Primary brain tumors, meningiomas and brain metastases in pregnancy:
report on 27 cases and review of literature.
Magali Verheeckea,b, Michael J. Halaskac, Christianne A. Lokd, Petronella B. Ottevangere,
Robert Frusciof, Karina Dahl-Steffenseng, Wojciech Kolawah, Mina Mhallem Gziria,b, Sileny
Naeyu Hana,b, Kristel Van Calsterena,b, Frank Van den Heuveli, Steven De Vleeschouwerj,
Paul M. Clementb,k, Johannes Mentenl, Frédéric Amanta,b,*
On behalf of the ESGO Task Force ‘Cancer in Pregnancy’
a
Gynecologic Oncology, University Hospitals Leuven, Herestraat 49, 3000, Leuven,
Belgium
b
Division of Oncology, KULeuven, Herestraat 49, 3000, Leuven, Belgium
c
Department of Obstetrics and Gynecology, 2nd Medical Faculty, Charles University, Ovocný
trh 5, 11636, Prague, CZ, Czech Republic
d
Department of Gynecologic Oncology, Center Gynecologic Oncology, Plesmanlaan 121,
1066 CX, Amsterdam, The Netherlands
e
Department of Obstetrics and Gynecology, Radboud University Nijmegen Medical Centre,
Geert Grooteplein-Zuid, 10, 6525 GA, Nijmegen, The Netherlands
f
Division of Obstetrics and Gynecology, San Gerardo Hospital, University of Milan-Bicocca,
Via Pergolesi, 33, 20900, Monza, Italy (R.F.)
g
Department of Radiotherapy and Clinical Oncology, Vejle Hospital, Brummersvej, 1, DK7100, Vejle, Denmark
h
University Hospital of Krakow (Jagiellonian University), Dept. of Gynecology and
Oncology, Gołębia, 24, Kraków, Poland
i
Physics department in Radiation-Oncology, University Hospitals Leuven, Herestraat, 49,
3000, Leuven, Belgium
j
Neurosurgery, University Hospitals Leuven, Herestraat, 49, 3000, Leuven, Belgium
k
General Medical Oncology, University Hospitals Leuven, Herestraat, 49, 3000, Leuven,
Belgium (P.M.C.)
l
Radiation-Oncology, University Hospitals Leuven, Herestraat, 49, 3000, Leuven, Belgium
*correspondence at Gynecologic Oncology, University Hospitals Leuven, and
Division of Oncology, KULeuven, Herestraat, 49, 3000, Leuven, Belgium. Tel +3216-344252, Fax +32-16-344205, frederic.amant@uzleuven.be
Abstract:
Background: The concurrence of intracranial tumors with pregnancy is rare. The purpose of
this study was to describe all reported patients registered in the international Cancer in
Pregnancy registration study (CIP study; www.cancerinpregnancy.org), and to review the
literature in order to obtain better insight in outcome and possibilities of treatment in
pregnancy.
Methods: We collected all intracranial tumors (primary brain tumor, cerebral metastasis, or
meningioma) diagnosed during pregnancy, registered prospectively and retrospectively by
international collaboration since 1973. Patients diagnosed postpartum were excluded. We
summarized the demographic features, treatment decisions, obstetrical and neonatal
outcomes.
Results: The mean age of the 27 eligible patients was 31 years (range 23 to 41 years), of
which 13 and 12 patients were diagnosed in the second and third trimesters, respectively.
Eight patients (30%) underwent brain surgery, 7 patients (26%) had radiotherapy and in 3
patients (11%) chemotherapy was administered during gestation. Two patients died during
pregnancy and 4 pregnancies were terminated. In 16 (59%) patients elective caesarean section
was performed of which 14 (52%) were still preterm (range 30 to 36 weeks, mean 33 weeks).
Five patients had a vaginal delivery (range 36 to 40 weeks). Of the 21 ongoing pregnancies all
children were born alive without visible congenital malformations and the available long-term
follow-up data (range 2 to 25 years) of 6 children were reassuring.
Conclusion: Adherence to standard protocol for the treatment of brain tumors during
pregnancy appears to allow a term delivery and a higher probability of a vaginal delivery.
Key words: pregnancy, brain tumor, surgery, radiotherapy, chemotherapy
Introduction
Cancer is the second most common cause of death of women in their reproductive years. In
developed societies, the incidence of cancer in pregnant women is estimated to be 1 in 10002000 pregnancies.1,2 In our international ‘Cancer in Pregnancy’ registry
(www.cancerinpregnancy.org) breast cancer, followed by cervical and hematological cancers,
remain the 3 most frequently diagnosed cancers in pregnancy (respectively 363 (43%) , 118
(14%), and 113 (13%) in 835 patients registered). However, as the incidence of most
malignancies rises with increasing age, and women tend to postpone childbearing to later in
life, the incidence of cancer in pregnancy may increase. Therefore, knowledge of the
consequences of different cancer treatment options in pregnancy is increasingly important.
Primary intracranial tumors are ranked as the fifth-leading cause of cancer-related death in
women aged 20-39 years.3 Different authors have stated that hormonal changes during
pregnancy can influence tumor growth and trigger the development of neurological
symptoms.4-6 However, since extensive data on care of pregnant patients diagnosed with brain
tumor are lacking, the management still poses diagnostic and therapeutic challenges. In the
present study, we selected all cases of intracranial tumors (primary brain tumor, cerebral
metastasis, or meningioma) from the database, collected prospectively and retrospectively
since 1973 by international collaboration, and we conducted a review of the literature to
address this issue.7
Methods:
We queried the database of the international Cancer in Pregnancy registration study (CIP
study; www.cancerinpregnancy.org) registered with ClinicalTrials.gov, number
NCT00330447. All patients with a primary brain tumors, meningiomas or cerebral metastases
were recruited. Patients diagnosed postpartum were excluded. Patient data on demographic
features, treatments and obstetrical and neonatal outcomes were collected. Lacking data were
retrieved from the referring physician and original patient files as much as possible. For those
patients where radiation therapy was delivered during the pregnancy, additional shielding was
provided to reduce the contribution of leakage radiation, according to the recommendations of
the AAPM (American Association of Physicists in Medicine) TG 36 report.9 The fetal dose
was calculated using a software tool Peridose8, which was shown to provide an adequate
estimate of the types of treatment (i.e. 3-dimensional (3D) conformal RT) encountered here.10
We performed a review of literature and searched for all the published case reports and
series, as well as articles on treatment options during pregnancy. Articles were identified by a
PUBMED search, with MESH terms “pregnancy,” “glioma,” “meningioma”, “brain,”
“chemotherapy,” “surgery,” and “radiotherapy.” The reference list of all retrieved articles was
reviewed for further identification of potentially relevant publications.
Results:
Demographic features, treatment characteristics and fetal and maternal outcome of each case
are demonstrated in Table 1.
Demographic features:
In total, 27 patients with brain tumors were retrieved from the registry. Patients were
diagnosed and treated between 1973 and 2012 in 6 different countries (Belgium (n=11), The
Netherlands (n=8), Czech Republic (n=3), Italy (n=3), Denmark (n=1), and Poland (n=1)).
Mean age at diagnosis was 31 years (range 23 to 41 years). Two patients (7%) were
diagnosed in the first trimester, 13 (48%) patients presented in the second trimester and 12
(44%) in the third trimester. Most common clinical features were focal neurologic symptoms
or disorders (n=10, 37%), epileptic seizures (n=11, 41%) and nonfocal symptoms (eg.
headache, nausea, vomiting) (n=8, 30%).
In 22 patients the tumor was discovered by magnetic resonance imaging (MRI). A computed
tomography (CT) scan was performed in 3 patients, 1 patient had a brain scintigraphy, and in
1 patient (who died during pregnancy), diagnosis was made by autopsy. The distribution of
tumor types was as follows: malignant glioma (anaplastic astrocytoma, glioblastoma
multiforme) (n=10, 37%), low-grade astrocytoma (n=6, 22%), meningioma (n=2, 7%),
cerebellar medulloblastoma (n=1, 4%), giant-cell non-Hodgkin T-cell lymphoma (n=1, 4%),
primary germ cell tumor with choriocarcinoma and yolk sac component (n=1, 4%), and brain
metastases from either primary lung carcinoma (n=2, 7%), melanoma (n=1, 4%), breast
carcinoma (n=1, 4%), or clear cell sarcoma of the kidney (n=1, 4%). In 1 patient there was no
specific histopathologic differentiation available.
Treatment characteristics:
Twelve patients (44%) were treated for their brain tumor or metastasis during pregnancy.
Eight (30%) patients underwent surgical resection of the brain tumor (complete or partial).
Another 6 patients had the surgical resection performed after delivery and in 1 patient it was
performed immediately following caesarean section. In 4 patients (15%), an open biopsy and
shunting was performed during pregnancy. In 1 patient a sternal bone metastasis was resected
by partial sternectomy.
Three patients (11%) received chemotherapy during pregnancy. In two patients the
chemotherapy was administered according to the standard protocol for the primary tumor.
Our third patient has a remarkable history. She was diagnosed with glioblastoma multiforme
at 14 weeks’ gestation and had concomitant radio- and chemotherapy (temozolomide)
administered after partial resection of the tumor. She received the concomitant temozolomide
at a dose of 75mg/m2 per day between week 18 and 22 of gestation and was irradiated by 3D
conformal technique and received in total 54 Gray (Gy). The estimated fetal radiation dose
was calculated and was 35 μGy per fraction, amounting to a total of 0,0105 Gy. Another 3
cycles of temozolomide were given during pregnancy at a dose of 150mg/m2/day during 5
days in week 26, 30 and 34. She delivered of a healthy boy after induction at 37 weeks’
gestation. She continued treatment by temozolomide monthly during 5 years (while the
standard scheme is only 6 cycles temozolomide post-radiotherapy). She is now two years
without antitumoral treatment and recent MRI (August 2013) showed no signs of residual
disease and her 7 year old son is doing well.
In total 7 patients (26%) received radiotherapy during pregnancy. Five patients received
whole brain RT by a 3D conformal technique, of who 1 patient with concomitant
chemotherapy (cfr. supra), and 2 patients received radiation by γ-knife. In all patients
additional shielding was provided to reduce the contribution of leakage radiation. (Figure 1)
The calculated fetal dose for the patients who received 3D conformal RT was between 0.01
and 0.1Gy.
Adjuvant radio- and/or chemotherapy in the immediate postpartum period of the 21 ongoing
pregnancies (exclusion of the terminated pregnancies) was given to 11 (11/21=52%)
respectively 5 (5/21=24%) patients.
Fetal and Maternal outcome:
Two of the 27 patients (8%) died during pregnancy because of rapid tumor growth causing
clinical deterioration with serious epileptic seizures. One patient who was pregnant of twins at
33 weeks’ gestation was found dead at home, and the other patient died during hospitalization
at 34 weeks’ gestation. In both cases intra-uterine death of the fetuses was observed. In 4
(15%) patients termination of pregnancy was advised because of diagnosis in early pregnancy
(GA of 8 weeks), rapid clinical deterioration (n=2), or pregnancy-related complications (n=1).
The latter was decided in a DCDA pregnancy at not viable GA of 23 weeks, due to the
diagnosis of growth discordance with worsening doppler flow in one of the fetuses. Because
the growth discordance was discovered at 17 weeks’ gestation, we assume that the
administration of both chemotherapy and radiotherapy could be related. In 16 (59%) patients,
elective caesarean section was performed. Fourteen were performed preterm (mean GA of 33
weeks, range 30 to 36 weeks) in order to start treatment immediately after delivery (n=8),
because of deteriorating symptoms (n=5), or because of pregnancy-related problems (n=1).
Five patients had a vaginal delivery (mean 38 weeks, range 36 to 40 weeks) and 4 of them
were treated for their brain tumor during pregnancy.
We obtained in October 2013 additional information on maternal outcome from diagnosis till
the last known follow-up consultation (mean follow-up 3 years and 2 months, range 9 months
to 19 years). Fifteen of the 27 patients died of disease progression, during pregnancy to 9
years and 9 months after diagnosis. Eight patients (cases 2, 7, 9, 11, 12, 13, 16, and 18 in
table 1) are still in remission with no evidence of disease and a mean follow-up 6 years and 7
months (range 15 months to 19 years). Four patients are stable after recurrence of disease
(mean follow-up 2 years and 6 months, range 9 months to 4 years). Seven of the patients who
died (7/14=50%) and 6 of the patients alive (6/12=50%) were treated during pregnancy.
Of the 21 ongoing pregnancies, clinical information regarding the children was registered at
birth and in the immediate neonatal period. No problems directly related to the followed
treatment were noted in any of the 21 children. However, two children born preterm at 32 and
33 weeks‟ gestation suffered from respiratory problems(pneumothorax and delayed closure of
the Botalli duct) in the first days after birth, but did recover well. There were 6 patients with
additional information on the long-term follow-up (mean 10 years and 2 months, range 2 to
25 years), of whom 5 had treatment during pregnancy. Four of them did well, and showed no
harmful effects on the cardiac function or neuro-cognitive development. One child that was
born at 34 weeks’ gestation initially, and of which the mother had a shunt and radiotherapy
during pregnancy, showed no problems during hospital stay at the neonatal intensive care
unit. However, at initiation of walking she was diagnosed with spastic displegia (without
visible brain lesions at MRI) and she had minor psychomotoric retardation. It is impossible to
exclude a causal relationship with the treatment, but, the radiation was performed with
shielding and the fetal dose was estimated below the threshold dose, making the association
unlikely. Moreover at 33 weeks’ gestation, oligohydramnios was seen by ultrasound, which
besides prematurity, may have caused the observed problems.
Discussion
In this report we summarized the history of 27 patients with primary brain tumors,
meningiomas and brain metastases diagnosed during pregnancy. We noted that seven mothers
treated during pregnancy could postpone the time of delivery to a mean GA of 37 weeks and
that 4 of them had a vaginal delivery. Moreover, 50% of the mothers treated during pregnancy
were in good health at the last follow-up consultation (mean follow-up 3 years and 2 months).
In addition, preterm delivery by elective caesarean section was performed in 8 of the 9
patients (89%) in whom treatment was postponed till after delivery. In order to safeguard the
maternal outcome, treatment should adhere to the treatment options as in non-pregnant
women, and administered without delay, if possible.
Neurosurgical resection remains the cornerstone of therapy for the majority of the malignant
and growing benign intracranial tumors. However the optimal time to perform the procedure
during pregnancy is still a matter of debate. It is recommended to delay surgery if possible
until after the first trimester to reduce the miscarriage risk.11,12 During the second and third
trimester surgery is considered safe and recommendations13 and a check list for safe surgery
during pregnancy is available.14 Complete surgical resection is a known favorable prognostic
factor, and several reports have stated that delay can cause progressive neurologic
deterioration and increasing risk of urgent intervention (resection and cesarean
section).11,12,15,16 A large retrospective population based study of 644 patients diagnosed with
intracranial lesions (benign and malignant brain tumors) during pregnancy showed no
significant association between adverse outcomes and the neurosurgical procedures
performed during the immediate neonatal period.17 Our patient data confirmed to this
statement, and moreover comments on the long-term follow-up with normal cognitive
development of 4 children.
Adjuvant chemotherapy improves the outcome of some aggressive brain tumors (eg.
glioblastoma). It has been shown in non-pregnant patients, that the addition of temozolomide
(a non-classical alkylating agent) to radiotherapy early in the course of glioblastoma results in
survival benefit.18 Data on the safety of use of temozolomide during pregnancy only exist in
the form of preclinical studies in rats and dogs (teratogenicity during first trimester) and as
described in some case reports.19-21 In this paper we describe the longest follow-up of a
patient treated with concomitant radio- and chemotherapy during pregnancy for glioblastoma.
She is now 7 years and 6 months after diagnosis, with no signs of progression, and there are
no adverse effects noted on the cardiac function or neuro-cognitive development of the child.
More general safety data on the use of other chemotherapeutic agents during pregnancy have
been published before. Transplacental transfer of anthracyclines, paclitaxel, docetaxel,
vinblastine, 4-hydroxyphosphamide, trastuzumab and carboplatin has been quantified in
rodent and baboon models. The study compared the levels of these chemotherapeutic agents
in maternal and fetal plasma, and showed a significantly lower concentration in fetal plasma
and organs.22,23 Drug levels were always lower in the fetal compartment and especially
taxanes and anthracyclines were significantly diluted (1 and 7% of the maternal levels,
respectively). A recent study summarized long-term data of children after antenatal exposure
to chemotherapy (and/or radiotherapy). The authors found a cardiac outcome equal to the
general population, and no adverse effects of treatment on the general health and ageappropriate neurocognitive (IQ, attention, behavior, memory) development.24
We report on 7 patients treated with cerebral radiotherapy during pregnancy. One child was
reported to suffer from neurologic deficits (spastic diplegia and minor psychomotoric
retardation). Whether this is related to the very low dose radiotherapy during pregnancy or
related to the preterm birth (GA 34 weeks) cannot be discerned. Our estimations of the
absorbed fetal dose were between 0.01 and 0.1Gy for the patients who received whole brain
RT by a 3D conformal technique. Two patients received radiation by γ-knife of which the
technique has been reported as a safe treatment by Cheng et al.25 Several reports have been
published on the estimated fetal dose of radiation during cancer therapy, and the potential
risks to the fetus.26,27 The adverse effects are depending upon the absorbed dose, the type of
radiation and the gestational age. Many of these toxic effects will only be induced above the
deterministic threshold of 0.1Gy. Most studies reporting on the administration of radiotherapy
to brain tumors showed that the fetal exposure never exceeded this threshold dose. These
radiotherapy schedules are therefore considered safe. Still, proper shielding should always be
used to further reduce the fetal dose - with 26% to 71% – this to comply the ALARA
principle (= as low as reasonably achievable).28,29 It is recommended to discuss treatment with
a physicist and to use a phantom to estimate the fetal dose as accurate as possible in order to
counsel parents on the potential risks of radiation-induced toxicity.30,31
Although treatment of malignant brain tumors during pregnancy is possible and safe, we
noted 10 preterm births in our series. Seven patients underwent an elective caesarean section
in order to start oncologic treatment. The complications of prematurity have been well studied
and include a higher need for respiratory assistance and an increased susceptibility for
respiratory diseases, bradycardia, necrotizing enterocolitis, intraventricular hemorrhage,
hypoglycemia and feeding problems, sepsis and seizures.32,33 Therefore iatrogenic preterm
birth should be avoided whenever possible by postponing or continuing treatment until a term
delivery can be achieved. The decision of performing an elective caesarean section preterm is
often based upon the risk of increased intracranial pressure associated with bearing-down
efforts during the second stage of labor. Nonetheless, if patients are clinically stable and
carefully discussed, and the individual risk of rapid tumor growth has been evaluated,
gestational advancement until fetal maturity should be considered, as well as the attempt to
have a vaginal delivery.18,34,35 However we also noted that 3 children died in utero because of
maternal death (1 twin at 33 weeks’ gestation and 1 at 34 weeks’ gestation). Thus, the balance
between waiting for fetal maturation and risk of intrauterine death remains difficult in patients
with highly malignant tumors.
In our report, 12 patients underwent treatment during pregnancy (surgery, radiotherapy and/or
chemotherapy), and could postpone their pregnancy (range 3 to 28 weeks, mean 13 weeks) till
a minimum GA of 30 weeks. Three other patients responded well to medications
(corticosteroids, anticonvulsants) and could also continue their pregnancy for 6 to 8 weeks.
We are well aware that this was a small case study of 27 patients, not including other common
benign lesions of the brain (eg. schwannoma, dermoid cysts, pituitary adenomas). Postpartum
diagnosed patients were also excluded, which may have an impact on the maternal outcome.
Because the cases were selected retrospectively through the CIP study database, we cannot
confirm that all patients diagnosed with brain tumors since the beginning of the registry in
2005 were recruited by the referring centers, so could be subject to case ascertainment bias.
Nonetheless, our data are complete and comment on the most long-term follow-up of the
children. In addition to our patient data, two case series also report on more term delivery and
good maternal and fetal outcome in the early postpartum period after treatment during
pregnancy. Elwatidy et al.36 reported on 5 of 9 patients diagnosed with different intracranial
lesions (benign and malignant) between 22 and 30 weeks’ gestation, who could continue their
pregnancy till term because of either surgical (resection by craniotomy) or drug
(corticosteroid) treatment. In the case series of Cohen-Gadol et al.11 4 of 14 patients (with
primary malignant lesions) diagnosed between 23 and 24 weeks’ gestation, succeeded in
having a normal term vaginal delivery after surgical resection during pregnancy. These
studies are in line with the present study confirming that treatment of brain malignancies
during pregnancy is possible and that term pregnancy can be achieved.
Conclusion
Treatment of brain tumors during pregnancy is feasible. Up to 50% of our treated patients
were still in good health at the last follow-up consultation (mean follow-up 3 years and 2
months). The children of the ongoing pregnancies were life births and main risks were mostly
related to preterm birth. The timing of the different treatment options should be coordinated
for each patient in a multidisciplinary setting based on the available evidence and experience.
The current data suggest that treatment by standard protocols including surgery, radiotherapy
and chemotherapy, during pregnancy, appears to allow a term delivery and a higher
probability of a vaginal delivery.
Conflict of Interest: Frédéric Amant is Senior Clinical Investigator for the Research FundFlanders. All other authors declare that they have no conflicts of interest.
Acknowledgements: Funding by the Research Foundation-Flanders and the Belgian Cancer
Plan, Ministry of Health, Belgium. The funding sources had no involvement in study design;
in the writing of the manuscript; nor in the decision to submit the paper for publication.
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Figure captions and tables
Figure 1: Radiation by 3D conformal technique at 28 weeks of pregnancy. Procedure
performed with double shielding.
Table 1: Demographic features, treatment characteristics, fetal and maternal outcome of the
reported cases from the CIP-study. Abbreviations: pp=postpartum, RT=radiotherapy,
CT=chemotherapy, TOP=termination of pregnancy, NA=not available