Archives of Gynecology and Obstetrics

, Volume 285, Issue 1, pp 195–205

Cancer in pregnancy. Part I: basic diagnostic and therapeutic principles and treatment of gynecological malignancies

Authors

    • Department of Obstetrics and GynecologyUniversity Hospital of Schleswig–Holstein
  • Roland Reibke
    • Department of Internal Medicine III; Klinikum GrosshadernLudwigs-Maximilians-University of Munich
  • Katrin Hornemann
    • Department of Thoracic Surgery, ThoraxklinikUniversity of Heidelberg
  • Marc Thill
    • Department of Obstetrics and GynecologyUniversity Hospital of Schleswig–Holstein
  • Doerte W. Luedders
    • Department of Obstetrics and GynecologyUniversity Hospital of Schleswig–Holstein
  • Katharina Kelling
    • Department of Obstetrics and GynecologyUniversity Hospital of Schleswig–Holstein
  • Amadeus Hornemann
    • Department of Obstetrics and GynecologyUniversity Medical Center Mannheim, University of Heidelberg
  • Michael K. Bohlmann
    • Department of Obstetrics and GynecologyUniversity Hospital of Schleswig–Holstein
Gynecologic Oncology

DOI: 10.1007/s00404-011-2058-8

Cite this article as:
Hoellen, F., Reibke, R., Hornemann, K. et al. Arch Gynecol Obstet (2012) 285: 195. doi:10.1007/s00404-011-2058-8

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 postponing childbearing to older age. To date, clinical guidelines 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

CancerMalignancyPregnancyChemotherapyRadiotherapyFetus

Introduction

Cancer in pregnancy is a rare circumstance. The coincidence 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 [13]. 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 obstetricians are faced with the challenge of providing the mother with the best treatment while preventing from doing harm to the fetus.
Table 1

Incidence of tumor types in pregnancy per number of gestations (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

This review article will focus on the diagnostic and therapeutic principles in general and on the treatment of nontrophoblastic malignancies diagnosed during pregnancy. 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.

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 physiological alterations due to pregnancy. Cervical cancer constitutes an exception, probably due to frequent gynecological examinations in pregnancy.

In general, biopsies, punctures, and endoscopy are considered safe during pregnancy.

X-ray diagnostic procedures should be avoided if possible as ionizing radiation may induce leukemia and solid tumors in children and adults. The Oxford survey of childhood cancer demonstrated an increased risk for leukemia (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 computed 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 mammography decreases in pregnant women due to an alteration of radiographic density of the breast and it is estimated to be 68%, whereas sonography provides a sensitivity of 93% [3].
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

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

Tumor marker levels are generally to be interpreted with caution, but especially during pregnancy. Elevated maternal 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. 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 investigated 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 chemotherapy 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 toxicity, 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 trespass the placental barrier more easily. The strong placental expression of drug-extruding transporters, such as P-glycoprotein (PgP), limits the transplacental transfer. Recent data suggest that tubulin-binding agents such as paclitaxel and vinca-alkaloids do not trespass the placenta due to the PgP transporting system [13].
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

In general, the application of chemotherapeutic agents known to produce medullar toxicity should cease 2 weeks before delivery to prevent neonatal infection with neutropenia. 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 trimester 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].
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/m2 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

As a small patient population is taken into account, there is a lack of data dealing with pharmacokinetics of chemotherapy 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 concentration and an increase in distribution volume and clearance in pregnant patients. To date, chemotherapy is administered according to standard dose regimens. However, 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, sensomotoric 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 chemotherapeutic 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-intercalation, and by interfering with topoisomerase 2 and damage to the cell wall. Topoisomerase 2α is overexpressed 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, respectively [20]. The application of anthracyclines in the second and third trimester seems to be safe. Preliminary data on 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 during pregnancy. A total of five heterogeneous malformations (3%) were reported [19] which may be comparable with the general population. However, possible long-term cardiotoxic 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/m2 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 lipophilic. 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 oxaliplatin): data to carboplatin are limited, but it showed less adverse fetal events in comparison with cisplatin [9]. However, carboplatin causes thrombocytopenia. Platinum derivates 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 carboplatin in 6 cases, both agents in one case). Two fetal malformations were reported after in utero exposure to cisplatin, but lacked proof of causality. Furthermore, in some cases acute respiratory distress, cytopenia, creatinine elevation, and hearing impairment were reported. Longest follow-up data are 40, 42 and 73 months without any evidence of sequelae in the children [24]. In general, platinum derivates 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 administration 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 pregnancy due to the limited safety data [25]. Several preclinical reports indicate that the placental P-glycoprotein system could prevent the transplacental transfer of taxanes and vinca-alkaloids. Thus, though not thoroughly examined, 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 application 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, cyclophosphamide) 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 elevated 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, ifosfamide), 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, showing growth deficiency, developmental delay, limb and craniofacial anomalies [28]. Cyclophosphamide as a part of combined chemotherapy regimens for breast cancer, primarily FAC (5-fluorouracil, doxorubicin, cyclophosphamide), 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 concerning the application of bleomycin during pregnancy [9].

Etoposide is a topoisomerase inhibitor. In some non-epithelial ovarian cancers, bleomycin, etoposide, and cisplatin are applied as the standard chemotherapy regimen. In one reported case, the newborn presented with ventriculomegaly and subsequent cerebral atrophy. Another 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 syncytiotrophoblast binds to the Fc portion of the IgG. As the Fc receptor is hardly expressed before the 14th week of gestation, the materno-fetal IgG transfer during the first trimester 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 physiological 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 bevacizumab 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 inhibitors sunitinib, sorafenib, pazopanib and BIBF 1120 as well. There are just a few cases of intravitreal injection of bevacizumab in patients with choroidopathy with unproblematic 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 published so far. In one case, the anti-EGFR agent erlotinib was administered during the first 2 months of unrecognized pregnancy 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 embryonic cardiac development, it is supposed to entail heart anomalies when administered during pregnancy. To date, 15 breast cancer patients have been reported with trastuzumab during pregnancy [1]. Among these 15 patients, 11 patients became unintentionally pregnant during trastuzumab therapy. The most striking effect was oligohydramnios 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 trastuzumab 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 administration 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 suppression 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 abnormalities, 3 of which were with complex malformations. Thus, imatinib should be avoided during pregnancy. However, in distinct cases when imatinib is indispensable, the pregnancy 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 postponed 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 ambiguous genitalia and Goldenhar syndrome in children exposed to tamoxifen in utero [13]. To our knowledge, there are no data concerning the administration of gonadotropin releasing hormone antagonists or aromatase inhibitors during pregnancy. As the application of aromatase 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 chemotherapy-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 trimester 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 × 12 mg betamethasone 24 h injected consecutively intramuscular to the mother if the operation takes place during the period of neonatal premature viability before 34 + 0 weeks of gestation. During the operation, 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. However, 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 melanoma, 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 malignancies 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 comparison 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 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 gestation 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 carcinoma 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 pulmonary 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 immediate 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 distinct cases, neoadjuvant chemotherapy might be performed to postpone surgery until fetal maturity is reached. Chemotherapy 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 conditions, 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-epithelial 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]. Epithelial 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%) [4749].

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 pregnancy, surgical staging and debulking should be performed, salpingo-oophorectomy at least of the affected side, peritoneal cytology and exploration. Marret et al. [44] recommend 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 salpingo-oophorectomy is performed in the first trimester, and the patient wishes to continue her pregnancy.

Chemotherapy should be postponed until after delivery if possible, or at least after 20 weeks of gestation. For advanced ovarian cancer, the gold standard chemotherapeutic regimen consists of six cycles of carboplatin AUC 5 and paclitaxel 175 mg/m2 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, 5153].

However, data on chemotherapy for ovarian malignancies 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 chemotherapy 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 ventriculomegaly and subsequent cerebral atrophy. Another newborn showed alopecia, hearing loss and hematological abnormalities which were contributed to etoposide. Meanwhile, in 11 case reports of patients treated with either bleomycin, etoposide and cisplatin or etoposide and cisplatin or cisplatin, vinblastine and bleomycin, no severe malformations or severe fetal adverse affects were attributed to chemotherapy 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 pregnancy 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 association 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 development of endometrial neoplasia [55, 56]. The presence of immature progesterone unresponsive endometrium has been discussed as a possible etiology of the unusual coincidence of endometrial carcinoma and pregnancy. The neoplasm may arise in foci of immature basal cells, which do not respond to hormonal stimulation [5759].

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 delivery 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, malignant vaginal tumors are most often squamous cell carcinomas (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 primary malignant lesion of the vagina is still a very rare event during pregnancy with only anecdotal reports been published [6672].

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 proctorectoscopy, abdominal ultrasound and chest X-ray (with adequate shielding of the uterus), which may be safely applied during pregnancy. However, other important diagnostic 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 difference 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 primary Cesarean section in the rare event that a pregnancy is preserved.

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