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GYNECOLOGIC ONCOLOGY
Cancer in pregnancy. Part I: basic diagnostic and therapeutic
principles and treatment of gynecological malignancies
Friederike Hoellen •Roland Reibke •Katrin Hornemann •
Marc Thill •Doerte W. Luedders •Katharina Kelling •
Amadeus Hornemann •Michael K. Bohlmann
Received: 22 June 2011 / Accepted: 2 August 2011
ÓSpringer-Verlag 2011
Abstract
Purpose Cancer in pregnancy is a rare circumstance.
However, the coincidence of pregnancy and malignancy is
supposed to increase due to a general tendency of post-
poning childbearing to older age. To date, clinical guide-
lines are scarce and experience regarding therapeutic
management is limited to case reports.
Methods This review focuses on general diagnostic and
therapeutic principles including systemic therapy for
malignancies in pregnancy.
Results In part I, we report on diagnosis and therapy of
gynecological tumors.
Conclusion The diagnosis of gestational cancer faces
both oncologist and obstetrician to the dilemma of applying
appropriate diagnostic techniques and adequate local and
systemic therapy to an expectant mother without harming
the fetus.
Keywords Cancer Malignancy Pregnancy
Chemotherapy Radiotherapy Fetus
Introduction
Cancer in pregnancy is a rare circumstance. The coinci-
dence is estimated to be 1:1,000 pregnancies. There are
3,500–6,000 new cases of malignancies diagnosed in
pregnancy in the US annually with cancer accounting for
one-third of maternal deaths during gestation [1–3]. Due to
a general tendency of postponing childbearing to older age
and reproductive assistance prolonging childbearing age,
the coincidence of pregnancy and malignancy is supposed
to increase. Up to 20–30% of all malignant tumors emerge
in women younger than 45 years [4]. The entity of most
common malignancies in gestation comprises cancers
which can generally be found in women in the reproductive
age, e.g., breast and cervical cancer, leukemia, lymphoma,
and melanoma [5] (Table 1). Recent population studies
matching pregnant to nonpregnant cancer patients refuted
the hypothesis of worse prognosis and worse response to
therapy in pregnant patients [2]. Oncologists and obstetri-
cians are faced with the challenge of providing the mother
with the best treatment while preventing from doing harm
to the fetus.
This review article will focus on the diagnostic and
therapeutic principles in general and on the treatment of
nontrophoblastic malignancies diagnosed during preg-
nancy. Therefore, we searched the relevant literature with a
special focus on diagnostic pitfalls, fetal side-effects of
therapeutic options, altered response rates, and special
challenges for women diagnosed with cancer during
gestation.
F. Hoellen (&)M. Thill D. W. Luedders K. Kelling
M. K. Bohlmann
Department of Obstetrics and Gynecology, University Hospital
of Schleswig–Holstein, Campus Luebeck, Ratzeburger Allee
160, 23538 Luebeck, Germany
e-mail: Friederike.Hoellen@uksh.de
R. Reibke
Department of Internal Medicine III; Klinikum Grosshadern,
Ludwigs-Maximilians-University of Munich, Munich, Germany
K. Hornemann
Department of Thoracic Surgery, Thoraxklinik,
University of Heidelberg, Heidelberg, Germany
A. Hornemann
Department of Obstetrics and Gynecology, University Medical
Center Mannheim, University of Heidelberg, Mannheim,
Germany
123
Arch Gynecol Obstet
DOI 10.1007/s00404-011-2058-8
Diagnosis of cancer in pregnancy
Diagnosis of cancer in gestation is often delayed as
symptoms and physical signs of malignancy may be
masked by those of pregnancy. Impairment of the general
condition and especially perceived alterations of organs,
e.g., the breast, are often attributed to physical and physi-
ological alterations due to pregnancy. Cervical cancer
constitutes an exception, probably due to frequent gyne-
cological examinations in pregnancy.
In general, biopsies, punctures, and endoscopy are
considered safe during pregnancy.
X-ray diagnostic procedures should be avoided if pos-
sible as ionizing radiation may induce leukemia and solid
tumors in children and adults. The Oxford survey of
childhood cancer demonstrated an increased risk for leu-
kemia (relative risk 1.3–3.0) in children after in utero
exposure, especially during the first trimester [3]. The
radiation effect on the fetus is both dose-dependent and
related to the stage of gestation. Deterministic biological
effects resulting from fetal cellular damage, e.g., congenital
malformations, miscarriage, stillbirth, mental retardation,
intrauterine growth retardation (IUGR), and premature
delivery, are considered to be dose dependent. Stochastic
effects due to fetal cellular mutations are defined by an
increase of their probability to emerge associated with an
increase of the radiation dose. They comprise secondary
tumors, myelodysplastic syndromes, and late injury of
normal tissues [4].
Direct and indirect radiation of the fetus carries the risk
of adverse effects, whose extent is also dependent on the
week of gestation (Table 2). Thus, abdominal plain films,
isotope scans, barium enemas, abdominal computerized
tomography, intravenous urography and positron emission
tomography (PET) should be avoided (Table 3). Chest
X-ray with abdominal shielding, ultrasound brain com-
puted tomography, mammography and magnetic resonance
imaging (MRI) scans (without gadolinium at least during
the first trimester of pregnancy) may be performed during
pregnancy at probably little risk. The sensitivity of mam-
mography decreases in pregnant women due to an alter-
ation of radiographic density of the breast and it is
estimated to be 68%, whereas sonography provides a sen-
sitivity of 93% [3].
Tumor marker levels are generally to be interpreted with
caution, but especially during pregnancy. Elevated mater-
nal serum concentrations of e.g., AFP, hCG, and CEA etc,
during pregnancy may rather be attributed to their
involvement in biological functions associated with fetal
development, differentiation, and maturation than in tumor
progression [6].
Radiotherapy in pregnancy
While diagnostic procedures based on low-dose ionizing
radiation may be performed in distinct cases, high-dose
ionizing radiation therapy threatens to harm the unborn
child. Ionization from radiation acts by breaking of
chemical bonds, production of free radicals, biochemical
changes and direct DNA damage resulting in mutations,
chromosomal aberrations, induction of apoptosis, and DNA
damage. During the second half of the twentieth century,
the science of radiobiology and health care emerged and
rules and guidelines for the protection of the individual,
and especially of pregnant women, from radiation were
introduced. The harmful effects of ionizing radiation can
be attributed to somatic, genetic and teratogenic effects.
Table 1 Incidence of tumor types in pregnancy per number of ges-
tations (adapted from [5], modified to descending order of incidence)
Malignancy Prevalence during gestation
Lymphoma 1:1,000–1:10,000
Breast cancer 1:3,000–1:10,000
Malignant melanoma 1:1,000–1:10,000
Carcinoma of the cervix 1:2,000–1:10,000
Ovarian cancer 1:10,000–1:100,000
Colon cancer 1:13,000
Leukemia 1:75,000–1:100,000
Table 2 Adverse effects of radiation on the fetus (summarized and simplified from [7])
Weeks of gestation Effects Estimated maximal dose (mGy)
Implantation (2–4 weeks p.m.) Spontaneous abortion or no adverse effect 50–100
Organogenesis (4–10 weeks) Congenital malformations (skeletal, eyes, limbs) 200
IUGR 200–250
Fetal period (10–17 weeks) Severe oligophreny 60–310
Microcephaly 200
Fetal period (18–27 weeks) Severe oligophreny 250–280
p.m. post menstruationem, mGy milli Gray
Arch Gynecol Obstet
123
While somatic effects are produced in the individual
exposed to radiation, genetic effects affect the offspring of
individuals exposed before pregnancy and teratogenic
effects affect the offspring during gestation. Congenital
birth defects have a threshold dose of about 100 mGy
(100 mSv). Consequently, termination of pregnancy is
usually not considered reasonable in cases of an irradiation
dose below this level [2]. While some authors regard
radiation of supradiaphragmatic sites (brain, neck, chest,
mediastinum, and axilla) as a possible therapeutic option in
distinct cases, especially in the first trimester due to the low
position of the uterus, most experts oppose the radiation
therapy in general during gestation [4]. Both adverse
effects from radiation therapy and chemotherapy depend
on the age of gestation. The first 2 weeks of gestation are
considered the period of the ‘‘all or nothing’’ effect, e.g.,
either spontaneous abortion or normal development.
Exposure during the period of organogenesis, e.g. weeks
3–12, result in either miscarriage or major congenital
anomalies. Exposure during the second and third trimester
usually results in minor anomalies in late-forming tissues,
stillbirth, IUGR, premature delivery, and myelosuppression
[4]. The development of CNS, gonads, teeth-palate, eyes,
and ears might be altered in this period. Luis et al.
reviewed 109 cases of radiation exposure in utero and
found 13 cases with adverse outcomes. In these patients,
radiation was mainly performed for Hodgkin’s lymphoma
and breast cancer (thoracal radiation), as well as the head
and neck area, always with abdominal shielding [8].
Systemic treatment in pregnancy
Systemic antineoplastic treatment comprises cytotoxic,
endocrine, targeted agents, and immunotherapy [9]. The
reproductive toxicity of new agents is commonly investi-
gated in three stages. The fertility and early embryo
developmental design (FEED) refer to administration of
the drug from conception until placentation, the embryo
fetal developmental studies (EFD) between placentation
until cleft palate closure and the pre- and post-natal design
(PPND) until weaning. In general, systemic chemotherapy
is regarded to carry significant risks when administered
during the first trimester. The risk of fetal malformations
following chemotherapy exposure in utero was estimated
to be 5–15% with the use of combination therapy and
*10% with the use of a single agent when administered
during the first trimester versus 1.3% during the second and
third trimester [10]. After the first trimester, the risk of
congenital malformations due to the application of che-
motherapy approaches the baseline population risk with
3% [11]. The main adverse effects of chemotherapy after
the first trimester are spontaneous abortion, low birth
weight, intrauterine growth restriction (IUGR), premature
birth, impaired functional development, myocardial toxic-
ity, and stillbirth.
During the period of organogenesis, e.g., 2–8 weeks
after conception, the embryo is especially vulnerable to
malformations (Table 4). Spontaneous abortion, embryonic
death, and major malformations may occur in up to 20%
[1]. Whenever chemotherapy in pregnant women is
regarded necessary, antineoplastic efficacy must be
weighed up against the adverse effects to the fetus [12].
Adverse effects depend on the materno-fetal transfer of the
administered drugs. Small molecules below 500 Da of
molecular weight and lipophilic agents are known to tres-
pass the placental barrier more easily. The strong placental
expression of drug-extruding transporters, such as P-gly-
coprotein (PgP), limits the transplacental transfer. Recent
data suggest that tubulin-binding agents such as paclitaxel
Table 3 Estimated fetal ionizing radiation dose from diagnostic
imaging, adequate abdominal shielding provided (modified from [7])
Imaging technique Fetal dose (mGy)
Cranial computed tomography \0.1
Chest X-ray \0.1
Limb X-ray (hips and pelvis excluded) \0.1
Thoracic computed tomography 1
Abdominal X-ray (a.p.) 3
Pelvic X-ray (a.p.) 6
Intravenous pyelography 6
X-ray lumbar spinal column (a.p.) 7
Abdomen/pelvis computed tomography 30
a.p. anterior posterior, mGy milli Gray
Table 4 Adverse effects of chemotherapy by gestational age (adapted and shortened from [5])
Gestational
age
Stage of embryonic/fetal development Adverse effects
Weeks 0–2 Undifferentiated cellular organism Spontaneous abortion or no impact; ‘‘all or nothing’’ rule
Weeks 3–12 Organogenesis Spontaneous abortion severe congenital anomalies
Second and
third
trimester
Intrauterine growth, functional maturation,
development of CNS, gonads, teeth, palate, eyes,
ears
Functional defects and minor malformations of late-forming
structures, stillbirth, IUGR, premature delivery, myelosuppression
Arch Gynecol Obstet
123
and vinca-alkaloids do not trespass the placenta due to the
PgP transporting system [13].
In general, the application of chemotherapeutic agents
known to produce medullar toxicity should cease 2 weeks
before delivery to prevent neonatal infection with neutro-
penia. Furthermore, delivery should be postponed until 2 or
3 weeks after chemotherapy as neonates and especially
preterm babies have limited capacity to metabolize and
eliminate drugs due to hepatic and renal immaturity. Thus,
the placenta should eliminate fetal drugs in utero [14].
Apart from the direct impact of chemotherapeutic agents
on the fetus (Table 5), the effects of chemotherapy during
pregnancy on the placenta must be taken into account as
well. A clinicopathologic analysis of 13 placentas of
women who had been treated with chemotherapy during
pregnancy showed that chemotherapy during the first tri-
mester induces excessive polyploidization of the chorion
laeve trophoblast representing an adapting response to
intraamniotic toxins. Villous hypoplasia, fibrin deposits,
and vascular anomalies can be found after chemotherapy
[15]. The second and third trimester exposure to cytotoxic
agents may predispose to impaired placental function [16].
As a small patient population is taken into account, there
is a lack of data dealing with pharmacokinetics of che-
motherapy during pregnancy. In a recent study, baboons as
well as human patients were exposed to chemotherapy with
pharmacokinetics being evaluated in the pregnant and in
the non-pregnant setting. The authors observed a decrease
in area under the curve (AUC) and maximal plasma con-
centration and an increase in distribution volume and
clearance in pregnant patients. To date, chemotherapy is
administered according to standard dose regimens. How-
ever, with regard to the decrease in plasma exposure,
dosage during pregnancy remains to be further investigated
and emphasis must be placed on long-term follow-up
results [17].
Aviles et al. presented a follow-up study of 84 patients
who had been exposed to chemotherapy in utero. Median
follow-up was 18.7 years and the authors presented even
data of some second-generation offspring. Growth, sen-
somotoric development, and intelligence did not differ
significantly between exposed individuals and controls and
no malignancies were reported.
Breast-feeding is regarded to be contraindicated during
chemotherapy [18]. Besides a possible transfer of chemo-
therapeutic agents to the child during breastfeeding, the
risk of local and secondary systemic maternal infections
due to breast rhagades has to be kept in mind.
Cytotoxic agents
Methotrexate (MTX) is an abortifacient and may lead to
severe malformations called the ‘‘aminopterin syndrome’’
[13]. MTX should not be administered during pregnancy
due to significantly increased adverse effects on the fetus,
especially during the first trimester [9].
Anthracyclines (doxorubicin, epirubicin, idarubicin,
mitoxantrone, daunorubicin) damage DNA by DNA-inter-
calation, and by interfering with topoisomerase 2 and
damage to the cell wall. Topoisomerase 2ais overexpres-
sed in rapidly growing tissues, and thus constitutes a target
of adverse effects for the embryo. Meanwhile, only low
concentrations of anthracyclines have been detected in fetal
tissues as anthracyclines cross the placenta partially. The
molecular weight of anthracyclines exceeds 500 Da and
their materno-fetal transport is limited by the placental
P-glycoprotein transporting system [19]. According to in
vitro studies, the global transplacental transfer value of
doxorubicin was 2.96 and 3.66% for epirubicin, respec-
tively [20]. The application of anthracyclines in the second
and third trimester seems to be safe. Preliminary data on
Table 5 Administration of chemotherapeutic agents during
pregnancy
Chemotherapeutic agent Recommendations for administration
in pregnancy
Methotrexate Contraindicated
Anthracyclines
(doxorubicin, epirubicin,
idarubicin)
Considered safe in 2nd and 3rd
trimester epirubicin or doxorubicin
preferred 70 mg/m
2
per cycle
doxorubicin maximal dose
Platinum derivates
(cisplatin, carboplatin)
Considered safe in 2nd and 3rd
trimester
Taxanes Not recommended due to limited data
Vinca-alkaloids Not recommended due to limited data
5-Fluorouracil Considered safe in 2nd and 3rd
trimester
Alkylating agents
(ifosfamide,
cyclophosphamide)
Applicable in distinct cases
Bleomycin Not recommended due to limited data
Etoposide Not recommended due to limited data
Monoclonal antibodies
Bevacizumab Contraindicated
Trastuzumab Not recommended due to limited data,
applicable if strictly indicated after
informed consent
Rituximab Not recommended due to limited data
Tyrosine kinase inhibitors
Imatinib Contraindicated, applicable if strictly
indicated after informed consent
Lapatinib Not recommended due to limited data
Sunitinib Contraindicated
Sorafenib Contraindicated
Anti-Endocrine therapy Contraindicated
Arch Gynecol Obstet
123
122 pregnant patients showed no adverse effects to the
fetus [13]. Germann et al. reviewed the literature and found
160 patients with anthracycline-based chemotherapy dur-
ing pregnancy. A total of five heterogeneous malformations
(3%) were reported [19] which may be comparable with
the general population. However, possible long-term car-
diotoxic effects remain of concern as sufficient follow-up
data are still missing. The risk of severe fetal toxicity is not
dependent on the duration of anthracycline exposure, but
dose dependent and increases 30-fold if the doxorubicin
dose exceeds 70 mg/m
2
per cycle [12]. Idarubicin should
not be administered due to its lipophilicity and the long
half-life of active serum metabolites [12]. Epirubicin is a
stereoisomer of doxorubicin which is slightly more lipo-
philic. It has a shorter half-life, faster influx and lower
retention in cells, fewer systemic and cardiac toxic effects.
Some authors recommend epirubicin in pregnancy to
reduce the risk of fetal myocardiopathy [21].
It is important to emphasize the fact that the main risk
for the fetus consists in maternal disease progression and if
indicated, anthracyclines should be administered during the
second and third trimester. The application should cease
2–3 weeks before delivery to prevent neonatal infection
due to neutropenia [19,22].
Platinum derivates (cisplatin, carboplatin, and oxalipla-
tin): data to carboplatin are limited, but it showed less
adverse fetal events in comparison with cisplatin [9]. How-
ever, carboplatin causes thrombocytopenia. Platinum deri-
vates are bound to plasma albumin to a great extent that the
unbound fraction may cross the placental barrier [23]. To
date, 43 cases of pregnant women who received platinum
therapy have been reported (cisplatin in 36 cases and car-
boplatin in 6 cases, both agents in one case). Two fetal
malformations were reported after in utero exposure to cis-
platin, but lacked proof of causality. Furthermore, in some
cases acute respiratory distress, cytopenia, creatinine ele-
vation, and hearing impairment were reported. Longest fol-
low-up data are 40, 42 and 73 months without any evidence
of sequelae in the children [24]. In general, platinum deri-
vates can safely be administered in the second and third
trimesters. The newborn should undergo an otologic
screening [23] due to the risk of (cis-) platinum-associated
ototoxicity.
Taxanes There are only few reports on the administra-
tion of taxanes in pregnancy. Till date, no severe fetal
adverse effects have been reported [9]. Meanwhile, most
authors preclude the routine use of taxanes during preg-
nancy due to the limited safety data [25]. Several preclin-
ical reports indicate that the placental P-glycoprotein
system could prevent the transplacental transfer of taxanes
and vinca-alkaloids. Thus, though not thoroughly exam-
ined, some authors hypothesize that taxanes and vinca-
alkaloids are safe during pregnancy. On the other hand,
paclitaxel, docetaxel and vinorelbine are metabolized by
cytochrome P450 isoforms. As the maturation of these
cytochromes takes part only in the neonatal period, the
fetus is unable to metabolize these agents and thus highly
susceptible for toxic effects [26].
Vinca-alkaloids (e.g., vinorelbine, vincristin) Mir et al.
[26] reviewed six cases of exposure to vinorelbine in
pregnancy and reported on healthy offspring with a median
follow-up of 23 months. Regarding the limited data for the
administration of vinca-alkaloids in pregnancy, the appli-
cation might be considered in distinct cases, but to date
there is no recommendation for its routine use.
5-Fluorouracil (5-FU) Hahn et al. [25] presented a
prospective study of 57 pregnant breast cancer patients
receiving FAC (5-fluorouracil, doxorubicin, cyclophos-
phamide) in the second or third trimesters of pregnancy.
There were no cases of perinatal mortality, the follow-up of
the children showed no significant neonatal complications
and the children seem to develop similar to reported norms
for the general population. 5-FU may be administered in
the second and third trimesters of pregnancy without ele-
vated risks for miscarriage or malformations. Meanwhile,
the risk for intrauterine growth retardation and preterm
delivery is increased. 5-FU should not be administered in
the first trimester due to suspected detrimental effects such
as miscarriage and teratogenicity [27].
Alkylanting agents, (e.g. cyclophosphamide, ifosfa-
mide), are considered as a human teratogen. There are only
single case reports of in utero exposure of a monotherapy
with alkylating agents; however, a distinct phenotype of
cyclophosphamide embryopathy has been depicted, show-
ing growth deficiency, developmental delay, limb and
craniofacial anomalies [28]. Cyclophosphamide as a part of
combined chemotherapy regimens for breast cancer, pri-
marily FAC (5-fluorouracil, doxorubicin, cyclophospha-
mide), has been investigated in one prospective and several
retrospective studies with good neonatal outcomes [9]. The
high risk of cyclophosphamide induced premature ovarian
failure has to be kept in mind as well.
Bleomycin is an antibiotic and used in combination with
cisplatin and etoposide in e.g., ovarian malignancies or as
part of the treatment of Hodgkin’s disease (e.g., ABVD).
There are only single case reports of patients who were
treated with bleomycin in the second and third trimesters. To
date, no severe fetal adverse effects or malformations due to
bleomycin have been reported. Meanwhile, in regard to the
limited data, no clear recommendation can be made con-
cerning the application of bleomycin during pregnancy [9].
Etoposide is a topoisomerase inhibitor. In some non-
epithelial ovarian cancers, bleomycin, etoposide, and cis-
platin are applied as the standard chemotherapy regimen.
In one reported case, the newborn presented with ventri-
culomegaly and subsequent cerebral atrophy. Another
Arch Gynecol Obstet
123
newborn showed alopecia, hearing loss and hematological
abnormalities which were contributed to the exposure to
etoposide. Meanwhile, in 11 case reports of patients treated
with either bleomycin, etoposide and cisplatin or etoposide
and cisplatin or cisplatin, vincristin and bleomycin no
severe malformations or severe fetal adverse affects were
attributed to chemotherapy in utero [9]. With regard to the
limited data, other chemotherapeutic agents with sufficient
data should be preferred during gestation [29].
Monoclonal antibodies
Most of the currently available monoclonal antibodies are
of the IgG1 subclass. The antibodies of the IgG subclass
are the only immunoglobulins which can pass the placental
barrier by active transport via specific receptor-mediated
transporting mechanism. The Fc receptor in the syncytio-
trophoblast binds to the Fc portion of the IgG. As the Fc
receptor is hardly expressed before the 14th week of ges-
tation, the materno-fetal IgG transfer during the first tri-
mester is minimal. Preclinical reproductive toxicity studies
have only been carried out for bevacizumab, panitumumab
and trastuzumab, with only trastuzumab having passed
FEED (fertility and early embryo developmental design),
EFD (embryo fetal developmental studies) and PPND (pre-
and post-natal design) (see above).
Bevacizumab, a vascular endothelial growth factor
(VEGF) inhibitor, is mainly used in the treatment of colon
cancer, metastasized breast cancer and in clinical trials of
ovarian cancer. As an important factor of angiogenesis,
VEGF plays a crucial role in embryogenesis and physio-
logical processes of the pregnancy [1]. Thalidomide, which
gained notoriety in the 1950s, despite other ways of action
comparably interferes with angiogenesis and resulted in
severe limb deformations. Thus, administration of bev-
acizumab during pregnancy is supposed to enhance serious
adverse effects and major complications and should not be
considered as a therapeutic option during pregnancy [1].
This applies for other drugs with anti-angiogenic
potential options such as the multi-tyrosine kinase inhibi-
tors sunitinib, sorafenib, pazopanib and BIBF 1120 as well.
There are just a few cases of intravitreal injection of bev-
acizumab in patients with choroidopathy with unproblem-
atic deliveries and healthy babies [30,31].
EGFR (epidermal growth factor receptor)inhibitors To our
knowledge, the administration of cetuximab and panitumumab,
both EGFR inhibitors, during pregnancy have not been pub-
lished so far. In one case, the anti-EGFR agent erlotinib was
administered during the first 2 months of unrecognized preg-
nancy resulting in the birth of a healthy child [32].
Trastuzumab targeting HER2neu is administered in
patients with HER2 overexpression in breast and gastric
cancer. However, as HER2 plays a pivotal role in embry-
onic cardiac development, it is supposed to entail heart
anomalies when administered during pregnancy. To date,
15 breast cancer patients have been reported with trast-
uzumab during pregnancy [1]. Among these 15 patients, 11
patients became unintentionally pregnant during trast-
uzumab therapy. The most striking effect was oligohy-
dramnios and anhydramnios by the inhibition of HER2neu
which is strongly expressed on the fetal renal epithelium.
Furthermore, trastuzumab inhibits VEGF as well, which
regulates the production and re-absorption of the amniotic
fluid. Azim et al. reviewed 12 pregnancies with trast-
uzumab exposure. Four neonatal deaths were reported after
trastuzumab exposure in utero, three other babies suffered
from respiratory and renal problems postnatally. The
authors recommend postponement of trastuzumab admin-
istration in metastatic breast cancer and in the adjuvant
setting after delivery. In distinct cases, trastuzumab might
be applied in the second and third trimesters on a weekly
basis with amniotic fluid controls at close intervals [9].
Rituximab This anti-CD20 monoclonal antibody
administered in B cell non-Hodgkin’s lymphoma or some
antibody driven autoimmunopathies has only been applied
in seven pregnant patients to date. These pregnancies were
uneventful; however, suppression of the B cell component
might lead to severe neonatal infections in the newborn.
The use of rituximab during pregnancy should be
restrained due to insufficient data [1].
Imatinib This antibody is designed for bcr-abl suppres-
sion in chronic myeloid leukemia and bcr-abl positive
acute lymphocytic leukemia and also very efficient in the
treatment of gastrointestinal stromal tumors (GIST). In a
review of 125 patients who received imatinib during
pregnancy, a total of 12 infants presented with abnormal-
ities, 3 of which were with complex malformations. Thus,
imatinib should be avoided during pregnancy. However, in
distinct cases when imatinib is indispensable, the preg-
nancy should be closely monitored considering termination
if significant abnormalities are identified [9,33].
Lapatinib To date, only one case of metastatic breast
cancer is known treated during pregnancy with lapatinib.
The patient, participating in a clinical trial, was treated for
11 weeks with this dual tyrosine kinase inhibitor. After
ceasing the treatment, she delivered a healthy baby without
complications in the 36th week of gestation.
Anti-endocrine therapy
Anti-endocrine therapy of breast cancer should be post-
poned until after delivery. Neonatal defects in the genital
tract of female mice due to tamoxifen exposure in utero
have been reported, and there is a single case report of
Arch Gynecol Obstet
123
ambiguous genitalia and Goldenhar syndrome in children
exposed to tamoxifen in utero [13]. To our knowledge,
there are no data concerning the administration of gona-
dotropin releasing hormone antagonists or aromatase
inhibitors during pregnancy. As the application of aroma-
tase inhibitors is not indicated in premenopausal women,
and the indication for GnRH single use is limited to
tamoxifen contraindication, these agents are consequently
not administered in pregnant women [34].
Supportive treatment
Supportive treatment is a major, integral part of systemic
cancer treatment, as up to 70% of all cancer patients suffer
from nausea and emesis due to chemotherapy. However, it
is mandatory for the pregnant woman to be in good general
condition, as weight loss and electrolyte deferral may harm
the fetus. Metoclopramide, antihistamines or setron-based
antiemetics are not considered to cause any malformations
neither in animal models nor in humans. The data for
granulocyte stimulating factor (G-CSF) in case of chemo-
therapy-induced cytopenias during pregnancy are limited,
but no teratogenic effects have been observed so far [14].
Data for the use of bisphosphonates, such as zoledronic
acid, pamidronate, ibandronate and clodronate, are also
very rare and teratogenic effects have not been reported
yet. However, these agents pass the placenta and could
cause hypocalcaemia that is associated with neonatal
deaths. Moreover, bisphosphonates could inhibit fetal
osteoclast activity and lead to skeletal deformation. So far,
none has been described. But, due to limited data, such
adverse effects cannot be excluded [35,36].
Surgery in pregnancy
Surgery of solid tumors has gained high importance during
pregnancy when it can be performed as a local therapy
without harming the fetus. Surgery is considered to be
safely performed in all three trimesters. It is, however,
recommended to postpone surgery until the second tri-
mester of gestation with regard to a discussed risk of
spontaneous abortions before this period due to surgery and
anesthesia [37]. In advance, fetal lung maturation should be
induced by 2 912 mg betamethasone 24 h injected con-
secutively intramuscular to the mother if the operation
takes place during the period of neonatal premature via-
bility before 34 ?0 weeks of gestation. During the oper-
ation, the fetus should be monitored in some cases and
especially in cases of abdominal operations, prophylactic
tocolysis, for e.g., with fenoterol, may be considered [37].
Intraoperatively, the patient should be placed in left lateral
position to prevent the compression of the inferior vena
cava, and thus a reduced uterine perfusion. Maternal blood
gases must be monitored as carbon dioxide insufflations
can induce maternal hypercapnia which may enhance fetal
hypercapnia, tachycardia, and hypertension [37].
Therapeutic abortion
Induced abortion was considered an important option in
cases of malignancy in pregnancy for a long time. How-
ever, the hypothesis of worsening of prognosis of cancer
and decrease of the treatment response due to pregnancy
has been refuted. The prognosis for pregnant patients with
breast cancer does not appear to be worse than that for age-
and stage-matched non-pregnant controls [25]. Similar case
control studies have been performed for other cancer
entities. Survival of pregnant women with malignant mel-
anoma, genital carcinoma and colorectal carcinoma, as
well as most hematological malignancies, did not differ
from survival in non-pregnant controls [38]. The extremely
rare hepatocellular carcinoma, questionably thyroid cancer,
and probably renal cell carcinoma constitute the only
exceptions with poorer prognosis compared with malig-
nancies in non-pregnant periods [34,39,40]. Thus, induced
abortion can usually no longer be considered a therapeutic
means to ameliorate the prognosis of cancer patients.
Abortion rather alleviates the patient’s fear of harming the
fetus by antineoplastic therapies. The concept of induced
abortion as a treatment modality emphasizes on the ethic
aspect of balancing the different therapeutic options and
the philosophical and biological paradox of the diagnosis
of cancer in pregnancy [2].
Distinct tumor entities—gynecological malignancies
Cervical cancer during pregnancy
One-third of all cervical carcinomas occur during the
reproductive period. The incidence of cervical cancer is
estimated to be 1:1,000 and 1:5,000 pregnancies [41]. The
diagnosis of cervical cancer in a pregnant woman poses a
lot of difficulties due to the critical—uterine—location
with regard to the fetus.
Diagnosis
The chance that cervical cancer during pregnancy is
diagnosed at an early stage is three times greater in com-
parison with non-pregnant controls due to routine prenatal
care. A Papanicolaou test is performed routinely in the first
trimester screening and colposcopy should be performed in
Arch Gynecol Obstet
123
case of abnormalities. Guided cervical biopsies can be
taken if possible. Seventy-six percent of malignant lesions
diagnosed during pregnancy are stage IB. Conization
should usually be postponed until after delivery. However,
if indispensable, conization should be performed during the
second trimester between the 14th and 20th week of ges-
tation as the risks for bleeding and abortion are reduced.
Conization in the first trimester of pregnancy is associated
with an abortion rate of up to 33% [41]. Meanwhile,
endocervical curettage is contraindicated because of the
risk for premature rupture of membranes [42].
Therapy
Microinvasive carcinoma (stage IA1) There are no clear
recommendations concerning microinvasive cervical car-
cinoma during pregnancy. Conization should be considered
to rule out invasive carcinoma. Alternatively, colposcopic
controls in short intervals of 1 month may be performed.
Invasive carcinoma (stages IA2–IIA) If the diagnosis is
done before the 16th week of gestation, therapy should not
be delayed. After the 16th week of gestation, fetal pul-
monary maturity may be awaited with informed consent of
the mother. If surgical treatment is performed before
20 weeks of gestation, radical hysterectomy—with the
fetus remaining in utero—and lymphadenectomy are
performed.
Considering the close location of pregnancy and
malignancy, radiotherapy cannot be performed in cases of
cervical cancer if the pregnancy is to be preserved. Azim
et al. reviewed four pregnant patients with cervical cancer
who underwent external beam radiotherapy, one of whom
even received brachytherapy. All patients experienced
miscarriage and intrauterine fetal death (IUFD) [9]. If the
mother opts for termination of the pregnancy and imme-
diate therapy, radiotherapy can be performed with the fetus
in situ which in most cases will lead to spontaneous
abortion. Meanwhile, it is necessary to empty the uterine
cavity before complementary brachytherapy [42]. In dis-
tinct cases, neoadjuvant chemotherapy might be performed
to postpone surgery until fetal maturity is reached. Che-
motherapy should be cisplatin-based [42].
In any case of invasive cervical cancer, delivery must be
performed by cesarean section. Vaginal delivery may result
in lymphovascular dissemination, excessive hemorrhage,
obstruction of the birth canal, laceration of the cervix and
implantation of malignant cells at the site of episiotomy
[43].
Invasive carcinoma (Stages IIB–IV) In these rare condi-
tions, therapy consists of chemotherapy based on the use of
cisplatin followed by radiotherapy and should not be
postponed [42]. However, limited live expectation despite
therapy should be kept in mind.
Malignant ovarian tumors during pregnancy
Malignant ovarian tumors rarely occur during pregnancy;
their incidence is estimated to be 1:10,000 and 1:50,000
pregnancies [44]. Whereas ovarian tumors, in general, are
found in 1:80 and 1:2,500 pregnancies, only 2–5% of these
tumors are malignant [45,46]. Thus, most adnexal masses
diagnosed during pregnancy are benign.
Several facts are characteristic for ovarian tumors in
pregnant women; on the one hand, adnexal masses are
usually detected at an early stage due to routine ultrasound
examinations during pregnancy. On the other hand,
symptoms may be masked by pregnancy and sonographic
findings might be misinterpreted.
Generally, ovarian malignancies can be subdivided into
the malignant variants of epithelial tumors and non-epi-
thelial tumors (germ cell tumors and sex-cord stromal
tumors). Borderline tumors form another important clinical
entity. The latter are among the most frequently diagnosed
histological subtypes in pregnancy (27–35%). Epithelial
malignant tumors have a peak incidence at around
60 years, whereas non-epithelial ovarian malignancies
commonly emerge in premenopausal women [44]. Epi-
thelial malignancies form 23–30% of all cases of ovarian
malignancies associated with pregnancy. In Caucasians,
dysgerminoma is the single most frequent malignant
ovarian tumor diagnosed during pregnancy (25–35%)
[47–49].
Typical tumor markers for ovarian malignancies are
restricted to specific diagnostic questions and cannot be
applied in general during pregnancy. For example, CA
12–5, which is typically elevated in patients with ovarian
cancer, may be false-positive as it increases during the first
trimester and may be elevated throughout the whole
pregnancy [47,50,51].
As in non-pregnant patients, the main therapeutic
approach consists of cyto-reductive surgery. During preg-
nancy, surgical staging and debulking should be performed,
salpingo-oophorectomy at least of the affected side, peri-
toneal cytology and exploration. Marret et al. [44] recom-
mend surgery to be performed after 15 weeks of gestation
for ovarian masses which persist into the second trimester,
are [5–10 cm in diameter or are solid or mixed solid and
cystic in sonography. The second-look laparotomy should
be performed after delivery in cases of malignancies to
extend the operation according to the present guidelines.
According to biological plausibility, the substitution of
progesterone has to be kept in mind when bilateral sal-
pingo-oophorectomy is performed in the first trimester, and
the patient wishes to continue her pregnancy.
Arch Gynecol Obstet
123
Chemotherapy should be postponed until after delivery
if possible, or at least after 20 weeks of gestation. For
advanced ovarian cancer, the gold standard chemothera-
peutic regimen consists of six cycles of carboplatin AUC 5
and paclitaxel 175 mg/m
2
every 3 weeks. This regimen is
also regarded the standard therapeutic approach in pregnant
patients, and to date no severe adverse fetal affects have
been reported [24,51–53].
However, data on chemotherapy for ovarian malignan-
cies in pregnancy are still restricted to case reports.
As in non-pregnant women, there is no indication for
chemotherapy of ovarian borderline tumors in pregnancy
[47].
Azim et al. presented a literature review, summarizing
18 cases of non-epithelial and 20 cases of epithelial ovarian
malignancies during pregnancy. All patients were treated
with chemotherapy; in 37 patients, platin-based chemo-
therapy regimens were given. One patient with malignant
germ cell tumor received vincristine, actinomycin-D and
cyclophosphamide [9]. All babies were born alive, one
newborn suffered from transient anemia and respiratory
distress. In some non-epithelial ovarian malignancies, e.g.,
malignant germ cell tumors and sex-cord stromal tumors,
bleomycin, etoposide and cisplatin are applied. In one
reported case, the newborn presented with ventriculomeg-
aly and subsequent cerebral atrophy. Another newborn
showed alopecia, hearing loss and hematological abnor-
malities which were contributed to etoposide. Meanwhile,
in 11 case reports of patients treated with either bleomycin,
etoposide and cisplatin or etoposide and cisplatin or cis-
platin, vinblastine and bleomycin, no severe malformations
or severe fetal adverse affects were attributed to chemo-
therapy in utero [9]. In regard to the limited data in general,
chemotherapy regimens with sufficient data should be
preferred in pregnancy [29]. Radiation is no part of the
therapeutic regimen in either pregnant or non-pregnant
women with ovarian malignancies.
Endometrial cancer during pregnancy
Endometrial cancer associated with pregnancy is extremely
a rare event. To the best of our knowledge, no case of
endometrial cancer diagnosed and treated during preg-
nancy with a favorable fetal outcome has been reported so
far. Endometrial carcinoma associated with pregnancy is
either diagnosed incidentally in early pregnancy in cases of
spontaneous abortion or bleeding or in cases of vaginal
bleeding post partum. Thus, there is rarely a dilemma
regarding the balance of fetal and maternal outcomes as
nearly all reported cases in the literature were in associa-
tion with miscarriage or in the postpartum period. The
existence of an endometrial malignancy before conception
likely creates an intrauterine environment that is
unfavorable for embryo implantation [54]. In contrast,
pregnancy has a protective effect regarding the develop-
ment of endometrial neoplasia [55,56]. The presence of
immature progesterone unresponsive endometrium has
been discussed as a possible etiology of the unusual coin-
cidence of endometrial carcinoma and pregnancy. The
neoplasm may arise in foci of immature basal cells, which
do not respond to hormonal stimulation [57–59].
Vulvar cancer during pregnancy
Vulvar carcinoma is rare in premenopausal women, and
consequently data of gestational vulvar cancer are limited
to a single case report [60]. However, the incidence of
invasive squamous cell carcinoma of the vulva in women
under 40 years of age has been increasing, particularly in
association with human papilloma virus and HIV [61].
Radical surgery, e.g., radical vulvectomy with groin lymph
node dissection, is the basic therapeutic approach in vulvar
cancer during pregnancy [47,62]. Management of vulvar
carcinoma is basically not modified during pregnancy, but
the week of gestation again must be considered [63,64].
With regard to an increased genital vascularisation in the
third trimester of pregnancy resulting in higher surgical
morbidity, treatment might be postponed until after deliv-
ery when the diagnosis is made after the 36th week of
gestation [47].
Vaginal cancer during pregnancy
Whereas primary vaginal cancers represent about 1–2% of
all cancers of the female genital tract, secondary malignant
involvement of the vagina due to cancers arising from the
vulva, uterine cervix or endometrium, bladder, rectum or
colon is seen more frequently [65]. Histologically, malig-
nant vaginal tumors are most often squamous cell carci-
nomas (80–90%), followed by adenocarcinoma (5–10%),
melanoma, and leio- or rhabdomyosarcoma. The mean age
at diagnosis of women suffering from a primary vaginal
malignancy is usually [60 years. The in utero exposure to
diethylstilbestrol has been established as a risk factor for
the development of a clear cell adenocarcinoma of the
vagina in young women. However, the diagnosis of a pri-
mary malignant lesion of the vagina is still a very rare
event during pregnancy with only anecdotal reports been
published [66–72].
Vaginal tumors may be associated with symptoms such
as increased discharge and irregular (contact) bleeding.
A Pap smear, colposcopy and guided biopsies may help to
establish the correct diagnosis. Staging examinations for
vaginal cancer usually include cystoscopy and proctorec-
toscopy, abdominal ultrasound and chest X-ray (with
adequate shielding of the uterus), which may be safely
Arch Gynecol Obstet
123
applied during pregnancy. However, other important diag-
nostic procedures for vaginal cancer, such as urography and
computed tomography of the pelvis, cannot be applied in
pregnant women without a significant fetal exposure to
radiation.
Due to its rarity, no recommendations or treatment
guidelines exist for vaginal cancers diagnosed during
pregnancy. For non-pregnant women with resectable
tumors, surgical therapy is dependent of the localization of
the tumor and may include local resection for very small
lesions or radical hysterectomy, radical colpectomy and
pelvic (and possibly paraaortic) lymph node dissection
when the tumor is located in the upper third of the vagina
followed by radiation. Radical vulvectomy and colpectomy
with inguino-femoral lymph node dissection, followed by
radiation, are performed in cases of tumor localization in
the distal part of the vagina. In more advanced stages,
exenteration and percutaneous and intracavitary radiation
with or without chemotherapy (cisplatin) are among the
therapeutic options. Some authors suppose that no differ-
ence in prognosis is seen between pregnant and non-
pregnant women suffering from vaginal cancer [73]. Due to
a low 5-year survival rate in general, the therapeutic
approach for pregnant women with vaginal malignancies
has to be planned individually, depending on the stage of
the cancer, the patient’s gestational week and her attitude
toward a possible continuation of the pregnancy. It is not
established whether therapeutic delay due to pregnancy
considerations may significantly change the patient’s
prognosis [73]. It is, however, plausible to perform a pri-
mary Cesarean section in the rare event that a pregnancy is
preserved.
Conflict of interest None.
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