Download Chemotherapy during pregnancy

Practice Guidelines
Chemotherapy during pregnancy
L. Heyns, K. Van Calsteren, S.N. Han, M. Mhallem Gziri, P. Augustijns, F. Amant
When a pregnant woman is diagnosed with cancer, treatment with chemotherapy can be
life-saving for the mother but might put the foetal development at risk. Haematologic
malignancies constitute approximately 20% of all cancers during pregnancy. Depending
on the type of cancer and the stage of disease at diagnosis, chemotherapy cannot always
be delayed until postpartum. Uncomplicated use of chemotherapy during pregnancy has
been reported, especially during the second and third trimester, however firm data on long
term maternal and foetal outcome are lacking. It appears from preclinical studies that the
placenta functions as a barrier and protects the foetus from cytotoxic effects. In clinical
practice, ABVD, R-CHOP and IFN-α are used for treatment of haematologic cancer during
pregnancy. Imatinib-mesylate is not recommended during pregnancy. Currently the same
dosages of chemotherapeutic agents are administered to pregnant and non-pregnant
patients. Albeit, gestational changes in haemodynamics and drug pharmacokinetics
render optimal chemotherapeutic dosage during pregnancy uncertain. In this review, we
discuss transplacental passage of chemotherapeutical agents, the toxicity in the three
trimesters of pregnancy, pharmacokinetics of chemotherapy during pregnancy and the
use of chemotherapeutical agents for haematologic malignancies.
(Belg J Hematol 2011;2:101-6)
Introduction
The diagnosis of cancer during pregnancy is relatively
uncommon and its incidence is estimated to be
about 1 per 1,000 pregnant women.1 The majority
of patients have a solid tumour, haematologic
malignancies represent almost 18% of cancer during
pregnancy.2 Hodgkin disease (HD) and high grade
non-Hodgkin lymphomas (NHL) have a peak
incidence in the second to fifth decade of life and
can thus be diagnosed in pregnant women. HD
is significantly more common than NHL, with an
incidence of 10 to 50 per 100,000 pregnancies.2 NHL
is rarely reported during pregnancy; however, the
HIV epidemic which increases the risk of developing
NHL 150-fold, along with the trend to delay childbearing, can make it more frequent in future.3 The
occurrence of leukaemia during pregnancy is very
rare with an estimated incidence of 1 per 100,000
pregnancies annually. The epidemiology of leukaemia
in pregnant women reflects the relative frequency in
the general population. Most leukaemias are acute,
two thirds myeloid (AML) and one third lymphatic
(ALL). Chronic myeloid leukaemia (CML) is found
in less than 10% of leukaemias during pregnancy.4
The coincidence of pregnancy and cancer presents
complex therapeutic problems requiring a
multidisciplinary approach. Although the treatment
options for the non-pregnant patient with cancer have
Authors: L. Heyns MSc, K. Van Calsteren MD PhD, S.N. Han MD, M. Mhallem Gziri MD, P. Augustijns PhD, F. Amant MD PhD, Department
of Gynecological Oncology
Please send all correspondence to: F. Amant MD PhD, UZ Gasthuisberg Leuven, Department of Gynecological Oncology, UZ Leuven,
Belgium. Herestraat 49, 3000 Leuven, Belgium, tel: 0032 16 344 252, email: [email protected]
Conflict of interest: The authors have nothing to disclose and indicate no potential conflict of interest. F. Amant is Sr. Clinical Investigator
for the Research Fund-Flanders.
Key words: cancer, chemotherapy, haematology, pregnancy
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3
been extensively examined, the current knowledge
and treatment of the pregnant patient with cancer is
based on anecdotical cases, small series with relatively
short follow up periods and mostly retrospective data.
The care of a pregnant patient with a malignancy
necessitates a difficult balance of trying to cure the
mother while minimising the effects on the foetus.
With the use of cytotoxic agents during pregnancy,
concerns arise with regard to the teratogenicity and
long term effects for the foetus.
The purpose of this review is to evaluate the
available data on the use of chemotherapy during
pregnancy, including trimester of exposure, changes
in drug metabolism during pregnancy and the
placental properties to minimise the foetal exposure
to chemotherapeutical agents.
Transplacental passage
The foetoplacental unit renders prenatal
chemotherapy administration possible. The placenta
provides a link between the circulations of two
distinct individuals but also acts as a barrier to protect
the foetus from xenobiotics in the maternal blood.
Since placental transfer of drugs from the maternal to
the foetal side primarily occurs by passive diffusion,
the physicochemical properties of the drugs, such
as lipid solubility, polarity and molecular weight,
the concentration gradient over the placenta and
the properties of the placenta determine the rate of
transfer across the placenta.5 Low molecular weight,
lipid soluble, non-ionised drugs can easily cross
the placenta.6 Drug binding to plasma proteins will
reduce placental transfer, due to the larger structure
of the complex that has been formed. Only a few
groups conducted transplacental studies (Table 1).
Gaillard et al. and Grohard et al. examined
transplacental transfer of epirubicin and doxorubicine
respectively by in vitro placental perfusion of term
human placenta’s. They found limited transfer to the
foetus for both antracyclines.7,8 Van Calsteren et al.
examined the transplacental materno-foetal transfer
of different drugs in a mouse model and a baboon
model. In the mouse model, important variations
were found between different chemotherapeutical
agents. High transfer was found for carboplatin, an
intermediate transfer for cytarabine, a limited transfer
for anthracyclines and vinblastin and undetectable
levels of paclitaxel in the foetal plasma.9 In the baboon
model, FEC, ABVD were administered to pregnant
Belgian Journal of Hematology
baboons and maternal and foetal bloodsamples were
taken simultaneously. Low transfer was found for
doxorubicin, epirubicin, vinblastin and (4-OH)CP, the
active metabolite of cyclofosphamide.10 Remarkable
was the fact that all P-glycoprotein substrates revealed
a limited transfer stressing the importance of ATPbinding cassette proteins in the protection of the
foetus from chemotherapeutics. Also supportive
treatment can interact with these proteins and may
possibly affect the transfer of chemotherapeutical
agents to the foetal compartment. To date these
interactions have not yet been examined and
supportive treatment can be given according to
general recommendations.11 Granulocyte colony
stimulating factors and erythropoietin can also be
used safely during pregnancy. Corticoids can be
used after the first trimester of pregnancy, though
prednisolone and hydrocortisone are preferred over
beta- and dexamethasone.12
Chemotherapy exposure in utero
Short term outcome
Chemotherapeutical agents are toxic for cells since
they cause chromosomal breaks, gene mutations,
aneuploidy and cell cycle disruption. Therefore
their administration during pregnancy generates
important concerns regarding the effects on the
developing foetus. The organogenesis, until the
tenth week after conception, is the most vulnerable
period of pregnancy. Since cytotoxic therapy may
interfere with organogenesis, teratogenic effects
will be maximal at this time of pregnancy and
chemotherapy administration is contraindicated.1
Including a safety period, it is strongly
recommended to wait until 14 weeks to initiate
chemotherapy. The risk of congenital malformations
when chemotherapy is administered after the
first trimester is about 3%, which approaches the
baseline population risk.13 During the second
and third trimester, chemotherapy is considered
relatively safe; however, cases of intrauterine
growth restriction, in utero and neonatal death,
haematopoietic suppression and preterm delivery
have been reported. Chemotherapy exposure in the
last 3-4 weeks before the delivery should be avoided,
since haematological toxicity can put the mother as
well as the foetus at risk for infections and bleeding
complications during delivery.12 In order to evaluate
the association of adverse events in the mother and
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Practice Guidelines
Table 1. Transplacental passage of chemotherapeutical agents.
Drug
MOUSE 9
BABOON 10, 33
PERFUSION MODEL 7,8
% transfer
(mean + SD)
% transfer
(mean + SD)
% transfer
(mean + SD)
daunorubicin
13.3 + 3.5
epirubicin
4.8 + 3.8
4.0 + 1.6
3.66 + 1.07
doxorubicin
5.1 + 0.6
7.5 + 3.2
2.96 + 0.75
ND
1.6 + 0.8
paclitaxel
docetaxel
vinblastine
ND
13.8 + 5.8
18.5 + 15.5
carboplatinum
117.0 + 38.9
57.5 + 14.2
cytarabine
56.7 + 22.6
(4-OH)CP
25.1 + 6.3
SD=standard deviation, ND=not detectable, (4-OH)CP=(4-hydroxy-)cyclophosphamide.
the foetus, Aviles et al. reviewed the literature and
found 1,395 cases which documented the use of
chemotherapy for haematological malignancies
during pregnancy.14 Congenital malformations were
reported in 5,8% of all newborns. Malformations
in hands, toes, extremities and hypospadias were
most frequently encountered. Based on these
findings, they concluded that chemotherapy
could be administered safely during second and
third trimester of pregnancy. Van Calsteren et al.
reported on 215 patients with cancer diagnosed
during pregnancy.15 In the group of patients who
were treated with chemotherapy during pregnancy,
an increase in small for gestational age (SGA)
children (birth weight below tenth percentile) was
observed. Most of them are from mothers with
haematological tumours, suggesting that the impact
on foetal growth might be related to specific cancer
types and treatments. In general, the incidence of
congenital malformations was not increased and the
malformations that were reported are also seen in
the normal population.
Long term outcome
Long term follow up studies are scarce. Only 2 series
have been described with a follow up till schoolage. Hahn et al. described 57 patients who were
treated for breast cancer during pregnancy.16 The
results were obtained by interviewing the parents
and teachers by telephone or email. Respiratory
problems were the most important neonatal
complications (N=10). One child suffered from
a subarachnoidal bleeding and three congenital
anomalies were registered. Forty children were
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followed until the age of 2 till 157 months, 43% of
them had no medical problems. Medical problems
that were reported included allergy, eczema (20%),
asthma (10%) and upper respiratory interactions.
Two of the 18 children who went to school needed
special attention. One need to underline that many
described problems on the short term are associated
with prematurity. Aviles et al. described a series
of 84 children from mothers with haematological
malignancies who received chemotherapy during
pregnancy.17 They reported that all children
had a normal birth weight, a normal learning
and educational performance, no congenital,
neurological or psychological abnormalities and no
malignancies.
Pharmacokinetics during pregnancy
Changes in maternal physiology and morphology
associated with pregnancy alter the absorption,
distribution, metabolism and excretion of drugs and
make it very difficult to predict pharmacokinetics
of chemotherapy during pregnancy. These changes
include an increase in distribution volume due to
increased blood volume, body fat and the development
of an extra (amniotic) fluid compartment.18 The higher
oestrogen and progesterone levels affect the activity
and expression of metabolising enzymes. Depending
on which metabolic enzymes are involved, a higher
or lower rate of metabolism will be seen.19 Also, renal
blood flow and glomerular filtration rate are increased
during pregnancy, leading to enhanced elimination
of drugs and lower steady state concentrations.20
These changes begin in early gestation but are most
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pronounced in the third trimester of pregnancy.
Most anticancer drugs have a wide inter-individual
pharmacokinetic variability and a narrow therapeutic
window, which may be increased in pregnancy. In
the absence of pharmacokinetically based dosing
guidelines for pregnancy, physicians use drug dosage
recommendations derived from studies conducted in
nonpregnant women. However, since the gestational
changes are not taken into account, anticancer drugs
levels might reach subtherapeutic or toxic levels.21
A recent study compared pharmacokinetics of
doxorubicin, epirubicine, paclitaxel and docetaxel
between the pregnant and the non-pregnant state.22
For all drugs tested, a decreased plasma drug
exposure (area under the curve and maximal plasma
concentration), an increased distribution volume
and clearance were observed in pregnancy. These
data underline the importance of further research to
translate the differences in plasma levels into alterations
in tumour concentration and treatment efficacy.
Clinical importance for haematology
Standard treatment as a combination scheme of
doxorubicin-bleomycin-vinblastine-dacarbazine
(ABVD) for HD; cyclophosphamide-vincristinedoxorubicin-prednisone with or without rituximab
(R-CHOP) for NHL and high dose combination
schemes including vincristine, methotrexate, an
anthracycline, cyclophosphamide and cytarabine for
leukaemia have been described during pregnancy.23
Based on different case reports, ABVD and (R)-CHOP
regimens seems to be safe when given during second
or third trimester. A recent review of the literature
yielded no foetal adverse events when ABVD was
given after the first trimester. One intra-uterine foetal
death (3%) occurred during third trimester.24 In
one patient who received CHOP during pregnancy,
transitory lymphopaenia in the newborn has been
reported, albeit without congenital malformations.25
Since rituximab is an antibody of the IgG isotype, it is
likely to cross the placental barrier and interact with
foetal B cells. One case report compared maternal and
foetal rituximab concentrations and B cells. Although
at birth rituximab concentrations were similar in
mother and child and the foetal B cells were severely
diminished (1% of normal) at birth, B cells recovered
after 6 weeks, to reach a normal level at 12 weeks.
No further adverse events or malformations were
seen during 16 months follow up.26 For this reason,
Belgian Journal of Hematology
rituximab, seems to be safe and without significant
consequences for the foetus.26
Administration of imatinib mesylate, a tyrosine
kinase inhibitor, during the first trimester is
associated with a considerable risk of congenital
anomalies and spontaneous abortions, while late
exposure does not have the same impact. It has been
reported that the concentration of imatinib mesylate
and its active metabolite were higher in the placenta
than in the maternal blood, while they were low
or undetectable in the umbilical cord.27 Although
these findings suggest limited placental transfer of
imatinib mesylate in late pregnancy it should not be
the treatment of choice because of the high risk for
malformations during first trimester.23
Interferon-alpha (IFN-α), an immune modulator,
does not cross the placenta to a great extent due
to its high molecular weight (19kDa) and does
not inhibit DNA synthesis in the foetus. No foetal
malformations were reported when interferon was
administered as monotherapy. All reported cases
of pregnant women with chronic myelogenous
leukaemia (CML), treated with interferon, resulted
in healthy babies and normal maternal outcomes.
Given the available pre-clinical and clinical data,
interferon can be safely administered throughout
pregnancy and it is the treatment of choice for
patients diagnosed with CML in pregnancy.28
Hydroxyurea is a cytotoxic drug, which inhibits DNA
synthesis and is capable of crossing the placenta.
Several cases of hydroxyurea administration during
pregnancy have been reported. Hydroxyurea
treatment should be avoid in first trimester and could
be given to patients who cannot tolerate interferon
therapy during second or third trimester.29
No data are available yet for administration of
alemtuzumab during pregnancy. Given that
alemtuzumab is a large molecule with a molecular
weight of (150 kDa), it is unlikely to cross the
placental and reach the foetus.
Cytarabine, an antimetabolite that is used in
combination with other chemotherapeutical agents
for the treatment of acute leukaemia, carries a
significant risk to the foetus. A review of 93 cases of
pregnant women exposed to cytarabine alone or in
combination with other chemotherapeutical agents
reported 4 cases of limb malformations associated
with first trimester exposure. Administration in
second and third trimester was associated with
transient neonatal cytopaenias in 5 cases, intrauterine
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Practice Guidelines
Key messages for clinical practice
1.
Cancer complicates 1 in 1,000 pregnancies.
2.
A multidisciplinary approach is mandatory.
3.
Chemotherapy during the first trimester results in increased rates of congenital malformations but it can be administered safely from the second trimester onwards.
4.
In absence of pharmacokinetic data, during pregnancy the same dosages of chemotherapy are administered as in non-pregnant women.
5.
The placenta partially protects the foetus against most of the chemotherapeutic agents.
foetal death in 6 cases, intrauterine growth retardation
in 12 cases and 2 cases of neonatal deaths from severe
infections.1 For these reasons, the use of cytarabine in
the first trimester is not advised and termination of
pregnancy is strongly preferred.
Antracyclines are an integral part of regimens
used for treatment of many malignancies
besides leukaemias, including lymphomas,
breast- and lungcancer and soft tissue sarcomas.
Idarubicin is more lipophilic compared to other
anthracylines and placental transfer is more likely to
occur. Therefore, idarubicin may be associated with
higher rates of adverse foetal outcomes and should
be avoided during pregnancy.
Doxorubicin has widely studied for breast cancer
during pregnancy and its use is considered relatively
safe throughout pregnancy.16 Since doxorubicin
seems to be as effective as the other anthracyclines
for the treatment of leukaemia, it is the preferred
anthracycline during pregnancy.23
First trimester exposure to all trans retinoic acid
(ATRA), a vitamin A derivative, carries an 85% risk
of teratogenicity, including severe neurological and
cardiovascular malformations. The administration
of ATRA alone or in combination with an
anthracycline during the second and third trimesters
has been reported in several case-reports.23 These
limited data suggest that ATRA seems to be safe
and well tolerated when given after first trimester,
however close foetal cardiac monitoring is mandatory
throughout pregnancy.30
Methotrexate, a folate antagonist, is highly
teratogenic. First trimester methotrexate exposure is
associated with an increased risk of miscarriage. And
Belgian Journal of Hematology
105
also exposure to high dose methotrexate after the
first trimester is associated with cranial dysostosis,
delayed ossification, hypertelorism, wide nasal
bridge, micrognatia, anomalies of external ears
and cleft palate.31 The risk for foetal malformations
diminishes as pregnancy advances. However,
termination of pregnancy is recommended for
patients prior to the twentieth week of gestation.
After the twentieth week, a modified anti-ALL
treatment, without methotrexate, may be used.28
Conclusion
Pregnant women diagnosed with cancer require
an individualised treatment, established by a
multidisciplinary team. Most chemotherapeutic
agents are assigned to Food and Drug Administration
pregnancy category D and carry a product label
warning about the potential risk to the foetus.
However, depending on the type of malignancy,
clinical stage of disease and health status of the
mother, it may not always be possible to delay
chemotherapy until postpartum. Available research
data demonstrate short term safety data for several
chemotherapy regimens in the second and third
trimester of pregnancy. However, in the absence of
firm long term outcome data, a certain prudence
should be taken into account. In absence of valid
data, currently standard doses of drugs adjusted
to continuing weight gain during pregnancy are
used. Although pregnancy induces physiological
changes, it is unknown if the pregnant patient is
optimally treated compared to the nonpregnant
patients. More extensive studies are required
Volume 2, Issue 3, September 2011
3
for accurate prediction of pharmacokinetics of
chemotherapeutical agents in pregnancy. Besides
the changes in pharmacokinetics in pregnant
women, the placental transfer of drugs leading
to a potential toxicity to the foetus are a major
concern in the treatment of a pregnant patient
with chemotherapy. The placenta acts as a barrier
between the mother and the foetus, mostly low
molecular weight and lipophilic drugs pass through
the barrier. Ongoing research is continued in order
to collect more data on pharmacokinetics and the
maternal and foetal outcome.32
Van Gemert W, et al. Cancer during pregnancy: an analysis of 215 patients
emphasizing the obstetrical and the neonatal outcomes. J Clin Oncol
2010;28:683-9.
16. Hahn KM, Johnson PH, Gordon N, Kuerer H, Middleton L, Ramirez M,
et al. Treatment of pregnant breast cancer patients and outcomes of children
exposed to chemotherapy in utero. Cancer 2006;107:1219-26.
17. Aviles A, Neri N. Hematological malignancies and pregnancy: a final
report of 84 children who received chemotherapy in utero. Clin Lymphoma
2001;2:173-7.
18. Krauer B, Krauer F, Hytten FE. Drug disposition and pharmacokinetics in
the maternal-placental-fetal unit. Pharmacol Ther 1980;10:301-28.
19. Anderson GD. Pregnancy-induced changes in pharmacokinetics: a
mechanistic-based approach. Clin Pharmacokinet 2005;44:989-1008.
20. Dawes M, Chowienczyk PJ. Drugs in pregnancy. Pharmacokinetics in
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