.90% (13/21). Four patients had resistance to EMACO documenting a resistance rate of 19.04% (4/21). In a study done by Shen et al., the EMACO regimen resulted in a complete remission rate of 67% (16/24) and the resistance rate was 33% (8/24) among ultra-high-risk patients.[12] In the study, the most common toxicities from EMACO chemotherapy were infections of 80.95% (17/21), hypokalemia of 71.42% (15/21), and anemia grade 2-4 of 71.24% (15/21). In the same study done by Shen et al., toxicities from EMACO chemotherapy were iii-iv degree neutropenia of 21.6% (36/167), anemia of 96.4% (161/167), and alopecia of 60.5% (101/167).

Five patients were given EP EMA wherein 40% (2/5) had biochemical remission and 20% (1/5) had resistance. She was given TP/TE followed by BEP from which she all had resistance. 60% (3/5) were offered palliative treatment secondary to the chemotherapy toxicities. EP-EMA regimen is the most commonly used salvage chemotherapy for patients who have chemoresistance with EMA-CO. Three studies documented EP-EMA use among metastatic high-risk GTN patients who had relapse/resistance with initial EMACO chemotherapy. Newlands et al. Documented a complete response rate of 75% (9/12) and an overall survival rate of 88% (30/34).[13] Mao et al. documented a complete response rate of 66.6% (12/18), including 82% (9/11) resistant patients and 43% (3/7) relapsed patients.[14] Lu et al. documented a complete response rate of 84.6% (11/13) in which 5 patients who had adjuvant surgery/brain irradiation. In all studies, myelosuppression was an observed side effect.[15] Following resistance to EP-EMA, no available studies recommend the following chemotherapy regimen that should be used. At present, pembrolizumab is a potential treatment option among drug-resistant GTN patients. It is monoclonal antibody that inhibits programmed cell death protein 1, which functions as a checkpoint protein to regulate various immune cells, including T cells, with potential antitumor activity.[16] Ghorani et al. reported response to pembrolizumab in 3 of the four patients drug-resistant GTN patients.[9]

Five (17.24%) patients received EP induction chemotherapy. One patient had multiple lung masses with the largest measuring 4 cm × 4 cm in the left apical region, single mass in segment VIII of the liver measuring 4.6 cm × 3.6 cm × 3.1 cm, and subcentimeter enhancing nodules are seen in both upper parietal lobes at the junction of the gray and white matter upon diagnosis. The next patient had tumor progression to the left high parietal region of the brain measuring 4 cm × 4.2 cm × 4.5 cm, mediastinum in the right mid to lower lung field measuring 7.5 cm × 7.5 cm, splenorenal region mass measuring 9 cm × 6 cm × 6.9 cm, and a pulmonary nodule on the mid lung field measuring 1.5 cm × 1.3 cm. Both achieved biochemical remission. The third patient had a mass in the left occipital lobe measuring 3.4 cm × 2.5 cm × 3.1 cm, innumerable subcentimeter nodules scattered diffusely throughout both lungs with the largest of which measured approximately 1.8 cm, a single mass at the segment II of the liver measuring 0.9 cm × 1.5 cm × 1.6 cm, a hypodense focus is noted in the spleen extending from the hilum extending into the splenic capsule and vaginal canal mass that measured 7.3 cm × 6.9 cm × 6.3 cm upon diagnosis. She expired after one cycle of EP induction chemotherapy and two cycles of EMACO chemotherapy with concurrent whole-brain radiation in the first cycle. The fourth patient had 10.2 cm × 9.5 cm lung mass seen at the right upper lobe and a cortical/subcortical right frontoparietal junction measuring 3.2 cm × 3.1 cm × 2.7 cm. She expired after one cycle of EP induction chemotherapy and one cycle of high-dose EMACO chemotherapy with concurrent whole-brain radiation. The last patient had parenchymal lesion in the left frontal lobe with approximate volume of 2.9 cc × 5.2 cc and kidney mass of 4 cm in size. She expired after two cycles of EP induction chemotherapy. All five patients presented with a high volume of disease in the critical organs, which could be at risk of hemorrhage when the full dose of EMACO chemotherapy is administered. Low-dose induction EP chemotherapy consists of etoposide 100 mg/m2 and cisplatin 20 mg/m2 on days 1 and 2, repeating weekly for one to two cycles before commencing EMA/CO. This has been used since 1994 with the rationale for a more gradual reduction in tumor volume reduces the risk of significant hemorrhage in critical organs in patients with high-volume disease. Alifrangis documented the reduction or early deaths to 0.7% (n = 1; 95% confidence interval [CI], 0.1% to 3.7%) compared with 7.2% (n = 11 of 151 patients; 95% CI, 4.1% to 12.6%) among high-risk patients whom induction chemotherapy was not administered.[17]

In the study, one patient was given only one consolidation course due to multiple chemotherapy toxicities despite reduced EP EMA chemotherapy doses and chemotherapy-induced chronic kidney disease. Consolidation chemotherapy consists of an additional three cycles for high-risk GTN given after the normal BhCG value (0–5 mIU/mL) is reached. This ensures complete eradication of all viable trophoblastic cells and minimize the risk for relapse.[18] The patient in the study relapsed 2 months after her consolidation course. She refused further treatment and eventually died.

Whole-brain irradiation gives the advantage of preventing intracranial bleeding and potentiating the effect of chemotherapy. In the study, seventeen patients were administered whole-brain radiation, eleven (64.70%) of which achieved biochemical remission. Five surviving patients who had brain radiation were contacted and reported to have no neurologic deficits. Studies that documented combined whole-brain radiotherapy with multidrug chemotherapy have reported survival rates of up to 75%. In comparison, systemic chemotherapy combined with intrathecal MTX has reported a patient survival rate between 71.5% and 85%.[7] MTX was administered in two patients. One (50%) achieved biochemical remission while one (50%) was offered palliative management. Three patients had adverse effects with radiotherapy in the study which were bilateral radiation-induced parotitis, radiation-induced otitis media, and optic atrophy.

Surgery is adjunctive in the management of GTN. It decreases the tumor load thereby decreasing the chemotherapy cycles that is needed to achieve biochemical remission. In the study, four patients underwent an adjunctive hysterectomy, two (50%) achieved biochemical remission, and two were offered palliative treatment. Indications of hysterectomy in GTN management are uterine rupture, vaginal bleeding, and resistance. Cagayan and Magallanes documented a 98.4% survival rate among 129 hysterectomies patients during GTN management.[19] Among GTN patients with brain metastasis who present with increased intracranial pressure, craniotomy is indicated for CNS decompression and stabilization. Isolated nodules resistant to drug treatment are excised, and this therapeutic regimen results in primary remission of 65% to 80% and up to 90% cure.[20]

There was note of residual tumors among the patients who had tumor relapse after the completion of chemotherapy. In a study done by Yang et al. among 187 patients who had biochemical remission, 155 (82.0%) had normal beta-hCG titer but with residual tumor in the lung or other organs. Among them, six patients with choriocarcinoma experienced progression of the disease after treatment.[21] Powles et al. however documented in a study that radiological abnormalities at the end of treatment are of no prognostic significance if the patient's β HCG levels remain normal, and excision of these lesions does not therefore seem reasonable.[22]

Five out of six (83.33%) contacted patients were documented to have resumed their everyday life. Gavanier reported sequelae in 11 of the 12 (92%) surviving patients; however, nine (75%) had resumed a normal life.[7] This positive functional outcome was also found in a study in the UK that observed that most of the patients involved had a usual quality of life several months after the end of treatment.[23]

One patient delivered 4 months after her last consolidation course. Delivery was unremarkable, and her baby did not have any congenital anomalies or malformation. Histopathological report of her placenta showed no diagnostic abnormality. One patient was not able to complete her chemotherapy cycles because she got pregnant before her first consolidation course. Tranoulis et al. had a meta-analysis evaluating reproductive and obstetrical outcomes after administration of chemotherapy among patients with GTN. The study concluded that nearly 90% of patients desiring future fertility after chemotherapy for gestational trophoblastic disease were able to conceive. In addition, adverse pregnancy outcomes were similar to that in the general population. Multi-agent chemotherapy does not seemingly increase the malformation rate.[24] The placenta is submitted for histopathology, and beta hCG is obtained 6 weeks postpartum among GTN patients who delivered because of the possibility of intraplacental choriocarcinoma. It is a rare form of GTN where in most cases were identified in the third trimester (n = 52; 84%) among asymptomatic women (n = 31; 50%) and with the macroscopically normal placenta in 29% (18/62).[25] Up to the time this paper was written, there were no reported pregnancy outcomes among GTN patients with incomplete chemotherapy.


  Conclusion Top


The study was able to document 33 (16.25%) patients with brain metastasis out of 203 metastatic high-risk GTN from January 1, 2010, to December 31, 2019. A total of 29 patients were included. Twenty-one patients were managed for at least 1 month and eight died in <1 month of admission. Thirteen patients (44.82%) achieved biochemical remission with EMACO chemotherapy. Four patients (13.79%) had resistance to EMACO and were given EP EMA. One patient was administered EP EMA due to tumor relapse. Four patients (13.79%) died during treatment and one patient (3.44%) was unable to continue her chemotherapy because she got pregnant before her first consolidation course. Three patients relapsed after biochemical remission. One achieved biochemical remission after treatment, one is currently on chemotherapy, and one died after refusing further treatment. After excluding early deaths, the survival rate between 3 and 7 years after treatment is at 61.9%. The mean survival time is 5.43 years.

Limitation of the study

Seven out of twelve patients who achieved biochemical remission were lost to follow-up. Documenting sustained remission or death among these patients could have eliminated bias making the study more valid. The study included patients from the recent past 10 years and hence was only able to document the proportion of patients surviving between 3 and 7 years after treatment. The study population was relatively small (N = 29) from the tertiary hospital chosen. Consequently, findings are not generalizable to GTN patients with brain metastasis across the country. Lastly, the study was purely descriptive and did not correlate the WHO prognostic factors with the outcome of the patients managed.

Recommendation

A stronger means of patient tracking after biochemical remission is recommended. For patients residing in provinces far from the National Capital Region, they may be referred to the nearest institution equipped with a trophoblastic specialist and a laboratory with serum beta hCG to increase the compliance of follow-up and beta hCG monitoring after achieving biochemical remission. Linkages among the different institutions are encouraged for proper referral. In the absence of a specialist in the area, telehealth in the institution is recommended.

In future studies, it is recommended that a longer time frame may be used to be able to include more patients and calculate for the 5 years survival rate among all patients who achieved biochemical remission. Similarly, correlation of the WHO prognostic factors and outcome of management can make the study more useful and relevant.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Berkowitz RS, Goldstein DP. Current advances in the management of gestational trophoblastic disease. Gynecol Oncol 2013;128:3-5.  Back to cited text no. 1
    
2.
Sita-Lumsden A, Short D, Lindsay I, Sebire NJ, Adjogatse D, Seckl MJ, et al. Treatment outcomes for 618 women with gestational trophoblastic tumours following a molar pregnancy at the charing cross hospital, 2000-2009. Br J Cancer 2012;107:1810-4.  Back to cited text no. 2
    
3.
Ngan HY, Seckl MJ, Berkowitz RS, Xiang Y, Golfier F, Sekharan PK, et al. Diagnosis and management of gestational trophoblastic disease: 2021 update. Int J Gynaecol Obstet 2021;155 Suppl 1:86-93.  Back to cited text no. 3
    
4.
Powles T, Young A, Sanitt A, Stebbing J, Short D, Bower M, et al. The significance of the time interval between antecedent pregnancy and diagnosis of high-risk gestational trophoblastic tumours. Br J Cancer 2006;95:1145-7.  Back to cited text no. 4
    
5.
Evans AC Jr., Soper JT, Clarke-Pearson DL, Berchuck A, Rodriguez GC, Hammond CB. Gestational trophoblastic disease metastatic to the central nervous system. Gynecol Oncol 1995;59:226-30.  Back to cited text no. 5
    
6.
Piura E, Piura B. Brain metastases from gestational trophoblastic neoplasia: Review of pertinent literature. Eur J Gynaecol Oncol 2014;35:359-67.  Back to cited text no. 6
    
7.
Gavanier D, Leport H, Massardier J, Abbas F, Schott AM, Hajri T, et al. Gestational trophoblastic neoplasia with brain metastasis at initial presentation: A retrospective study. Int J Clin Oncol 2019;24:153-60.  Back to cited text no. 7
    
8.
Xiao C, Yang J, Zhao J, Ren T, Feng F, Wan X, et al. Management and prognosis of patients with brain metastasis from gestational trophoblastic neoplasia: A 24-year experience in Peking union medical college hospital. BMC Cancer 2015;15:318.  Back to cited text no. 8
    
9.
Ghorani E, Kaur B, Fisher RA, Short D, Joneborg U, Carlson JW, et al. Pembrolizumab is effective for drug-resistant gestational trophoblastic neoplasia. Lancet 2017;390:2343-5.  Back to cited text no. 9
    
10.
Cagayan MS, Lu-Lasala LR. Management of gestational trophoblastic neoplasia with metastasis to the central nervous system: A 12-year review at the Philippine general hospital. J Reprod Med 2006;51:785-92.  Back to cited text no. 10
    
11.
Savage P, Kelpanides I, Tuthill M, Short D, Seckl MJ. Brain metastases in gestational trophoblast neoplasia: An update on incidence, management and outcome. Gynecol Oncol 2015;137:73-6.  Back to cited text no. 11
    
12.
Shen T, Chen LL, Qin JL, Wang XY, Cheng XD, Xie X, et al. EMA/CO regimen for chemotherapy 24 patients with ultra high-risk gestational trophoblastic neoplasia. Zhonghua Fu Chan Ke Za Zhi 2018;53:371-6.  Back to cited text no. 12
    
13.
Newlands ES, Mulholland PJ, Holden L, Seckl MJ, Rustin GJ. Etoposide and cisplatin/etoposide, methotrexate, and actinomycin D (EMA) chemotherapy for patients with high-risk gestational trophoblastic tumors refractory to EMA/cyclophosphamide and vincristine chemotherapy and patients presenting with metastatic placental site trophoblastic tumors. J Clin Oncol 2000;18:854-9.  Back to cited text no. 13
    
14.
Mao Y, Wan X, Lv W, Xie X. Relapsed or refractory gestational trophoblastic neoplasia treated with the etoposide and cisplatin/etoposide, methotrexate, and actinomycin D (EP-EMA) regimen. Int J Gynaecol Obstet 2007;98:44-7.  Back to cited text no. 14
    
15.
Lu WG, Ye F, Shen YM, Fu YF, Chen HZ, Wan XY, et al. EMA-CO chemotherapy for high-risk gestational trophoblastic neoplasia: A clinical analysis of 54 patients. Int J Gynecol Cancer 2008;18:357-62.  Back to cited text no. 15
    
16.
Wherry EJ. T cell exhaustion. Nat Immunol 2011;12:492-9.  Back to cited text no. 16
    
17.
Alifrangis C, Agarwal R, Short D, Fisher RA, Sebire NJ, Harvey R, et al. EMA/CO for high-risk gestational trophoblastic neoplasia: Good outcomes with induction low-dose etoposide-cisplatin and genetic analysis. J Clin Oncol 2013;31:280-6.  Back to cited text no. 17
    
18.
Seckl MJ, Sebire NJ, Fisher RA, Golfier F, Massuger L, Sessa C, et al. Gestational trophoblastic disease: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2013;24 Suppl 6:i39-50.  Back to cited text no. 18
    
19.
Cagayan MS, Magallanes MS. The role of adjuvant surgery in the management of gestational trophoblastic neoplasia. J Reprod Med 2008;53:513-8.  Back to cited text no. 19
    
20.
Lurain JR, Singh DK, Schink JC. Role of surgery in the management of high-risk gestational trophoblastic neoplasia. J Reprod Med 2006;51:773-6.  Back to cited text no. 20
    
21.
Yang JJ, Xiang Y, Wan XR, Yang XY. Prognosis of malignant gestational trophoblastic neoplasia: 20 years of experience. J Reprod Med 2008;53:600-7.  Back to cited text no. 21
    
22.
Powles T, Savage P, Short D, Young A, Pappin C, Seckl MJ. Residual lung lesions after completion of chemotherapy for gestational trophoblastic neoplasia: Should we operate? Br J Cancer 2006;94:51-4.  Back to cited text no. 22
    
23.
Newlands ES, Holden L, Seckl MJ, McNeish I, Strickland S, Rustin GJ. Management of brain metastases in patients with high-risk gestational trophoblastic tumors. J Reprod Med 2002;47:465-71.  Back to cited text no. 23
    
24.
Tranoulis A, Georgiou D, Sayasneh A, Tidy J. Gestational trophoblastic neoplasia: A meta-analysis evaluating reproductive and obstetrical outcomes after administration of chemotherapy. Int J Gynecol Cancer 2019;29:1021-31.  Back to cited text no. 24
    
25.
Jiao L, Ghorani E, Sebire NJ, Seckl MJ. Intraplacental choriocarcinoma: Systematic review and management guidance. Gynecol Oncol 2016;141:624-31.  Back to cited text no. 25
    


    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]



 

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