The optimal management of brain metastases from gestational trophoblastic neoplasia

ABSTRACT

Introduction

Gestational trophoblastic diseases and neoplasias (GTDs and GTNs) comprise a spectrum of diseases arising from abnormally proliferating placental/trophoblastic tissue following an antecedent molar or non-molar pregnancy. These can spread to the brain hematogenously in about 10% of patients, mostly in high-risk disease. The optimal management of patients with brain metastases from GTN is unclear, with multiple systemic regimens under use and an uncertain role for radiotherapy.

Areas covered

Here, we review the epidemiology, workup, and treatment of GTN with central nervous system (CNS) involvement. Literature searches in PubMed and Google Scholar were conducted using combinations of keywords such as ‘gestational trophoblastic disease,’ ‘gestational trophoblastic neoplasia,’ ‘choriocarcinoma,’ and ‘brain metastases.’

Expert opinion

Systemic therapy is the frontline treatment for GTN with brain metastases, and radiotherapy should only be considered in the context of a clinical trial or for resistant/recurrent disease. Surgery has a limited role in palliating symptoms or relieving intracranial pressure/bleeding. Given the highly specialized care these patients require, treatment at a high-volume referral center with multidisciplinary collaboration likely leads to better outcomes. Randomized trials should be conducted to determine the best systemic therapy option for GTN.

KEYWORDS:

• Gestational trophoblastic neoplasia
• choriocarcinoma
• brain metastases
• EMA-CO
• whole-brain radiation therapy

Article highlights

• GTNs(particularly choriocarcinomas) have apropensity for hematogenous spread and hemorrhage

• GTNcan be diagnosed after persistent elevation of hCG after pregnancy after other causes are excluded; tissue diagnosis is not necessary for treatment initiation as this may be clinically urgent

• FIGOscoring stratifies GTNs into low (<7) and highrisk(≥7) groups; scores ≥13 confers aworse prognosis; essentially all patients with brain metastases have FIGO score ≥7

• ~10% of GTN (~20% of choriocarcinoma) cases have brain metastases, the vast majority of which will have neurologic symptoms; almost all will have concomitant pulmonary or vaginal metastases

Systemic therapy

-Patients with GTN and brain metastases should be treated with multiagent chemotherapy as initial therapy -There is no randomized data to guide the choice of chemotherapy; however, we recommend EMA/CO with high-dose methotrexate (1000 mg/m²) unless on a clinical trial, as this is the most commonly used regimen internationally Induction therapy with low-dose EP prior to EMA-CO should be considered for patients with FIGO score ≥13 -Randomized clinical trials should be conducted to compare the efficacy of different chemotherapy regimens for high-risk (FIGO ≥7) GTN (with and without brain metastases) -In the relapsed/refractory setting, patients should be enrolled on clinical trials if available; there is no good data to guide a choice of salvage chemotherapy, and targeted biologic therapies such as immune checkpoint inhibitors can be considered

Radiation therapy

-Guidelines from major international groups differ on their recommendations for whole-brain radiotherapy (WBRT) and stereotactic radiosurgery (SRS) -We do not recommend WBRT or SRS as part of initial management for GTN with brain metastases when multiagent chemotherapy (e.g. EMA-CO) is available -WBRT and/or SRS can be considered for persistent/recurrent disease despite multiagent chemotherapy or for patients who cannot tolerate multiagent chemotherapy (though see above for options such as immunotherapy) -WBRT and/or SRS can also be considered in a palliative setting for symptom management -When possible, WBRT should be performed with hippocampal sparing technique

Conflict of interest

M Foote has received honorarium and research support from Elekta AB and is a Consultant to Varian. A Sahgal has served as an advisor/consultant for AbbVie, Merck, Roche, Varian (Medical Advisory Group), Elekta (Gamma Knife Icon), BrainLAB, and VieCure (Medical Advisory Board); served as a Board Member for: International Stereotactic Radiosurgery Society (ISRS); Co-Chair: AO Spine Knowledge Forum Tumor; Past educational seminars with Elekta AB, Accuray Inc., Varian (CNS Teaching Faculty), BrainLAB, Medtronic Kyphon; has received a research grant from Elekta AB; has received travel/ accommodation expenses from Elekta, Varian, BrainLAB; has been a member of the Elekta MR Linac Research Consortium, Elekta Spine, Oligometastases and Linac Based SRS Consortia. SS Lo is a member of the Elekta Gamma Knife ICON Expert Group.

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosure

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Correction Statement

This article has been republished with minor changes. These changes do not impact the academic content of the article.

Additional information

Funding

The authors have no funding to report.