Cancer and pregnancy: Poena magna, not anymore

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Review

Cancer and pregnancy: Poena magna, not anymore George Pentheroudakis, Nicholas Pavlidis* Department of Medical Oncology, Ioannina University Hospital, University of Ioannina, 45 110 Ioannina, Greece

A R T I C L E I N F O

A B S T R A C T

Article history:

Cancer diagnosed during pregnancy constitutes a difficult clinical condition with a devas-

Received 20 September 2005

tating impact on the patientÕs somatic and psychosocial health and possibly on foetal

Accepted 6 October 2005

integrity. This circumstance also raises several moral, religious, social and familial dilem-

Available online 2 December 2005

mas. In this review we critically present available evidence regarding the incidence, epidemiology and genetics of cancer in pregnant women, its presentation, diagnosis and staging

Keywords:

as well as therapeutic management. Issues such as maternal/foetal prognosis, need for ter-

Cancer

mination of pregnancy, risk of foetal health injury and necessity of psychosocial support

Pregnancy

are reviewed. Recent accumulating evidence suggests that, with appropriate management,

Foetus

poena magna should not be used to define neither cancer nor pregnancy.

Chemotherapy

Ó 2005 Elsevier Ltd. All rights reserved.

Radiotherapy

1.

Introduction

Cancer diagnosed during pregnancy is a dramatic event with profound impact on the lives of the patient, offspring, family and physician. As women in developed societies defer childbearing to the third or fourth decade of life, this rare association is likely to become more common. Curing the patient should still remain the top priority when this is deemed feasible. The dilemma of continuing pregnancy till birth of a viable foetus may turn out to be a complicated one and medical, social, personal, moral as well as religious factors interact to define the chosen course of action. Thorough evaluation of the patient and foetus, the biology and stage of the tumour and of therapeutic alternatives available are necessary for correct prioritization of goals and rationalization of management. The complex issues arising render this clinical condition extremely demanding for expertise and multidisciplinary care. In this article, data are reviewed and key aspects of epidemiology, diagnosis, management and outcome of pregnant women with cancer and embryos are presented.

2.

Epidemiology and genetics

Cancer association with pregnancy (CAP) is poorly studied epidemiologically. The estimated incidence in developed societies is 1:1000 pregnancies, while it is probably lower in developing nations due to the younger age of pregnant women [1]. CAP is becoming more common over the last thirty years, the main reason being the increasing number of women childbearing at older age [2]. The incidence of malignant diseases during the reproductive age has not increased over time but is known to be higher with advancing age. Cancer is the second leading cause of death of women of reproductive age [3]. The stricter follow-up of pregnant women may also have contributed to more frequent diagnosis of CAP cases before delivery. To date there are no data to correlate pregnancy with the development of cancer, either as a causative or as a risk factor. Consequently, the parameters that modulate the risk of development of CAP are the genetic and environmental ones that define the risk of non pregnancy-associated cancer in the

* Corresponding author: Tel./fax: +30 26510 99394. E-mail address: [email protected] (N. Pavlidis). 0959-8049/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.ejca.2005.10.014

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general population. The malignant diseases most frequently diagnosed in pregnant women are malignant melanoma, breast and cervical cancer distantly followed by the less common lymphomas, leukaemias, ovarian, gastrointestinal and genitourinary cancers (Table 1) [1,2]. Cervical cancer is the most common tumour encountered during gestation. One third of cervical cancer cases are diagnosed in women aged less than 35% and 1–5% during pregnancy, with one new case per 2000–10,000 pregnancies reported as annual incidence [4]. The frequent gynaecological examinations of pregnant women contribute to the high probability of early diagnosis of cervical cancer (stage I disease three times more common in pregnant than in nonpregnant patients). Breast cancer is the most common female tumour and when diagnosed in young women, is often a poorly differentiated, hormone-receptor negative, aggressive neoplasm associated with genetic conditions predisposing to malignant transformation (BRCA1/2, p53, PTEN germ-line mutations) [5]. Consequently, pregnancy-associated breast cancer (0.76–3.8% of breast cancer cases) has the above features more often than the general population cases, since it occurs in relatively young women. Breast carcinoma is the second most common CAP, seen once per 3000–10,000 pregnancies annually, though some confusion exists by defining cases occurring within one year post-partum as pregnancyassociated breast cancer. A recent survey reported an incident rate of one in 7700 pregnancies [6]. A Swedish study in women diagnosed with breast cancer before the age of 40 suggested that BRCA1/2 mutation carriers were at increased risk of developing the disease during pregnancy, indicating a role for circulating estrogens in accelerating malignant transformation [7]. The incidence of melanoma is rising rapidly and is uniformly distributed across all age groups, including young women. One third of melanoma cases in women occur during the patientÔs reproductive age and 1 case per 1000– 10,000 pregnancies are diagnosed each year. Dillman and colleagues have reported an incidence rate of 2.8–9 cases per 100,000 gestations [8]. Approximately 1% of all female patients are pregnant. In fact, melanoma makes up 8–10% of all CAP cases and is the third most common tumour in pregnant women [9]. The epidemiology of leukaemias in pregnant women mirrors their relative frequency in the general population, with acute myelogenous ranking first, followed by acute lymphoblastic leukaemia. Chronic leukaemias, commonly found in

Table 1 – Incidence of cancer during pregnancy Malignancy Malignant melanoma Breast carcinoma Carcinoma of the cervix Lymphoma Leukaemia Ovarian carcinoma Colon cancer

Incidence (per number of gestations) 1:1000–10,000 1:3000–1:10,000 1:2000–10,000 1:1000–1:6000 1:75,000–1:100,000 1:10,000–1:100,000 1:13,000

Reproduced with permission from: Pavlidis NA. Coexistence of pregnancy and malignancy. Oncologist. 2002;7(4):279–87.

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the elderly are exceptionally rare in pregnant women [10]. HodgkinÕs disease (HD) and high-grade non-HodgkinÕs lymphomas (NHL) have a peak incidence in the second to fifth decades of life and are thus encountered in women during gestation, ranking fourth among gestational tumours [1]. HD is significantly more common than NHL, with an incident rate of 1:1000–6000 pregnancies [11]. Although only 110 cases of gestational NHL have been reported to date, the HIV epidemic which increases the risk of developing NHL 150-fold, along with the trend for child-bearing at later ages, may make them more frequent in the future [12]. Ovarian cancer is quite rare in both the reproductive age and during gestation, with half of the gestational cases being germ-cell tumours [13]. Colorectal cancer in pregnant women is very rare with rectal primaries representing 65–85% of the total of cases [14]. Gestational colorectal cancer cases may be associated with genetic conditions conferring a high risk of developing the disease at young age, such as familial adenomatous polyposis and hereditary non-polyposis colorectal cancer syndromes. Thyroid cancer during pregnancy is very rare, without any apparent association between gestational hormonal changes and the tumour or its biologic behaviour. Choriocarcinoma usually appears in the context of mole pregnancy but is rarely associated with term pregnancy, with a reported incidence of 1:40,000 gestations [15]. Only few case reports have described diagnosis of central nervous system tumours, bronchogenic carcinoma and sarcomas in pregnant women.

3. Diagnostic work-up and radiological imaging The diagnostic work-up of the pregnant woman with cancer should limit exposure to ionizing radiation and be restricted to procedures that do not endanger foetal health. Physical examination should be thorough with particular emphasis on search for palpable lymph nodes, skin lesions, breast abnormalities, enlarged liver or spleen. Gentle meticulous examination of the abdomen, pelvis and rectum is warranted in several clinical settings. In general, fine needle aspiration and excisional or incisional biopsies of tumourous lumps can be safely performed, although general anesthesia carries a 1–2% risk of spontaneous abortion during the first trimester of pregnancy [16]. Major operations can be safely performed throughout gestation without increased maternal risk, but a 1–3% risk of foetal loss and a minimally increased relative risk (1.5–2.0) for low birth weight and premature delivery exits [17]. Esophagogastroscopy, bronchoscopy, lumbar puncture and bone marrow aspiration/biopsy are quite safe and should be done when clinically indicated, with appropriate caution to avoid excessive use of intravenous sedatives and opioids. Pulse oximetry monitoring should be implemented to avoid maternal/foetal hypoxia. The radiobiological phenomena induced by relatively low doses of ionizing radiation (less than 200–500 mGy) are stochastic (non-deterministic) and the probability of their occurrence is analogous to the dose absorbed, without a threshold dose below which the risk of injury is zero. Accordingly, the utilized strategy of radioprotection is based on the principle of the ‘‘acceptable risk’’ of appearance of adverse radiobiological events. Ionizing radiation has been associated with

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abortion, still birth, malformations, growth retardation and carcinogenesis. The risk and nature of adverse events are dependent on the radiation dose, field and fractionation as well as the gestational age [18]. According to experimental data from animal models, during the pre-implantation and implantation period (first 2 weeks from conception), the ‘‘all or nothing’’ rule applies: irradiation of the undifferentiated embryo results in either death or normal development and doses as low as 100 mGy can cause embryonic death, with a reported incidence of 50% with doses of 1 Gy. During the period of organogenesis (weeks 3–12), embryonic death or developmental malformations are frequent with radiation doses of 1 Gy and may occur with doses as low as 50–250 mGy. The foetal dose of 100 mGy (10 rad) during the first trimester is frequently cited as a ‘‘threshold dose’’ for the risk of teratogenesis [1,18,19]. Exposure to 250 mGy or higher doses of ionizing radiation during the second and third trimesters is associated with growth retardation, mental retardation, malformations of late-forming tissues (central nervous system, gonads) and premature birth. Animal model data as well as observations from the Hiroshima/Nagashaki atom bomb explosion survivors and offspring suggest a threshold dose of 250–600 mGy for an acceptable risk of 5% of the above [20–22]. The rate of IQ decline was 13–21 units per Gy of absorbed energy in Hiroshima embryos. When low dose rate or intense fractionation of ionizing radiation is applied, the aforementioned ‘‘acceptable risk’’ threshold doses are probably higher by a factor of 3–6. The Oxford clinical series showed a 6.4% risk of carcinogenesis during childhood, adolescence and young adulthood per Gy of radiation exposure during gestation [20,23]. Observational data from atom bomb survivors also confirmed the carcinogenic potential of embryonal exposure to radiation [21,24]. Embryonal development and impact of toxic insults is summarized in Table 3. Any imaging modality to be used in the pregnant patient should be justified. Average doses to which the embryo is exposed are given in Table 2, though body size, hardware specifications, protective measures and radiologic techniques modify these indicative values. According to the 96/29 European Union Directive, the threshold dose of foetal exposure to diagnostic ionizing radiation considered as safe is no higher than 1 mGy. This threshold dose is extremely safe, as in cases of inadvertent exposure of pregnant women to radiation, ter-

Table 2 – Imaging procedures and associated average uterine/foetal doses Procedure

Uterine/foetal dose (mGy)

Chest X-ray Pelvic-Lumbar spine X-ray 2-view mammogram Chest CT scan Abdominal-pelvic CT scan Intravenous urography Barium enema ERCP Tc99m-MDP bone scan

0.0004 0.45–1.0 4 0.17 18–25 45 36 0.4 1st trimester 4.5 2nd trimester 2–4 3rd trimester 1.8–2.0

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mination of pregnancy is not recommended if the foetal dose does not exceed 100 mGy. Generally, doses less than 100 mGy (10 rads) are quite safe, as they are associated with a less than 1% risk of malformation or carcinogenesis [1,18,19]. Most investigators accept the rule of restricting the foetal dose associated with diagnostic procedures to 50–100 mGy. During the first trimester of pregnancy, only absolutely necessary radiologic work-up is justified. When needed, staging of the pregnant woman with cancer should be done by means of chest X-ray and abdominal ultrasound. Chest X-ray seems safe with appropriate radioprotection (lead apron). Two-view mammography, though associated with more intensive radiation exposure than plain chest X-rays, appears to be safe as well. Abdominal plain films, radionuclide isotope scans and computerized tomography (CT) scans should be avoided [25]. For imaging of the brain, liver or bones in the context of clinical suspicion for metastases, magnetic resonance imaging (MRI) has been advocated, though the examination was not without drawbacks for the safety of animal embryos. Gadolinium crosses the placenta and causes foetal abnormalities in rats, while the high-energy radiowave-stimulated magnetic fields used carry the risks of foetal heating and cavitation [26]. Some radiologists avoid MRI in the first trimester of pregnancy, others recommend against the use of gadolinium in that period: no consensus on the matter currently exists.

4. Safety of pharmacotherapy of the pregnant patient with cancer Cytotoxic chemotherapy causes genetic damage in exposed somatic cells, including chromosomal breaks, translocations, deletions, gene mutations, aneuploidy and cell cycle disruption [27]. When administered during pregnancy, considerable concern has been generated by cell culture and animal data regarding the mutagenic, teratogenic and carcinogenetic effects on the developing embryo as well as the induced placental damage. Most cytotoxic drugs have a molecular weight less than 600 KDa, and can cross the placenta and reach the embryonal circulation, unless they are extensively bound to plasma proteins [28]. Pregnant women have decreased gastrointestinal motility, fluid retention in the intracellular and intravascular compartments, decreased concentration of plasma albumin and increased of other proteins as well as increased hepatic oxidation and renal clearance [5,29]. These peculiarities make pharmacokinetic–pharmacodynamic modeling of drug action and prediction of untoward effects very complicated. The impact of chemotherapy on foetal health seems to depend on the type, duration and dose of drugs given, as well as the gestational period (Table 3). During the first 2–4 weeks from conception, cell differentiation and organogenesis are minimal. Accordingly, toxic injuries result in either no effect or embryonal growth arrest and death (abortion). Later on and during the first trimester of pregnancy, chemotherapy may interfere with organogenesis, with the risk of teratogenesis being maximal (10% for single agents, 20% for combinations of chemotherapeutic drugs) [30,31]. During the second and third trimesters organogenesis is complete with the exception of the CNS and gonads. Accordingly, toxic effects from chemotherapy consist of

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Table 3 – Stages of embryonal development and impact of toxic insults Gestational stage

Embryonal/foetal development

Impact

Weeks 0–2

Undifferentiated multicellular organism

Weeks 3–12

Organogenesis

2nd and 3rd trimester

Intrauterine growth and maturation, continuing development of CNS, gonads, teeth-palate, eyes, ears

functional disorders, intra-uterine growth retardation, still birth, premature delivery, low birth weight and maternal or neonatal myelosuppression (incidence 10–30%). Overt teratogenesis is rare (2–3%, no higher than the general population incidence), although sterility and central nervous system maturation defects or diminished IQ may be seen in later life [31,32]. Antimetabolites (especially methotrexate, aminopterin) and alkylators (cyclophosphamide, bousoulphan, chlorambucil, dacarbazine) have been reported as having the higher teratogenic potential (as high as 25% when given in the first trimester) [1,31,33]. Conflicting reports on the effects of cytosine–arabinoside on the developing foetus have been published. Vinca alkaloids and anthracyclines are much safer, especially if not administered during the first trimester and in doses less than 70 mg/m2 for doxorubicin [31,34]. No anthracycline-induced embryonal cardiotoxicity or late cardiotoxicity in childhood/adolescence has been reported to date after the first trimester. Still, epirubicin should be avoided due to increased lipophilic nature/placental transfer and limited data on its use, while idarubicin has been linked to malformations of the heart and coronary vessels in human embryos [35,36]. Recently, several case-reports on the uneventful administration of taxanes and platinum salts in pregnant women with breast or ovarian cancer have been published. Still, caution is advised as in five cases, cisplatin was associated with hearing loss, cardiac and cerebral malformations [37–39]. Data on adverse effects of various cytotoxic drugs on the embryo are at best indicative, as they consist of case reports and often combinations of several drugs are administered. Available data on possible late effects of intrauterine chemotherapy exposure are reassuring. Aviles presented the largest series of 84 children aged 6–29 exposed to chemotherapy in utero and found no difference in body growth, neurological maturation, scholar progress and IQ in comparison to matched controls [40]. Data on the development of second tumours, on the reproductive potential and integrity of germ-cells of children, adolescents and young adults exposed to chemotherapy in utero are at best scant [41]. Still, there is no evidence to suggest increased risk of second tumours or diminished reproductive ability in comparison to the general population. In addition to cytotoxic drugs, hormonal therapy and supportive care, medications are commonly used for the management of the non-pregnant patient with cancer. Tamoxifen is teratogenic in animals and has been associated with 10 cases of foetal abnormalities among 50 pregnant women exposed to it [42]. Its use should be delayed until delivery. Analgesic medications, both opioids and non-steroidal anti-inflammatory agents, are safe for use during gestation with minimal terato-

‘‘All or nothing’’, spontaneous abortion or normal development Spontaneous abortion, major congenital anomalies Functional defects and minor anomalies of late-forming tissues, still birth, intrauterine growth retardation, premature delivery, myelosuppression

genic risks documented so far. Opioids carry the risk of foetal tolerance and addiction upon prolonged use, a complication easily managed during the immediate post-partum period. Biphosphonates cross the placenta and they have been incriminated for bone developmental abnormalities as well as derangements of calcium metabolism in animal experiments and should be avoided during pregnancy. Two case reports of pamidronate use during the third trimester of pregnancy described reversible neonatal hypocalcemia [43,44]. The antiemetics ondansentron and metoclopramide have been used during gestation without adverse effects to the foetus and recently found to be safe in this setting in two international prospective trials [45,46]. Erythropoietin does not cross the placenta and seems to be devoid of teratogenic effects in the reported case series of pregnant women [47]. There is a paucity of data on the use of granulocyte colony stimulating factor (GCSF), though experiments in pregnant rats and few case reports did not show detrimental effects on foetal integrity [48]. GCSF may be used for the management of febrile neutropenia in pregnant women with cancer but not for the intensification of chemotherapy regimes. Molecularly targeted agents increasingly make it from laboratory benches to the day-to-day clinical practice. These ‘‘smart’’ drugs selectively attack malignant cells bearing specific molecular aberrations and offer hope for improved prognosis in cancer patients. Pregnant women with breast cancer are likely to harbor tumours overexpressing Human Epidermal Growth factor Receptor type 2 (HER2) and thus may benefit from treatment with transtuzumab (HerceptinR), a monoclonal antibody that binds HER2. Still, HER2 expression is high in embryonic tissues, placental transfer of the antibody has been observed in animal studies and a case report of reversible anhydramnios in a pregnant woman make its use during gestation not advisable [49]. Rituximab, a monoclonal chimeric IgG1 antibody targeting CD20-positive B lymphocytes that crosses the placenta, has been administered in two pregnant women with lymphomas without adverse effects to the foetus [50,51]. Imatinib (GleevecR), a specific BCR/ABL, C-KIT and PDGFR tyrosine kinase inhibitor used for the management of patients with chronic myelogenous leukaemia and gastrointestinal stromal tumours, crosses the placenta and is teratogenic in rats. Two case reports of three pregnancies of CML patients exposed to imatinib throughout gestation describe term delivery of healthy but low birth weight babies in two cases and spontaneous abortion in one case [52]. Overall, the evidence is scant but indications of interference with foetal development exist to advise against the use of molecular-targeting agents during pregnancy, especially in the first trimester.

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5.

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Radiation therapy during pregnancy

The developing human embryo and foetus are extremely sensitive to ionizing radiation, which might cause pregnancy loss, malformations, growth retardation and neurobehavioral defects. Most such anomalies appear at foetal doses in excess of 200 mGy, though avoidance of exposure to doses higher than 100 mGy is advised because of the non-deterministic nature of radiobiological events [19,24]. Radiation doses used in cancer therapy are in the range of 30–70 Gy. However, the effective foetal dose depends on the size of the irradiation field, the target dose, the distance from the embryo/foetus to the edges of the field, the shielding measures and the specific radiation machine and leakage. In fact, the foetal dose results from internal scatter (source of irradiation, size and site of treatment fields), leakage from the tube head and scatter from the collimator/blocks (reducible by a factor of 2–4 with proper shielding with lead blocks over the uterus). Several investigators support the use of external beam radiotherapy for the treatment of breast cancer, supradiaphragmatic HodgkinÔs lymphoma, head and neck cancer and brain tumours in pregnant women. Irradiation of the maternal breast or chest wall will expose the foetus to 0.1– 0.3% of the total dose (usually 50 Gy). Accordingly, the estimated foetal dose without shielding will be 30 mGy at 8 weeks of gestation, 200 mGy at 24 weeks and 1.4 Gy at 36 weeks of pregnancy, for treatment with a 6–25 MeV linear accelerator [53]. With appropriate shielding, reported foetal doses are less than 50 mGy. For patients with HodgkinÕs disease, effective doses of the shielded first trimester embryo for neck or axilla, neck-mediastinum and mantle field irradiation range from 28 to 245 mGy. Respective foetal doses for the second to third trimesters range from 20 to 500 mGy [54]. There are several case series reporting birth of healthy babies without subsequent childhood malignant disorders from mothers treated with supradiaphragmatic radiotherapy [55]. The foetal doses for radical irradiation of brain gliomas (54–60 Gy), palliative whole brain irradiation (30 Gy in 10 fractions) and radical head and neck irradiation (64–70 Gy) are less than 100 mGy, in keeping with reported case series describing birth of healthy babies from mothers managed with external beam radiotherapy [24]. Termination of pregnancy is usually advocated upon administration of effective foetal doses in excess of 100 mGy. Still, this limit was derived from Japanese nuclear bomb explosion survivors, exposed to single doses at high dose rate. Administration of the radiation energy over a long time period with low fractional doses, as done in clinical practice, most probably shifts the ‘‘safety limit’’ necessitating abortion to foetal doses of 200 mGy [18,19,29,24].

6. Basic principles of management of the pregnant cancer patient Accumulating evidence suggests that during the first trimester, when treatment cannot be delayed or is administered, termination of pregnancy is advisable. Still, one must bear in mind that even in cases of uterine exposure to combination chemotherapy during the first gestational trimester, the chances of normal embryonal development are around 75%.

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Previous studies in leukaemic patients suggested that treatment during the first trimester can be accomplished safely. Therefore, any recommendations for pregnancy termination during the first three months should be made in the context of the malignant disease and probability for cure; drugs to be used; and wishes of the patient. If possible, chemotherapy should be delayed to the second trimester, to minimize the risk of foetal anomalies. Though quite safe during the second and third trimesters, chemotherapy is associated with a 2fold relative risk of foetal growth retardation, still birth, premature birth and maternal/foetal myelosuppression. The patient should be counseled regarding these issues and adhere to a strict foetal monitoring scheme with frequent ultrasonographic evaluation. Nowadays, a recommendation to terminate pregnancy is only valid if pregnancy itself is an obstacle to drastic treatment, is associated with unacceptable risks for the health of mother and foetus or is thought to be morally unacceptable in the presence of incurable maternal cancer. Settings required for termination include: need for immediate treatment of abdominal/pelvic tumours; advanced disease with dismal prognosis; fulminant disease course, poor general patient condition, inadvertent foetal exposure to more than 100 mGy during the first trimester and reluctancy of the parents to accept the risks associated with in utero exposure to chemotherapy during the second and third trimesters. It should be stressed that most case series did not show therapeutic abortion to be associated with improved outcome of pregnant women with cancer when appropriate anti-neoplastic therapy was implemented [1,2,5,31,42]. If possible, radiotherapy should be delayed until the postpartum period. Nowadays, most pregnant women can benefit from neoadjuvant chemotherapy regimens and ‘‘watch and wait’’ policies in several clinical circumstances allow ionizing radiation therapy to be deferred until delivery. When radiotherapy cannot be postponed, an experienced medical physicist and a radiation oncologist should assess the foetal dose, implement proper treatment fields, energies and abdominal shielding for relatively safe treatment of breast primaries, supradiaphragmatic lymphomas, head and neck cancers and brain tumours. Foetal doses should be less than 100– 200 mGy, lower than the threshold doses for deterministic effects and carrying a slightly increased relative risk for stochastic effects [24]. In such instances, the second trimester is the preferable time period for irradiation so as to avoid the critical period of organogenesis (first trimester) and the small distance between the uterus and the irradiated supradiaphragmatic sites (third trimester) [56]. Overall, the uncertainty regarding the probability of late cytogenetic effects, the necessity for radiation physics expertise and the threat of litigation as well as the lack of medical urgency, render radiotherapy during gestation neither safe nor required. Thanks to the progress made in the field of intensive care, a highly favourable outcome of preterm neonates delivered at 32 weeksÕ gestation has been established in the medical literature, with the safety time threshold shifting to even earlier gestational ages. The decision regarding timing and path of delivery (induced vaginal, cesarean section) should be jointly reached by a multidisciplinary team of oncologists, obstetricians and neonatologists. Chemotherapy should not be given after week

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35 as spontaneous delivery may occur at the peak of maternal/ foetal myelosuppression, with resulting risks of infection and hemorrhage. The delay of delivery for three weeks after chemotherapy allows for both resolution of maternal/foetal myelosuppression and for placental drug excretion from the foetus. In cases of women who opt to continue with pregnancy and refuse administration of chemotherapy as well as in cases where chemotherapy should continue, induced vaginal delivery or cesarean section at 32–35 weeks of gestation, three weeks after the last chemotherapy cycle, is a safe compromise [5,30,31]. Breast feeding is not recommended until at least 2–4 weeks after the completion of chemotherapy, since several cytotoxics have been detected in breast milk (cyclophosphamide, methotrexate, doxorubicin, cisplatin). Infant neutropenia of a baby breastfed during maternal treatment with cyclophosphamide has been reported [57].

7. Presentation, diagnosis and management by tumour type 7.1.

Cervical cancer

Cervical cancer is probably the most common CAP of visceral organs. Median age at diagnosis of pregnant women is 30–35. Common presenting symptoms are vaginal bleeding, discharge or rarely, pelvic pain. The majority of women with cervical CAP are asymptomatic, diagnosed by abnormal cytology at early stages of the disease (stages IA–IIA in 80% of CAP cases) [58]. It is not yet known whether this presentation with early cancer is due to the frequent gynaecological examinations during prenatal care or implies a ‘‘benign’’ tumour biology. Atypical cytologic findings are common during pregnancy due to hyperplasia and eversion of the endocervical glandular epithelium followed by squamous metaplasia, lymphocytic infiltration, human papilloma virus infection and simulation of high-grade cervical intraepithelial neoplasia (CIN) by trophoblastic cells migrating to the cervix [59]. Still, dysplastic changes should not be attributed to gestation without appropriate work-up. When cervical pathology is suspected from clinical evaluation and smear cytology, colposcopic examination, including biopsies of suspicious lesions, is warranted (sensitivity 70–90%). The risk of hemorrhage from colposcopy-directed biopsies is extremely low (1–3%) [60]. Of note, considerable expertise is required on the part of both pathologist/cytologist and colposcopist. Conization or loop-excision are associated with increased risks of vaginal bleeding (5– 15%), abortion (25%), infection, premature delivery (15%) and residual disease (30–50%) [61]. Therefore, cone biopsy should be regarded as diagnostic and used only for patients with evidence or suspicion of microinvasive or invasive disease on biopsy/colposcopy, also such a diagnosis will alter the timing or mode of delivery. When indicated, conization should be performed between 14 and 20 weeks of gestation [62]. Cervical CAP are predominantly squamous in 80–90% of cases, the remainder being adenocarcinomas. Staging should consist of physical examination, chest X-ray and MRI of the abdomen/ pelvis, preferably non-enhanced during the first trimester. CIN should be managed with strict follow-up by means of cytology and colposcopy. In a retrospective series of 98 pregnant patients with grade I–III CIN, 84% of cases regressed after

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delivery [63]. In cases of invasive cervical cancer, radical treatment (surgery, radiotherapy) cannot be performed with preservation of foetal life. Accordingly, when tumour is diagnosed in pregnancy, a choice must be made between abortion/therapy or treatment postponement with disease monitoring. In the case of microinvasive (stage IA) cervical cancer, evidence from 82 cervical IA CAP cases opting for treatment deferral established the relative safety of this strategy (tumour progression in only 3 cases) [64]. Women with less than 3 mm depth of invasion can be followed up and deliver vaginally, whereas women with 3–5 mm depth of invasion and/or lymphatic/vascular invasion should deliver by cesarean section as soon as foetal maturity is reached (32–36 weeks of gestation). No consensus exists on the matter, as Van Calsteren advise immediate management of positive margin IA1 disease as well as any IA2 disease with radical hysterectomy [59]. Second or third trimester pregnant patients with IA cervical cancer, are easily amenable to treatment deferral. Radical treatment may follow post-partum. Laparoscopic staging of pelvic lymph nodes has been suggested during the first and second trimesters, to allow for accurate identification of patients with microscopic, node-negative tumours, eligible for a watch and wait policy [65]. For patients in the first or second trimester of pregnancy and invasive cervical cancer (stage IB–IVA), pregnancy termination and immediate institution of therapy is traditionally advised. Third trimester pregnant patients with invasive disease may opt for deferral of therapy and week 32–36 delivery, as retrospective case series did not show an adverse impact on prognosis[59,62,64]. In such a setting, neoadjuvant chemotherapy for stage IB–IVA disease may be given during the second and third trimesters of pregnancy so as to buy time for delivery of a viable foetus and post-partum radical treatment [66]. Radical treatment consists of radical hysterectomy with nodal dissection or radiotherapy for stages I–IIA and chemoradiotherapy for stages IIB–IVA tumours. If the foetus is viable, a prompt cesarean section is advised with radical hysterectomy performed simultaneously. An outline of therapeutic strategies is provided in Fig. 1. Pregnancy did not affect patient outcome, when compared to non-pregnant women matched for age, stage and year of diagnosis in a retrospective review of 260 cases [59]. The complications following radical hysterectomy or radiotherapy are no different in pregnant women either [62,67]. Despite a trend for higher still birth rates and lower birth weight, Zemlickis and others reported that foetal outcome is not significantly different in pregnancies complicated by maternal cervical cancer from normal pregnancies [68,69].

7.2.

Breast cancer

Breast cancer, the most common reproductive age malignant disorder in females, ranks among the most frequent CAP. In contrast to other tumours, breast CAP is defined as a tumour diagnosed during pregnancy and up to 12 months postpartum. Median age at diagnosis of pregnant patients with mammary tumours is 33 years. In retrospective series, the disease manifested as a painless palpable breast lump in respectively, 82% and 95% of British and American patients [70,71]. Bloody nipple discharge, nipple retraction, inflamma-

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Fig. 1 – Algorithm of therapeutic strategies for cervical CAP.

tory breast cancer (1.5–4% of breast CAP) and refusal of the baby to feed from the diseased breast are seen less commonly. Thorough physical examination of the breast, neck and axilla is imperative, the increased size and density of the mammary gland contribute to delayed diagnosis in several cases. The delay ranges from 2 to 15 months and may be seen in up to 78% of pregnant patients [42]. It results in a 2.5-fold increased risk of a pregnant woman presenting with advanced stage disease (40% of breast CAP cases), compared to a non pregnant one [72]. Diagnosis should be made by means of mammography, ultrasonogram or non-enhanced MRI in difficult cases. The dense, proliferating mammary glands of young, pregnant women may make mammographic diagnosis difficult (sensitivity less than 70%) [5,72]. Fine-needle aspiration (FNA) or core-needle biopsy can establish the diagnosis, though FNA has been associated with both false-positive and false-negative results [73,74]. It is imperative that the pathologist is informed of the presence of pregnancy and in dubious cases, a open surgical biopsy, the gold standard, or core-needle biopsy be performed. The latter two have sensitivity and specificity rates in excess of 90%. For lactating women, stopping milk production with ice packs, breast binding and bromocryptine one week prior to biopsy reduces the risk of hematoma and fistula. Staging should be done by means of chest X-ray, ultrasonogram of the abdomen and axilla, using MRI for imaging of the brain, liver and adrenals when warranted [25]. Serum alkaline phosphatase doubles during pregnancy, but serum transaminases, LDH and CA 15-3 are not affected, allowing the physician to use them as screen for metastases.

The predominant histological type of invasive breast CAP is ductal adenocarcinoma (80–90% of cases), followed by lobular adenocarcinoma. The majority of tumours are highgrade malignancies, with axillary nodal involvement seen in 60–90% and hormone-negative status in 40–70% of pregnant patients [5,42,72]. These figures do not seem to be significantly different from age-matched non-pregnant women with breast cancer. The overexpression of HER2 and p53 in breast CAP cases was reported as 28–58% and 50% respectively, in keeping with published data for non-pregnant women aged less than 35 [75]. Recent data suggest that pregnancy does not modify the natural course of breast cancer neither does it adversely affect patient outcome, despite high circulating estrogen levels. Several retrospective series showed that survival of pregnant women with breast cancer is similar to that of non-pregnant patients of similar stage, grade and hormonal status [5,42,72]. Berry and colleagues reported 5-year survival rates in excess of 75% for stage II/III pregnant patients [76]. Some reports suggest adverse prognosis of patients diagnosed with breast cancer soon after delivery, an observation probably due to the diagnostic delay. Modified radical mastectomy with axillary node dissection is the treatment of choice for patients with stage I–II and selected stage III breast cancer patients during the first two trimesters of pregnancy. Patients with localised disease diagnosed in the third trimester may be managed with breast-conserving surgery and post-partum breast irradiation. Sentinel lymph node biopsy should still be considered experimental and avoided in pregnant women in view of the unknown foetal risk from the radioisotope, though

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reported exposure is low (<5–15 mGy) [77]. Patients in need of adjuvant chemotherapy (node-positive tumours, nodenegative tumours high-grade or >1 cm) can relatively safely have it administered after the first trimester. CMF or anthracycline-based regimens (AC, CAF) have been administered with only 1.3% risk of malformations after the week 12 [5,31,35,36,78]. Evidence regarding the use of taxanes is slowly accumulating but is still limited. It has been postulated that placental P-glycoprotein expression will protect the foetus from taxane exposure [39,79]. As stated previously, the administration of hormonal therapy and transtuzumab should be avoided throughout gestation. Patients with metastatic disease may be managed with palliative combination chemotherapy (AC, CAF) preferably rather than newer agents (taxanes, vinorelbine) beyond the first trimester of pregnancy. In such cases, the issue of pregnancy termination should be discussed in the context of the disease course, prognosis and patient fitness. Finally, apart from inadvertent first trimester exposure to chemotherapy, the short- and long-term outcome of foetuses is excellent and there are only slightly increased risks for still birth, low birth weight, premature delivery and transient myelosuppression [64,80].

7.3.

Melanoma

Melanoma incidence is rising rapidly over the last 40 years with two-thirds of cases developing from pre-existing nevi. Common presenting symptoms and signs in pregnant women are a change in the size, colour of a melanotic lesion with appearance of ulceration or bleeding [8]. Occasionally lympadenopathy, dyspnoea, bone pain or seizures are manifestations of metastatic spread. A diagnostic delay has been demonstrated in several reviews, resulting in disease presentation with thicker primary lesions and nodal metastases, without any difference observed in site, ulceration, vascular invasion or distant spread [81,82]. Excisional biopsy is warranted for diagnosis and assessment of risk factors with thorough physical examination and laboratory work-up. Superficial spreading melanoma accounts for 74% of gestational cases, followed by nodular melanoma (16%), in keeping with the histological profile seen in matched controls [83]. If sentinel lymph node mapping is undertaken, a dye instead of radioisotope should be used. In the absence of clinical suspicion, staging should be restricted to a chest X-ray and an abdominal ultrasound. Wide surgical excision with 1–3 cm margins according to the thickness of the primary is the treatment of choice for localised melanomas. Nowadays, general anesthesia and surgery can be safely performed throughout gestation, as shown by a 5405 operation series by Mazze and colleagues [17]. Regional lymphadenectomy of involved nodes should be performed and although interferon has been safely administered in pregnant women with viral hepatitis, myeloma and hematologic disorders; adjuvant regimens for resected high-risk melanoma employ higher doses and should be avoided. The toxicity and impact of intensive interferon regimens on pregnancy have not been studied and such therapy should be implemented post-partum. Management of metastatic melanoma is at best palliative. Continuation or termination of pregnancy should be discussed with the patient before

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embarking on dacarbazine or cisplatin-based chemotherapy during the second or third trimester. Observations of immunosuppressive and estrogenic milieu, high MSH serum levels and increase in the number and size of melanotic lesions in pregnant women generated concern about the biologic behaviour of malignant melanoma during gestation. Pack and colleagues have described aggressive disease course and poor prognosis of 32 women with melanotic CAP in 1951 followed by other case series reporting short disease-free intervals and frequent nodal relapse for gestational melanomas [84,85]. Subsequent cell culture experiments showed that despite presence of hormonal receptors in some melanoma cells, estrogens have in vitro mixed proliferative, anti-angiogenic and growth-suppressing effects and probably negligible in vivo effects. Pennoyer and colleagues observed and charted nevi of 22 pregnant women and found gestational size changes in only 6.2% of the nevi [86]. Large case series over the last 15 years encompassing a total of more than 400 pregnant patients suggest that the survival of pregnant women with melanoma is similar to that of non-pregnant patients matched for age and tumour thickness. Cited 10-year survival rates are 94% for stage I and 82% for stage II melanoma. In multivariate analyses of two large retrospective cohorts by Grin and colleagues, and Lens, pregnancy was not identified as an independent prognostic factor for relapse or survival [9,83]. Foetal morbidity or mortality does not significantly increase either, in comparison to the general population [9,33].

7.4.

Lymphomas

The median age of pregnant patients at diagnosis of HodgkinÕs disease (HD) is 32 years, while that of patients with non-HodgkinÕs lymphomas (NHL) is 37–42. Experience with gestational NHL is clearly inferior to the much more common HD. The presentation does not seem to be different during pregnancy, with painless lympadenopathy in 70–80% of patients and B symptoms in 20% [87]. There is intriguing evidence from a case series of 37 NHL pregnant patients for presentation with uncommon non-bone marrow extranodal manifestations (breast, cervix, ovaries, GI mucosa in 28 women) more frequently than anticipated [88]. Recent data from Princess Margaret Hospital, Toronto show that stage I–II HD at presentation is seen in 70% of both pregnant and non-pregnant women, suggesting absence of diagnostic delay during gestation [89]. In contrast, pregnant women present with stage III–IV NHL in 70–80% of cases with more than 40% experiencing a diagnostic delay longer than 30 days. Diagnosis should be based on excisional lymph node biopsy. Staging should include bone marrow aspiration/ biopsy, chest X-ray, abdominopelvic ultrasound and laboratory work-up. Erythrocyte sedimentation rate and serum alkaline phosphatase may be elevated due to gestation. Ear, nose and throat examination, gastroscopy, spinal tap and MRI should be implemented when indicated. Nodular sclerosis is the most common histology for HD, while gestational NHL was usually high-grade in a series of 96 patients (B-diffuse large cell lymphoma 36%, Burkitt-like 23%, B-lymphoblastic 11%, mantle cell 10%, peripheral T-cell 10%) [90]. The causative association of chronic Epstein-Barr virus

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infection with HD and some NHL is no different in pregnant women. Combination chemotherapy is imperative as most HD and NHL patients need treatment with curative intent. When the diagnosis is made in the first trimester, pregnancy termination with prompt institution of chemotherapy is advisable, especially in the presence of B-cell symptoms, bulky stage I– II disease, advanced stage III–IV disease or evidence of fulminant course of the lymphoma. In the absence of the above or upon refusal of abortion by the mother, single-agent vinblastine may be given or treatment may be deferred until the second trimester. During the second and third trimesters, the relative safety of chemotherapy administration has been demonstrated in several retrospective series, for both mother and foetus. The risk for still birth was 4%, for miscarriage 10% while gestational age and birth weight did not differ from the general population. ABVD is preferred for HD and CHOP for most high-grade NHL in pregnant women [87,89,90]. Alternatively, third trimester pregnant patients may be managed expectantly with 32–35th week delivery and post-partum chemotherapy. Limited-field supradiaphragmatic radiotherapy has been advocated for stage IA lymphocyte-predominant HD, but most physicians would defer any ionizing radiation therapy after delivery. Intrathecal chemotherapy seems safe as well as high-dose intravenous methotrexate after the first trimester. Rituximab improves survival in NHL patients but administration during pregnancy is not advised due to lack of safety data. The rare patients with low-grade lymphomas may be managed expectantly, receive second or third-trimester single-agent chemotherapy or limited-field radiotherapy, according to preferences and expertise. Several large retrospective series show that the prognosis of pregnant patients with HD or NHL is not inferior to that of non-pregnant patients matched for age, histology and stage. Long-term remissions were obtained in 88% of pregnant women with HD and 45% with NHL in a series from Stanford University, while a series of 84 HD patients diagnosed during gestation reported 10-year survival rates of 80– 90% for stage I–II disease and 50–75% for stage III–IV [91,92]. In a case-control study, survival was similar between 48 pregnant and 144 non-pregnant patients with malignant lymphomas [89].

7.5.

Ovarian cancer

Pregnancy and its associated hormonal changes are inversely related to the risk of developing ovarian adenocarcinoma. Ovarian cancer is rarely diagnosed during pregnancy, with 98% of ovarian masses seen in pregnant women (1:80–2500 gestations) being benign. When a malignant ovarian tumour is diagnosed during gestation, it is adenocarcinoma in 35%, borderline malignant tumour in 30% and germ-cell/sex cord stromal tumour (mostly dysgerminomas) in 35% of cases. Ovarian germ-cell and borderline malignant tumours are most often diagnosed in early stages (FIGO stage I–II). Most epithelial adenocarcinomas are confined to the abdomen/pelvis, but a clear picture on stage distribution is not possible [93]. Despite fears for delayed diagnosis of ovarian adenocarcinomas due to pregnancy, Dgani and colleagues found 74% of gestational malignant ovarian carcinomas to be of early FIGO

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stage [94]. In sharp contrast, Ferrandina recently found only two stage I/II cases among ten reviewed [95]. Diagnosis and staging should rely on transabdominal ultrasonic examination of the pelvis/abdomen and chest X-ray. Tumour markers such as CA 125, bHCG and AFP may be falsely elevated during gestation and are of limited diagnostic utility. MRI may be a valuable adjunct to imaging. There is general agreement that when suspicious ovarian lesions are diagnosed in pregnant women (larger than 6 cm, solid or of complex appearance, bilateral, persisting into the second trimester, ascites), laparotomy or laparoscopy are warranted and should not be delayed [96]. Surgery should focus on diagnosis, accurate staging of disease extent and extirpation of malignancy, according to standard oncologic protocols in gynaecology. For low bulk tumours, removal of the ovary bearing the tumour and tube, of peritoneal implants, omentum and enlarged lymph nodes is advised. The contralateral ovary should be biopsied when suspicious or in the case of germ-cell tumours. Bilateral salpingo-oophorectomy after the gestational week 7 is compatible with continuation of pregnancy since hormonal production is taken up by the trophoblast. In the case of bulky, high-grade tumours, termination of pregnancy followed by radical debulking including hysterectomy is wise. If it is estimated that pregnancy may continue and the pregnant woman wishes so, hysterectomy is not performed. In general, laparotomy should be performed during the first trimester (after week 7 if pregnancy is to continue) and second trimesters with individualization of the therapeutic strategy for third trimester women. A long delay is not justified in the third trimester either, the appropriate strategy being delivery of a viable foetus with cesarean section and radical surgical therapy including hysterectomy. Some investigators recommend the initial use of the less traumatic laparoscopy for diagnosis and staging before proceeding to laparotomy in case of high-grade malignancy [97]. Combination chemotherapy should be administered according to standard oncologic guidelines, with relative safety during the second and third trimesters. Some physicians are recently employing neoadjuvant chemotherapy during the last two trimesters in order to postpone radical surgical extirpation of advanced ovarian cancer after delivery with cesarean section. There is no evidence from available anecdotal experience that the prognosis of pregnant women with ovarian malignant tumours is inferior to that of nonpregnant patients. At a median follow-up of 19 months, eight out of ten women diagnosed with advanced ovarian epithelial cancer during pregnancy were disease-free [95].

7.6.

Leukaemias

The occurrence of leukaemia during pregnancy is very rare but it is an awe and fear-inspiring clinical diagnosis for both pregnant patient and physician. Acute myeloid leukaemia (AML) represents two-thirds and acute lymphoblastic leukaemia (ALL) one-third of all cases, while chronic myeloid leukaemia is found in less than 10% [90]. Diagnosis may be delayed as the disease is manifested with non-specific symptoms and signs such as pallor, dyspnoea, fatigue, often attributable to gestation. Infections, bleeding diatheses and lymphadenopathy are occasionally present [98]. Diagnosis is

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based on morphologic, immunophenotypic, cytochemical and cytogenetic studies of bone marrow samples. Pregnant women with acute leukaemia should be treated as non-pregnant ones, with immediate institution of chemotherapy. When in the first trimester, pregnancy should be terminated because of the 15–25% risk of malformations. Classical induction regimens include cytarabine and anthracyclines for AML with the addition of vincristine and steroids for ALL. Combination chemotherapy regimens appear safe during the second and third trimesters with reported increased risk for abortion, still birth, growth retardation, premature delivery and transient neonatal myelosuppression in 10–30% of cases [34]. For the management of pregnant women with acute promyelocytic leukaemia (APL), combined or sequential therapy with all-trans-retinoic acid (ATRA) and chemotherapy is safe and effective after the first gestational trimester. Embryonal exposure to ATRA during the first trimester should be avoided as it has been associated with a constellation of specific malformations [99]. Chronic myeloid leukaemia (CML) is usually diagnosed in the initial chronic phase, making conservative management with safe therapies such as interferon, leukapheresis or hydroxyurea feasible until delivery [90,100]. There are no data on the safety of imatinib, a BCR/ABL tyrosine kinase inhibitor, apart from two case-reports, and its use should be withheld until delivery [52]. Hairy cell leukaemia patients may be managed with interferon as no experience regarding the use of 2chlorodeoxyadenosine (cladribine) during pregnancy exists. Splenectomy is safe during the second trimester [101]. For the rare chronic lymphatic leukaemia pregnant patients (5 reported cases), watchful waiting or management with leukapheresis or interferon are safe options [102]. Aggressive therapeutic approaches for the management of patients with acute leukaemias or CML include autologous or allogeneic bone marrow/peripheral stem cell transplantation. When continuation of pregnancy is elected, such therapies should be withheld until after delivery. The survival of pregnant women with acute leukaemia has improved with availability of modern chemotherapy and intensive care. Remission rates of 70–75% and median survival times of 6– 12 months reported in the literature are no different from those achieved in non-pregnant women [98].

7.7.

Gastrointestinal cancer

Tumours of the gastrointestinal tract affect people after the fifth decade of life, consequently their coexistence with pregnancy is rare. Colorectal cancer (CRC) makes up for most of the gestational cases (300 reported until year 2003) and medical history should always focus on possible presence of hereditary cancer syndromes in young patients with this malignancy. Bernstein and co-workers observed abundance of rectal cancer (80% of all CRC cases) in 205 pregnant patients, while others reported increased frequency of adenocarcinomas of mucinous histology and poor differentiation [103]. It is unclear if these unvalidated epidemiological features reflect different biologic behaviour of the tumour or simply result from frequent pelvic/rectal examinations in pregnant women. Presenting signs and symptoms are rectal bleeding, diarrhoea or constipation, anaemia, abdominal

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cramps, nausea and weight loss. This constellation of signs and symptoms are either masked from or attributed to pregnancy [104]. As a result, colorectal cancer pregnant patients present with ileus or perforation and are diagnosed with locally advanced or metastatic disease (Dukes C and D in 59% of 39 pregnant women) more often than non-pregnant ones. Ovarian metastases have also been reported more often in pregnant women (25% versus 3–5% in the general population) [105]. Diagnosis and staging should be done with chest X-ray, abdominopelvic ultrasound or MRI, transrectal ultrasound and sigmoidoscopy or colonoscopy with biopsies. Published evidence from 28 colonoscopies and 59 sigmoidoscopies in pregnant women establish the safety of these procedures, provided nasal oxygen administration, vital sign monitoring, suppression with meperidine only and mildness of manipulations are applied [106]. Carcinoembryonic antigen levels are only marginally elevated during gestation and can be used for monitoring the course of colorectal cancer. Localised CRC (Dukes B-C) should be managed with colectomy and regional lymphadenectomy. During the first 20 weeks of gestation, radical surgical extirpation of the tumour can be safely performed while leaving the uterus in situ with minimal detrimental impact on the foetus (embryonal death was seen in 3.8% of laparotomies) [107]. Hysterectomy should be performed in the presence of tumour invasion or when needed for adequate operative exposure of rectal tumours. When diagnosed in the second half of gestation, surgery should be delayed until 1–2 weeks after the delivery of a viable foetus (week 32–34), to allow for vascular decongestion of pelvic structures [108]. Delivery may be either induced vaginal or by cesarean section in the presence of bulky rectal tumours. In the case of massive bleeding, perforation or obstruction, emergency operation should be done at any gestational stage. 5-Fluorouracil-based chemotherapy, either adjuvant or palliative, is relatively safe during the second and third gestational trimesters, with a relative risk of 2–3 for still birth, premature delivery and low birth weight [31]. For localised, second or third trimester Dukes C tumours, adjuvant chemotherapy is usually given after delivery, following surgery. When advanced CRC is diagnosed after the gestational week 20, chemotherapy may be either instituted or withheld until delivery in the absence of high disease burden or fulminant course. No data are available on the safety of irinotecan, oxaliplatin, cetuximab or bevacizumab during pregnancy. Adjuvant pelvic radiotherapy is warranted for Dukes B2-3, C rectal tumours but should be given after delivery, if continuation of pregnancy is elected. Patients with locally advanced, unresectable rectal carcinomas should have their pregnancy terminated and be managed with induction chemoradiotherapy. When adjustments for the delay in diagnosis and advanced stage at presentation are made, the prognosis for pregnant CRC patients is similar to that of non-pregnant women (5-year survival of 75–83% for Dukes B, 27–50% for Dukes C, 0–5% for Dukes D) [103,104]. Rates of foetal survival of 80% have been reported to date [109]. Only 131 cases of gastric cancer in pregnant women have been reported. Again, the presenting clinical picture (early satiety, nausea/vomiting, anaemia, weight loss) is masked by gestation resulting in delayed diagnosis. In two case reviews, 65–80% of cases have been diagnosed after gestational

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week 30, while only 3% of 103 Japanese and none out of 31 Western pregnant patients had tumours limited within the gastric wall. Consistent with observations in all young patients, pregnant women have poorly differentiated adenocarcinomas (Lauren diffuse type) with metastatic spread to lymph nodes, peritoneum, ovaries more often (20–40% of cases) rather than the liver (<10% of cases) [110,111]. Oesophagogastroscopy is safe, allows histologic diagnosis and should be done in pregnant patients with persistent signs or symptoms (especially nausea/vomiting persisting beyond gestational weeks 12–16). Surgical management of resectable tumours should be implemented during the first 20–24 weeks of gestation. Later on, delay until delivery, termination of pregnancy and surgery or surgery with concurrent attempt for continuation of pregnancy are therapeutic alternatives worth discussing with the patient, surgeon and anesthetist. In the presence of advanced disease, a decision should be jointly reached regarding pregnancy, taking into account motherÔs fitness, life expectancy and gestational age. If pregnancy continues, multiagent 5FU, anthracycline or platinumbased chemotherapy may be given after the first trimester. Dismal prognosis has been reported for pregnant women with gastric cancer (3-year survival rates of 8%), no different though from that of age-, stage-matched non-pregnant patients [112]. In the Japanese and Western case-series, 72% of 134 pregnant women gave birth to healthy babies. Finally, only 40 cases of hepatoma and four cases of pancreatic cancer have been described in pregnant women. Diagnosis, staging, pregnancy termination or continuation and surgical/medical management of these patients should follow sound oncologic principles and general guidelines.

7.8.

Other tumours (lung cancer, cancer of the thyroid)

Twenty-three cases of lung cancer diagnosed in pregnant women have been published to date. Median age at presentation was 37.6 years. Of note, lung cancer patients aged <40 years, the proportion of females is as high as 24–46% [113]. Sixty percentssss of the pregnant lung cancer patients were smokers, with the all of them being in the second or third gestational trimesters. In 60% of the cases, visceral metastases were present, while the most common presenting symptoms consisted of cough, dyspnoea, hemoptysis and bone pain. Small-cell lung cancer was present in 33% of pregnant women, the rest (67%) being adenocarcinoma and large-cell carcinoma [114]. Diagnosis and staging should rely on chest X-ray, bronchoscopy and biopsy, upper abdominal ultrasound and mediastinoscopy when warranted. Patients with stage I/II tumours should undergo potentially curative thoracotomy which does not necessitate termination of pregnancy [115]. Women with stage IIIA/IIIB non-small-cell lung cancer should be informed about the prognosis, so they can elect either abortion or neoadjuvant combination chemotherapy which is safe after the first trimester. Radiation therapy may follow delivery. Patients diagnosed after week 30 of pregnancy may be treated after delivery of a viable foetus in weeks 32–34. Pregnant women with metastatic non-small-cell lung cancer or any small-cell lung cancer have dismal prognosis which makes pregnancy termination advisable in the first or second trimesters. Combinations of cisplatin and vinorel-

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bine or etoposide have been administered in pregnant women with lung cancer without detrimental foetal effects in the second and third trimesters [116]. In published case-reports, the median survival of pregnant lung cancer patients was 4 months, ranging though from 2 days to 42 months. Considering the advanced disease stage at presentation due to diagnostic delays, the outcome is not significantly different from that of stage-matched controls. Thyroid cancer has a reported incidence of 3.6 new cases per 100,000 pregnancies [117]. The disease presents as a palpable painless thyroid nodule or with neck pain, hoarseness, and dyspnoea. Reported series suggest delayed diagnosis in pregnant women due either to attribution of symptoms/signs to gestation or to hesitancy to embark on radiologic investigations. The vast majority of pregnant patients have well-differentiated thyroid tumours (papillary or follicular). Diagnosis and staging consist of ultrasound of the thyroid, fine-needle aspiration biopsy and chest X-ray. Technetium or iodine radioisotope scans are not advised [118]. Management of well-differentiated thyroid cancer consists of thyroidectomy, the extent of which ranges from lobectomy to total thyroidectomy. Third trimesters patients may be followed-up until delivery, given the indolent course and good prognosis of the disease. First trimester patients may be managed either expectantly until the second trimester or with immediate thyroidectomy. The risk of abortion or malformations is minimally elevated upon first trimester operations. Second trimester thyroidectomy is even safer, but no consensus exists on its application rather than treatment after delivery. TSH suppression with oral thyroxine administration is warranted at all gestational periods. Diagnostic I123 and ablative I131 scans for eradication of metastases should be done after delivery [119,120]. In the larger series of 61 pregnant women with thyroid cancer, Moosa compared disease course and patient outcome with that of 528 non-pregnant controls. They reported no difference in the rates of locoregional relapse, distant metastasis or survival between the two groups [121].

8. Placental and foetal metastases and subsequent pregnancies Vertical transmission of malignant cells to the placenta or foetus is uncommon. In the most updated literature review in 2003, only 62 cases are included [122]. Placentofoetal malignant seeding takes place via hematogenous spread and less often via lymphatic spread or contiguous invasion (pelvic tumours). The malignant neoplasms more commonly affecting the placenta and foetus are melanomas (32% of reported cases), leukaemias/lymphomas (15%), breast cancer (13%), gastric cancer (3%), lung cancer and gynaecologic tumours (3%). Presence of malignant cells in the intravillous space, part of the maternal vascular system, is seen more often than frank invasion of the villi [123]. Foetal metastases occur in no more than 25% of cases of placental malignant involvement, with rejection by the foetal immunologic system probably constituting a protective barrier. Melanoma accounts for 58% of gestational tumours affecting the embryo, in which case neonatal prognosis is poor with reported median survival of less than 3 months. The

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likelihood of embryonal metastasis in a pregnant patient with melanoma has been estimated to be about 17% [124]. Advanced-stage maternal malignancy, presence of maternal visceral metastases, and male foetal gender seem to increase the risk. Placental overexpression of melanocytes, tumour expression of adhesion molecules, growth factors and angiogenic compounds favouring placental seeding and foetal immaturity of the immunologic system have been suggested to explain the ‘‘melanoma tropism’’ for trophoblastic tissue[125]. Leukaemias and lymphomas rank second in the incidence of embryonal metastasis, with five reported cases. Macroscopic and histopathologic examination of the placenta with meticulous study of the intravillous spaces and villi should be routinely done in every case of malignancy coexisting with pregnancy. Cytological examination of umbilical cord blood ‘‘buffy-coat’’ preparations may also be done. Some investigators recommend a close follow-up of the healthy baby with six-monthly physical examination, chest X-ray and liver function tests for the first two years of life. In the presence of placentofoetal metastasis, immunohistochemical studies of maternal and foetal malignant deposits as well as caryotypic, cytogenetic and HLA typing of the tumour, mother and embryo are advised for accurate identification of the malignant clone [126]. Overall, the general consensus is that women diagnosed with cancer during pregnancy have reasonable chances for cure after appropriate management and may opt for further child-bearing as soon as the critical period of follow-up for potential recurrence is completed. This period has been defined as the first 2–5 years post-partum and is shaped by the diagnosed malignancy, the risk profile for recurrence, the patientÕs age and wishes, as well as the physicianÔs beliefs [1,2,5,30,83]. Contraception should be adhered to during this time, to allow for strict follow-up and in the case of relapse, immediate institution of salvage therapy and avoidance of further pregnancies in women with recurrent disease and poor prognosis. In case of prior I131 ablation for management of thyroid cancer metastases, pregnancy should be avoided for at least 12 months [127]. No evidence has emerged to date that subsequent gestation modify the risk of malignant recurrence, or that foetal health is compromised.

9. Psychosocial support of the pregnant patient and family As experienced by the future mother, the coexistence of cancer with pregnancy is a dramatic circumstance when two irreconcilable realities: the process of creating life with the process of destroying life, meet. At a time of great joy and hope, comes a devastating blow along with the fear of death. As medical, psychological, religious, social and moral standards tower over them, both patient and physician will struggle to find the right balance that combines maximum patient benefit with minimum foetal harm [128]. Some times, this is not attainable. Pregnancy may have to be terminated, especially in the first trimester, or the mother may opt to defer antineoplastic treatment until delivery at the cost of increased risk to her own health. A multidisciplinary team including oncologists, obstetricians, surgeons, neonatologists, geneticists, nurses, psychiatrists, psychologists and social workers

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should reach out to the patient and family, probe their psychological-intellectual capabilities and needs, inform them and lead them through the process of decision-making [129]. Such a strategy must be individualized and respectful towards the patientÕs wishes. The final decision reached should be a merge product of informed understanding of the illness and therapeutic options, medical advice, acknowledgement of her personal values and beliefs, reconciliation of familial conflicts and awareness of the available supporting structures. According to the decision reached, the pregnant patient may be overwhelmed by feelings of fear, depression, hopelessness, anger, guilt and shame. Shock, anger, denial and acceptance are stages through which the patient may transit at any order. Psychosocial support from the multidisciplinary team should aim towards informed active involvement of the patient in her care, development of a new way of life with renewed targets as well as better communication between her and the familial environment. Alleviating feelings of guilt and facilitating sentimental expression are also worthwhile. Any program of psychosocial intervention should diffuse from the hospital to other areas like work, household and community [130]. The latin phrase ÔPoena MagnaÕ has a dual meaning and it is ironic that it had been used by ancient scholars to describe both cancer and pregnancy: Ômajor punishmentÕ for cancer and Ômajor painÕ (followed by relief and joy) for gestation. In the current era of breakthroughs in molecular biology of cancer; in pharmacological management; and in gynaecologic, obstetric and neonatal care, it does not have to be that way. Patient prognosis does not have to be compromised and, when appropriate for gestation to continue, foetal health can be safeguarded. Development of skills, communication and evidence will pave the way for even safer and more efficient approaches in the management of pregnant women with cancer.

Conflict of Interest Statement None declared.

R E F E R E N C E S

1. Pavlidis NA. Coexistence of pregnancy and malignancy. The Oncologist 2002;7:279–87. 2. Antonelli NM, Dotters DJ, Katz VL, et al. Cancer in pregnancy: a review of the literature. Part I–II. Obstet Gynecol Surv 1996;51:125–42. 3. Jemal A, Murray T, Samuels A, et al. Cancer statistics 2003. CA Cancer J Clin 2003;53:5–26. 4. Nevin J, Soeters R, Dehaeck K, et al. Cervical carcinoma associated with pregnancy. Obstet Gynecol Surv 1995;50:228–39. 5. Pavlidis NA, Pentheroudakis G. The pregnant mother with breast cancer: Diagnostic and therapeutic management. Cancer Treat Rev 2005;31(6):439–47. 6. Smith LH, Dalrymple JL, Leiserowitz GS, et al. Obstetrical deliveries associated with maternal malignancy in California, 1992 through 1997. Am J Obstet Gynecol 2001;184(7):1504–12.

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