Abeloff's Clinical Oncology, 4th Edition

Part II – Problems Common to Cancer and its Therapy

Section H – Special Populations

Chapter 68 – Special Issues in Pregnancy

Andrew Grigg

SUMMARY OF KEY POINTS

  

   

Cancer complicates 1 in 1000 pregnancies; the most common malignancies are breast and cervical cancer, lymphoma, and melanoma.

  

   

There is no evidence that pregnancy alters the clinical behavior of cancer, but cancer often is advanced at diagnosis owing to the overlap of symptoms with those of a normal pregnancy.

  

   

Important factors in management include assessment of gestational age, maternal staging with limited exposure to ionizing radiation, the urgency for therapy, and the impact of therapy on maternal prognosis and fetal outcome.

  

   

Physiologic changes in pregnancy affect the metabolism of chemotherapy drugs, but there are few practical guidelines about how dosing should be adjusted to take this into account.

  

   

Alkylators and antimetabolites should be avoided in the first trimester, but these agents and other cytotoxics are generally not contraindicated in the second and third trimesters.

  

   

The scheduling of chemotherapy should be planned to minimize the risk of complications at the time of delivery.

  

   

There is no evidence that exposure to chemotherapy results in long-term adverse effects on physical or intellectual development, and there is no increased risk of malignancy in surviving children.

  

   

Therapeutic radiation jeopardizes fetal outcome and should be reserved for the postpartum period when possible.

  

   

Subsequent pregnancy after cancer diagnosis and effective therapy is usually possible.

INTRODUCTION

This chapter focuses on the issues related to the care of cancer diagnosed during the gestational period. Cancer is the second leading cause of death in women between the ages of 20 and 39 and complicates 1 in 1000 pregnancies. The most common cancers diagnosed in pregnant patients are those that are seen in nonpregnant women of similar age: breast, cervix, lymphoma, and melanoma.[1] Although pregnancy is associated with immunologic tolerance, there is no evidence of an increased incidence of cancer or of more aggressive behavior of malignancies that are diagnosed during pregnancy. However, many cancers in pregnancy are diagnosed at an advanced stage, often because symptoms of the malignancy overlap with those that are experienced in a “normal” pregnancy.

FETAL DEVELOPMENT AND PHYSIOLOGY

The three phases of fetal development are implantation, organogenesis, and growth. The implantation phase lasts from conception to 2 weeks and often ends in a spontaneous abortion after exposure to a toxic stimulus. Organogenesis occurs between 2 and 7 to 12 weeks; noxious stimuli at this time may lead to organ dysgenesis, resulting in fetal malformation or death. The growth phase occurs from the second trimester to term; toxic stimuli to the mother and fetus may result in fetal growth retardation, which can be associated with abnormal brain development and subsequent learning difficulties. However, as will be discussed, this has not been demonstrated to be a significant clinical concern in women receiving chemotherapy during the second and third trimesters.

As most chemotherapy drugs are uncharged, lipophilic, of low molecular weight, and minimally protein bound, they cross the placenta to the fetal circulation. The placenta is the primary portal of exit of waste products and toxins from the fetus. However, the metabolites are generally more polar than is the parent compound, might not cross the placenta as easily, and hence may accumulate in fetal tissues or amniotic fluid. The fetal liver can metabolize drugs as early as 7 to 8 weeks of pregnancy, but the extent to which fetal liver and kidneys participate in drug elimination is minimal.[2]

MATERNAL PHYSIOLOGY: RELEVANCE TO CHEMOTHERAPY AND SURGERY

Pregnancy induces a number of important physiologic changes that cause significant alterations in the metabolism and efficacy of commonly used medications ( Box 68-1 ). However, few data exist to guide physicians in adjustment of drug dosing (see the section on chemotherapy dosing).

Box 68-1 

PHYSIOLOGIC CHANGES IN PREGNANCY THAT MAY AFFECT THE METABOLISM AND EFFICACY OF CHEMOTHERAPY AGENTS

  

   

Alteration of drug absorption due to delayed gastric emptying and gastrointestinal mobility

  

   

Increased plasma volume leading to dilutional anemia, increased volume of distribution, and decreased peak plasma concentration of drugs

  

   

Increased enterohepatic circulation leading to increased drug bioavailability

  

   

Enhanced hepatic oxidation enhancing drug clearance

  

   

Altered levels of plasma proteins altering the pharmacokinetics of drugs with significant protein binding

  

   

Increased glomerular filtration resulting in enhanced drug clearance

Physiologic changes in pregnancy also affect surgical treatment and planning. Pregnancy is accompanied by increased plasma volume and dilutional anemia, reduced mean arterial pressure, increased oxygen consumption, and a narrow respiratory reserve. Cardiac output is increased by 30% to 50% as early as the second trimester, but in the supine position, the gravid uterus can compress the inferior vena cava, resulting in decreased venous return and reduction in cardiac output. Fetal development or viability may be jeopardized by hypotension and hypoxemia. Nevertheless, surgery can usually be performed safely during pregnancy; there is a small but increased risk of low birth weight and spontaneous abortion but no increased risk of fetal malformation.

DIAGNOSTIC RADIOLOGY FOR STAGING

The practitioner who is responsible for the radiologic examination must take all reasonable steps beforehand to advise the pregnant patient of the potential risks to the embryo or fetus that are associated with in utero exposure.

Radiation can be divided into ionizing and nonionizing radiation. Ionizing radiation has the ability to penetrate tissue and damage cellular DNA, resulting in mutation and ultimately affecting the development and viability of the fetus. Numerous studies of radiation exposure after atomic bomb detonations in Japan confirmed that this effect is dependent on dose and stage of fetal development at the time of exposure ( Table 68-1 ).[3] Fetal abnormalities after exposure to excessive ionizing radiation include microcephaly, eye malformation, and growth retardation.[4] The American College of Obstetricians and Gynecologists has published recommendations for imaging during pregnancy that state that 5-cGy exposure to the fetus is not associated with any increased risk of fetal loss or birth defects.[5] Radiation exposure is well below this for most procedures except for the maximum dose with CT scanning of the abdomen and pelvis ( Table 68-2 ). A more relevant concern is an increased risk of childhood cancer. After a gestational age of 3 to 4 weeks, the number of excess cancer cases (leukemia and solid tumors) up to age 15 years following radiation in utero is estimated to be 1 in 17,000 per 0.1 cGy. The baseline cancer risk in the first 15 years is about 1 in 650, so a fetal dose of 2.5 cGy will approximately double the risk; however, this represents an excess lifetime fatal cancer risk of less than 0.5%.

Table 68-1   -- Estimates of Threshold Doses for Effects Following Fetal Radiation in Utero

 

MINIMAL DOSE (MGY)

Age (in weeks)

Death

Gross Malformations

Mental Retardation

0 to 1

No threshold at day 1; 100 thereafter

No threshold at day 1?

Analysis of Japanese data suggest a dose related reduction of about 3 IQ points per 10 cGy for children irradiated in utero from 8 to 15 weeks post fertilization. The threshold is ill defined and may lie between 6 and 30 cGy

2 to 5

250 to 500

200

 

5 to 7

500

500

 

7 to 21

>500

Very few observed

 

To term

>1000

Very few observed

 

 

 


Table 68-2   -- Typical Ranges of Fetal Doses Following Common Diagnostic Procedures

Examination

Mean Dose (cGy)

Maximum Dose (cGy)

CONVENTIONAL X-RAY

Abdomen

0.14

0.42

Chest

<0.01

<0.01

Cervical spine

<0.01

<0.01

Lumbar spine

0.17

1.0

Pelvis

0.11

0.4

Thoracic spine

<0.01

<0.01

COMPUTED TOMOGRAPHY

Abdomen

0.8

4.9

Pelvis

2.5

7.9

Chest

0.006

0.096

Cervical spine

<0.01

 

Brain

<0.005

<0.005

NUCLEAR MEDICINE

99m Tc bone scan (phosphate)

0.33

0.46

67 Ga tumors and abscesses

1.2

131 I thyroid metastases

2.2

The radiation doses have been estimated from surveys conducted in the United Kingdom for a range of diagnostic radiology.

 

 

 

Ultrasound and Magnetic Resonance Imaging

Ultrasound is accepted as being safe in pregnancy and can be particularly useful in assessing the breasts and liver. Magnetic resonance imaging (MRI) does not expose the patient to ionizing radiation, and there has been no indication that MRI during pregnancy has produced deleterious effects. Hence, MRI may be used in pregnant women if other nonionizing forms of diagnostic imaging are inade quate or if the examination provides important information that would otherwise require exposure to ionizing radiation (e.g., fluoroscopy, CT). Contrast agents such as gadolinium cross the placenta and are contraindicated. MRI of the abdomen is limited by motion artifact of the bowel.

Position Emission Tomography Scanning

Pregnancy is a relative contraindication to positron emission tomography (PET) scanning but termination is not generally recommended if a patient is found to be pregnant after a PET scan. After a PET/CT scan, a representative dose is 8 mGy (PET) and 0.3 cGy (CT). The dose to the fetus may be higher owing to close proximity of the mother's bladder, where fluorodeoxyglucose is excreted.

TERATOGENICITY OF CHEMOTHERAPY

The U.S. Food and Drug Administration (FDA) has defined risk categories for all drugs based in part on the evidence in animals of fetal harm ( Table 68-3 ). The majority of chemotherapeutic agents are Category D. Extrapolation of teratogenic and mutagenic effects of chemotherapeutic agents from animals to human organogenesis is difficult, however, because of differences in susceptibility between species.[6] The timing of fetal drug exposure is critical. Drugs that are administered with one week of conception may produce a spontaneous abortion or a healthy fetus. During the first trimester, when organogenesis occurs, drugs may produce congenital malformations and/or result in spontaneous abortion. Other factors that may influence the probability of teratogenesis include the frequency of drug administration, duration of exposure, synergistic effects of multiple drugs, radiation, and individual genetic susceptibility.


Table 68-3   -- Food and Drug Administration Risk Categories for Drugs Administered During Pregnancy

Category

Description

A

Controlled studies in women do not show risk to the fetus during the first trimester; there is no evidence of risk in late trimesters, and the possibility of fetal harm is remote.

B

Animal reproduction studies have not shown a fetal risk, but there are not controlled studies in pregnant women; or animal reproduction studies have shown an adverse effect (other than a decrease in fertility), but this has not been confirmed in controlled studies in women in the first trimester (no evidence of a risk in later trimesters).

C

Studies in animals have revealed adverse effects on the fetus (teratogenic, embryocidal, or both), and there are no controlled studies in women, or studies in animals and women are unavailable. Drug should be given only if potential benefit justifies the risk to the fetus.

D

There is positive evidence of human fetal risk, but the benefits from use in pregnant women may be acceptable despite the risk (if the drug is needed in a life-threatening situation for which other safer drugs are not available).

X

Studies in humans and animals have shown fetal malformations; there is evidence of fetal risk based on human experience or both. The risk of use in a pregnant woman clearly outweighs any potential benefit. This drug is contraindicated in women who are or may become pregnant.

 

 

Most human data about chemotherapy during pregnancy involve small series or case reports, which are prone to reporting bias. There is limited specific or systemic information about the teratogenicity of individual cytotoxics or modern multiagent chemotherapy regimens, particularly in the first trimester. Many reported malformations have occurred after exposure to multiple agents, making it difficult to apportion blame to a single causative agent. Interpretation of these data should be tempered by the reality that the overall incidence of major congenital malformations is approximately 3% of all births, the incidence of minor malformations may be as high as 9%, and between 10% to 15% of all pregnancies result in a miscarriage or spontaneous abortion.[7] Extrapolation from older data might also not be appropriate, as many of these drugs (e.g., alkylating agents such as nitrogen mustard and busulfan and antimetabolites such as aminopterin) are now rarely used. Limited experience in the first trimester with regimens such as adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) and cyclophosphamide, adriamycin, vincristine, and prednisolone (CHOP) suggests low rates of teratogenicity.[8] In the second and third trimesters, drugs extremely rarely cause significant malformations but could impair fetal growth and development, probably mainly indirectly due to maternal ill-health. The available literature suggests that learning or behavioral problems (functional teratogenesis) do not result from chronic prenatal chemotherapy exposure. Overall, the use of systemic antineoplastic therapy alone appears to be accompanied by significantly lower risk than is commonly appreciated.

SPECIFIC CHEMOTHERAPY DRUGS

Table 68-4 details the available experience on the use of some of the more commonly used chemotherapy drugs in animals and at various stages of pregnancy, in humans, together with the FDA category. [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] The recommendations are those published by Briggs and colleagues,[9] with some additional comments from the author. An excellent review by Cardonick and Iacobucci is recommended.[35]


Table 68-4   -- Summary of and Recommendations[9] for Chemotherapy Drug Experience in Pregnancy

Drug

First Trimester

Second Trimester

Recommendations

Risk Category

Author Comment

Alkylators in general[10]

Inadequate data; teratogenic in animals

Case reports without apparent fetal harm

Contraindicated in first trimester

D

 

Anthracyclines

Teratogenic in rats; little human data as single agent

No reports of specific fetal abnormalities; idarubicin associated with neonatal cardiomyopathy[11]

Contraindicated in first trimester

D

Doxorubicin preferred

Bleomycin

Teratogenic in rats; use in combination not associated with fetal malformations

Use in combination has not been clearly associated with fetal abnormalities

Not specified

D

Oxygen during delivery may aggravate pulmonary toxicity[12]

Cisplatin

Teratogenic in animals; little human data

Case reports suggest safety [13] [14]

Contraindicated in first trimester

D

 

Corticosteroids

Associated with nonsyndromic orofacial clefts[15]

Repeated exposure to dexamethasone may increase leukomalacia and neurodevelopmental abnormalities[16]

Potential maternal benefit outweighs embryo/fetal risk

C: second/third trimester
D: first trimester

 

Cyclophosphamide

Yes: cyclophosphamide embryopathy[17]

Main concern is neonatal myelosuppression

Contraindicated in first trimester

D

 

Cytarabine

Yes: limb abnormalities[18]

Main concern is maternal myelosuppression and sepsis with secondary effects on the fetus

Not specified; relatively contraindicated in first trimester

D

 

Etoposide

Teratogenic in animals; no human data

IUGR and myelosuppression when used in aggressive combination regimens

Not specified

D

 

Imatinib

Limited data; malformations reported[19]

Limited data suggest safety

D

Consider in second or third trimester if poor disease control

Methotrexate

Yes: methotrexate embryopathy;[20] minimal risk at 6 to 8 weeks post-conception at doses ≥10 mg/week[21]

Neonatal myelosuppression; accumulates in ascitic fluid

Contraindicated at all stages

X

 

Rituximab

Not teratogenic in animals; limited data suggest no adverse effects [22] [23]

Limited case reports suggest safety [24] [25] [26] [27] [28]

C

Benefit outweighs risk in most circumstances

Taxanes

Teratogenic in animals; no human data

Reports suggest no significant risk to the fetus [29] [30]

Not specified

 

Consider in second/third trimester if clear maternal benefit

Trastuzumab

No fetal harm in monkeys

One report of reversible anhydramnios[31]

B

Not contraindicated but use with caution

Vinca alkaloids

Teratogenic in rats, but limited human data suggest relatively safe [8] [32] [33] [34]

No reports of specific fetal abnormalities

Not specified

D

Vinblastine has been recommended as single agent in HL in first trimester

Briggs GG, Freeman RK, Yaffe ST: Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk, 7th ed. Philadelphia, Lippincott Williams and Wilkins, 2005.

Refer to text for additional comments.

 

 

 

 

Antimetabolites

Methotrexate is widely distributed, including into fluid spaces such as amniotic fluid, and is closely associated with fetal abnormalities when given during the first trimester, characterized by cranial dysostosis, hypertelorism, micrognathia, limb deformities, and mental retardation.[20] However, methotrexate does not uniformly cause malformations, and there may be a critical dose above which fetal malformations occur.[21] Exposure to methotrexate in the latter trimesters has not been associated with significant malformations,[9] but its elective use at this time, particularly in high dose, is still not recommended.

5-Fluorouracil (5-FU) was associated with multiple congenital malformations in the fetus of a patient who was found to be pregnant at week 14 after she began receiving chemotherapy for colon cancer at week 12 and hence is not recommended for use during the first trimester.[36] Cytosine arabinoside, alone and in combination with other drugs, during the first trimester has also been associated with congenital anomalies.[18]

Alkylating Agents

Alkylating agents are commonly used in the treatment of lymphoma, acute lymphocytic leukemia, and breast cancer. Among 47 at-risk pregnancies, six malformations were reported when alkylating agents were used in the first trimester, usually as part of combination therapy.[10] Cyclophosphamide is clearly teratogenic in animals, with similar malformations noted in different species. A distinct and similar embryopathic phenotype in humans has been described after exposure to cyclophosphamide as a single agent, with one dose (20 mg/kg) during the sixth week after conception.[17] Second- and third-trimester exposure has not been associated with malformations. Other alkylating agents, such as thiotepa and dacarbazine, are teratogenic at high doses in rats, but little is known about their effects in humans apart from case reports of lack of side effects when used in the second trimester or beyond. Exposure to chlorambucil during the first trimester has been reported to cause renal aplasia, cleft palate, and skeletal abnormalities.[37]

Platinum

A number of case reports documenting platinum use after the first trimester have not noted any congenital malformations. [13] [14]

Vinca Alkaloids

Although vinblastine is highly teratogenic in animal models, the literature suggests that its use in the first trimester may be relatively safe. No congenital malformations were reported in 11 pregnancies that were exposed to vincristine, three being in the first trimester.[32] Vinorelbine, vinblastine, and vincristine had been used during the latter trimesters without fetal harm. [8] [31] [34]

Anthracyclines

There is little information about the effects of these drugs in pregnancy as single agents; malformations have been reported when they are used in combination regimens in the first trimester. Idarubicin is more lipophilic, which favors placental transfer, and has been associated with neonatal cardiomyopathy.[11]

New Agents

There are minimal human data with respect to the following:

  

   

Topoisomerase-1 inhibitors such as topotecan (used in ovarian and small cell lung cancer) and irinotecan (used for colorectal cancer and non-small-cell lung cancer)

  

   

Ertotinib, an epidermal growth factor receptor tyrosine kinase inhibitor that is used in metastatic lung and pancreatic cancer

  

   

Bevacizumab, a humanized monoclonal antibody with an antiangiogenic effect that is used for metastatic colorectal cancer. Because it is teratogenic in rabbits (according to Roche product information), consistent with a crucial role of angiogenesis during normal fetal development, bevacizumab should not be administered to pregnant women.

  

   

Oxaliplatin. This is embryotoxic in animals, classified as a Category D drug and is not recommended for use in pregnancy.

  

   

Capecitabine is an oral drug akin to 5-FU used in bowel and breast cancer. This is embryotoxic in animals, classified as a Category D drug, and is not recommended for use in pregnancy.

Miscellaneous Agents

Granulocyte colony-stimulating factor (G-CSF) is not teratogenic in rats, and no congenital malformations or toxicities attributable to G-CSF have been reported in humans.[9] G-CSF is a Category B drug and should not be withheld in pregnancy if there is a significant potential benefit to the mother.

5-Hydroxytryptamine-3 (5HT3) antagonists, such as ondansetron, are widely used to prevent and treat chemotherapy-induced nausea and vomiting. These drugs are not teratogenic in animals, and the small number of reports of ondansetron for hyperemesis gravidarum and chemotherapy in pregnancy suggest effectiveness and safety. 5HT3 antagonists have been classified as Category B drugs in pregnancy.[9]Aprepitant (Category B) is an effective antiemetic for delayed nausea after chemotherapy. Animal studies have not revealed harm to the fetus after exposure to aprepitant (according to Merck, Sharp and Dohme product information), but there are no data on its use in pregnant women.

Recombinant human erythropoietin (Category C) does not cross the human placenta and does not appear to present a major risk to the fetus,[9] and the benefit of its appropriate use for maternal anemia appears to outweigh any known or potential risks.

CHEMOTHERAPY IN PREGNANCY: OVERVIEW

An overview of the approach to treatment is detailed in Figure 68-1 .

 
 

Figure 68-1  Overview of the treatment approach to cancer in pregnancy.

 

 

First Trimester

Patients should be counseled that the incidence of teratogenicity as a result of exposure to a particular chemotherapy drug or a drug combination in the first trimester is not well established. Counseling regarding the effects of chemotherapy needs to be performed using as much information as possible, which may involve asking the relevant pharmaceutical company for updated information. In addition, for many malignancies, there is no evidence either way that delaying chemotherapy from the first trimester until the completion of fetal organogenesis early in the second trimester adversely affects theultimate outcome. A therapeutic abortion is usually recommended for cancers diagnosed in the first trimester that require urgent multiagent chemotherapy. There are multiple factors, such as desire to avoid termination, risk of delay, and interim use of truncated chemotherapy protocols with drugs with a low probability of teratogenicity, that need to be considered in each patient.

Second and Third Trimesters

The administration of most chemotherapeutic agents in the second and third trimesters has not been associated with specific adverse effects on the fetus; hence, in general, chemotherapy-based treatment of the underlying malignancy at this stage of pregnancy should not be delayed and should follow the same guidelines as for nonpregnant women. The main risk to the fetus appears to be secondary to neutropenic sepsis, anemia, and nutritional deficiency in the mother.[35] The parents can be assured that long-term studies have shown that in the absence of chemotherapy-embryopathy, children who are exposed to chemotherapy in utero are not different physically or intellectually from matched controls, and there is no suggestion of a significantly increased risk of malignancy in the neonate (i.e., transferred from the mother) or in long-term follow-up.[8]

Chemotherapy Dosing

An anecdotal observation of fewer chemotherapy-related side effects during antenatal treatment compared with identical chemotherapy postpartum has been reported,[35] consistent with physiologic changes in pregnancy leading to lower plasma levels and reduced area under the concentration × time curve. Pharmacokinetic studies have not been done. Accordingly, particularly when given with curative intent, chemotherapy doses should not be empirically dose-reduced. A practical approach, particularly in curable hematologic malignancies such as Hodgkin's lymphoma in which low hematotoxicity is an independent prognostic factor for a poorer treatment outcome, may involve regular blood counts with individualized dose adjustments (up or down) according to the level of myelosuppression.[38]

SPECIFIC MALIGNANCIES

Breast Cancer

The incidence of breast cancer during pregnancy is estimated to be 1 in 3000.[39] Women with a genetic predisposition to breast cancer, particularly BRCA2 mutations, might be overrepresented in this group.[40] Despite its long-term protective effect on the development of breast cancer, pregnancy itself may temporarily increase the risk of disease, again particularly in women with BRCA2 mutations. Breast cancer in pregnancy is more likely to be advanced (almost 50% stage IV, with lymph node involvement in 65%), is thought to reflect a delay in diagnosis as the physiologic breast changes of pregnancy may mask a malignant mass, and possibly involves a higher incidence of Her-2/neu positivity and a lower incidence of estrogen receptor positivity (there is conflicting literature) than breast cancer in nonpregnant women. [40] [41] [42] The majority are poorly differentiated infiltrating ductal adenocarcinomas. However, stage-specific survival is similar to that of nonpregnant patients. [43] [44]Placental metastases of breast cancer have been reported, but rarely, and there are no reports of fetal involvement.[45]

The principles of diagnosis are similar to those for nonpregnant women. Mammography is safe, as there is negligible radiation dose to the fetus with abdominal shielding, but may be associated with high false-positive rates. Ultrasonography can distinguish solid from cystic masses. Gadolinium-enhanced MRI of the breast is contraindicated. Fine needle aspiration biopsy is acceptable, but accurate interpretation requires an experienced pathologist who is aware that the woman is pregnant. If nondiagnostic, solid masses should be subject to excisional biopsy. Safe staging procedures include a chest x-ray and MRI without contrast. A chest CT scan is not contraindicated (see the section on radiology), but a MRI of the thorax is preferred. Bone evaluation if required, can be with a modified bone scan with maternal hydration and frequent voiding to limit fetal radiation exposure from radionuclides in the adjacent maternal bladder.[46] The serum alkaline phosphatase level rises physiologically during pregnancy and is not useful as an indicator of bony secondaries.

National Comprehensive Cancer Network Guidelines for the treatment of nonmetastatic breast cancer during pregnancy are available and are reproduced in Figure 68-2 . International expert recommendations have also been published recently.[47] Treatment should not be unnecessarily delayed, as delay may result in significantly worse disease-free survival. Therapeutic abortion does not appear to alter maternal survival.

 
 

Figure 68-2  National Comprehensive Cancer Network Guidelines for the treatment of nonmetastatic breast cancer during pregnancy.  (Reproduced with permission from The NCCN 1.2007 Breast Cancer During Pregnancy Clinical Practice Guidelines in Oncology. Available at: www.nccn.org. Accessed December 2006. To view the most recent complete version of the guidelines, go online to www.nccn.org.)

 

 

 

Considerations and selection of optimal local therapy are similar to that recommended in non-pregnancy-associated breast cancer. Breast and axillary surgery during any trimester appears to be reasonably safe for the mother and associated with minimal fetal risk. Axillary lymph node dissection is important, as nodal metastases are common and nodal status affects the choice of adjuvant therapy. At present, sentinel lymph node biopsy has not been systematically evaluated and is not generally recommended.[47] Therapeutic radiation has been contraindicated during pregnancy, as this is calculated to expose the fetus to 10 cGy in early pregnancy and 200 cGy in late pregnancy, which are above the acceptable limits;[39] however, this view has recently been questioned.[48] Accordingly, mastectomy is a consideration in early gestation when radiation therapy is significantly delayed. Breast-conserving surgery is an option in the second or early third trimester with neoadjuvant chemotherapy or by itself late in the third trimester.

Adjuvant chemotherapy should be delayed to beyond the first trimester. FAC (5-FU, adriamycin, cyclophosphamide) during the second or third trimesters has not been associated with spontaneous abortions or fetal abnormalities; methotrexate is usually avoided.[49] Tamoxifen is contraindicated owing to its association with spontaneous abortion, birth defects, fetal death, and, in pregnant rats, breast cancer in female offspring.[47] International guidelines suggest avoiding taxanes and dose-dense anthracyclines during pregnancy owing to the paucity of data, although the limited literature has not demonstrated any adverse fetal effects with taxanes that are administered beyond the first trimester. [29] [30] Trastuzumab (herceptin), a pregnancy category B drug, is a monoclonal antibody that blocks the human epidermal growth factor receptor Her-2/neu and that in combination with adjuvant chemotherapy has been shown to improve disease-free and overall survival for early-stage Her-2 positive breast cancer.[49] Reports have demonstrated either no adverse effect or reversible anhydramnios in women who are exposed to trastuzumab in the first trimester. [31] [50] [51] Consideration should be given to the use of trastuzumab and/or taxane compounds beyond the first trimester if there is a strong likelihood of maternal benefit.

There is no evidence that a future pregnancy worsens the prognosis with respect to recurrence; in fact, on early follow-up, pregnancy may lower the risk of death.[52] However, most oncologists advise women to wait two to three years before another pregnancy, as the risk of recurrence is highest during this time. Recent literature has highlighted the impact of chemotherapy regimen, age, and time since treatment on ovarian function after breast cancer treatment in premenopausal women.[53]

Cervical Cancer

Cervical cancer is the most common malignancy diagnosed during pregnancy (1 in 750) probably owing to routine Papanicolaou screening.[54] Unlike other malignancies in pregnancy, cervical cancer is often detected early because of this; advanced cervical cancer is rarely encountered. Symptoms such as vaginal bleeding or discharge may overlap with those of pregnancy. Human papillomavirus is involved in most cervical cancers. There is no evidence that the relative immunosuppressive state of pregnancy modifies the aggressiveness of human papillomavirus infection.[55] Cone biopsies may result in significant hemorrhage and fetal death and should be done only if necessary for diagnosis of invasive malignancy.[56]

Management recommendations differ according to disease stage. There is evidence that delay of treatment of early-stage cancer until fetal maturity in a desired pregnancy is not deleterious to the mother. An algorithm of treatment options for early-stage cancer at less than 20 weeks gestation has been described.[55] If advanced disease is diagnosed and the fetus is viable, then delivery by cesarean section is recommended, followed by commencement of therapy. Neoadjuvant chemotherapy is a consideration if treatment needs delay for fetal indications. If the fetus is not viable and stage IIB–IVA disease is detected, treatment should be directed with curative intent. Chemoradiation should be initiated promptly, which will lead to abortion of the fetus.

Melanoma

While overall there is a male preponderance, age-specific incidence rates are higher among females until age 40 years, leading to speculation that some causes may be hormonally driven.[57] However, there is no clear evidence that exogenous hormone use increases the risk,[58] that the incidence of melanoma is higher in pregnancy,[59] or that pregnancy influences the prognosis.[60] Treatment principles are similar to those for the nonpregnant patient. An approach to the management of pregnant women with high-risk melanoma has been published.[61] Melanoma is the most common malignancy associated with transplacental metastases to the fetus. With placental involvement, the fetal risk of melanoma metastasis is approximately 22%, with a high fatality rate in affected infants.[62]

Ovarian Cancer

Invasive epithelial ovarian cancer is uncommon during pregnancy, the majority of cases being diagnosed early owing to frequent use of pelvic ultrasound and generally having germ cell or low malignant potential histology. [63] [64] Surgical staging and treatment of ovarian neoplasms include debulking surgery, including omentectomy, lymph node and peritoneal biopsy, and assessment of peritoneal washings. Germ cell tumors are typically treated with bleomycin, etoposide, and cisplatin; experience with these agents in the latter trimesters of pregnancy with this combination is limited but has been associated with prematurity and ventriculomegaly in one report.[65] Low malignant potential neoplasms are treated with surgery alone. Invasive epithelial ovarian cancer is treated with postoperative chemotherapy consisting of platinum and paclitaxel; the safe use of this combination in the second trimester has been reported. [13] [66]

Gestational Choriocarcinoma

Gestational choriocarcinoma is a highly malignant vascular neo-plasm of the cytotrophoblast and syncytiotrophoblast that readily metastasizes. Choriocarcinoma can be preceded by any gestational event; most arise after a hydatiform mole or a spontaneous abortion or after a normal pregnancy. Diagnosis concurrent with a normal pregnancy is extremely rare.[67] A scoring and risk factor system for gestational choriocarcinoma from the International Federation of Gynecology and Obstetrics (FIGO) has been published; chemotherapy recommendations depend on the FIGO risk score.[68] In tumors that are diagnosed after pregnancy, a high cure rate can be achieved with single-agent chemotherapy (usually methotrexate) for low-risk disease, but responses are lower in high-risk disease, for which multiagent chemotherapy is the treatment of choice.[69] However, the cure rate for choriocarcinoma concurrent with pregnancy is poor. Simultaneous choriocarcinoma in the mother and infant is rare but may be curable in both if recognized and treated early.[70]

Colorectal Cancer

About 300 cases of colorectal cancer during pregnancy have been reported; underlying risk factors such as hereditary or familial syndromes and long-standing inflammatory bowel disease are likely to be particularly relevant in this younger age group.[71] Unlike the general population, in which only 20% to 25% of colon cancers occurs in the rectum, a higher incidence of rectal presentation may result from increased local symptoms from rectal compression by the pregnant uterus or more frequent rectal or pelvic examinations. Sigmoidoscopy is safe. While the safety of colonoscopy during pregnancy is not well established, the limited literature suggests no increase in adverse outcome to the mother or children.[71] Abdominal ultrasound is safe, but CT scanning of the abdomen and pelvis, especially in the first trimester, is problematic (see the section on radiology). Of note, ovarian metastases occur in 25%,[71] and serum BHCG may be elevated owing to ectopic production by the cancer cells.[72]

Surgical recommendations are complex and are well summarized in a recent review.[71] Adjuvant chemotherapy with 5-FU or related drugs such as capecitabine is contraindicated in the first trimester. Later trimester exposure to 5-FU has not been associated with increased fetal loss or development abnormalities but with intrauterine growth retardation and prematurity. Delaying adjuvant chemotherapy is an option, but whether the beneficial effect is maintained is unclear. Preoperative or postoperative radiotherapy is contraindicated during pregnancy. Survival is generally poor, owing to late presentation and advanced pathologic stage, but is no different from that in the general population when stratified for pathologic stage.[73]

Thyroid Cancer

The most common presentation is that of an asymptomatic nodule. The outcome does not appear to be affected by pregnancy.[74] Recommendations include delaying surgery to the second trimester for tumors that are diagnosed early in pregnancy and, if required, administration of radioiodine after delivery, as it might cause cretinism in the fetus.[75] Conventional chemotherapy is not particularly effective in resistant disease.

Other Cancers

Gastrointestinal pancreatic and hepatic cancers are very rare in pregnant women, except for gastric cancer in Japan. Delays in diagnosis are common. A detailed review of these malignancies in pregnancy has recently been published.[76]

Genitourinary malignancies are rare, although the risk of renal cell cancer may be increased by pregnancy.[77] Lung cancer has a poor prognosis in pregnancy,[14] and metastasis of small cell carcinoma from mother to fetus has been reported. [14] [78] Sarcomas are rare in pregnancy. There appears to be no interaction between pregnancy and the natural history of osteogenic carcinoma.[79] Successful delivery of chemotherapy to the mother has been reported for Ewing's sarcoma.[80]

HEMATOLOGIC MALIGNANCIES

Hodgkin's Lymphoma

Hodgkin's lymphoma, with an incidence of 1 : 1000 to 1 : 6000, is the most common lymphoma in pregnancy.[81] Reasonable options for staging in pregnancy include a CT scan of the neck and chest with MRI of the abdomen and pelvis.

The majority of patients who are found to have Hodgkin's lymphoma during pregnancy do not require immediate intervention. Asymptomatic or minimally symptomatic patients can be followed carefully, with treatment reserved for threatening or more symptomatic disease; many patients can carry the pregnancy to term without any treatment becoming necessary.[34]

Options for symptomatic disease that is diagnosed in the first trimester include single-agent chemotherapy or multiagent chemotherapy with or without a prior therapeutic abortion. There are no large studies of the teratogenic effects in the first trimester of commonly used regimens such as ABVD, although the limited literature has not demonstrated any adverse effect. [8] [35] Vinca alkaloids, anthracyclines, bleomycin, and steroids appear to be relatively safe in the first trimester, but alkylators such as cyclophosphamide and dacarbazine may be teratogenic. Options that have been proposed include ABV or vinblastine alone. [34] [35] Mantle field radiotherapy for supradiaphragmatic disease has not been associated with adverse fetal effects, as the estimated fetal dose after uterine shielding is below the threshold for major congenital malformations.[81] Nevertheless, it is rarely indicated, and its use during pregnancy cannot be considered standard, as there is a lack of reliable clinical data on late effects.

Multiagent chemotherapy such as ABVD appears to have minimal fetal risk when administered during the second or third trimester, with only one minor malformation in 10 patients treated with ABVD (n= 9) or ABV (n = -1) (E. Cardonick, personal communication).[35] An option is single-agent vinblastine, which almost always induces some disease regression and allows disease control until after delivery, at which time multiagent chemotherapy can be delivered.[34] These alternatives—that is, (1) prompt potentially curative chemotherapy with protocols such as ABVD after counseling that there does not seem to be an increased risk of congenital birth defects or of significant long-term neurologic sequelae or (2) minimizing fetal risk by delay of definitive therapy until after delivery—need to be discussed in each case, considering factors such as symptoms and aggressiveness of the tumor. Supradiaphragmatic radiation is problematic in the third trimester, as fetal exposure is increased owing to uterine proximity.

The role of allogeneic stem cell transplantation for Hodgkin's lymphoma is controversial, but this approach is occasionally used in patients with relapsed disease after an autograft. In the absence of a histocompatible sibling, alternative sources of allogeneic stem cells include marrow, peripheral stem cells, or cord blood from an unrelated donor. Cryopreservation of umbilical cord blood at delivery is an issue that might need to be addressed in some patients with high-risk disease.[82]

Non-Hodgkin's Lymphoma

Aggressive non-Hodgkin's lymphoma (NHL) in pregnancy is rare, with an incidence of approximately 1 in 100,000. Indolent NHL usually does not require immediate therapy.[82] The NHL that is most likely to require treatment in pregnancy is CD20 positive diffuse large B cell NHL. These lymphomas are usually aggressive and advanced at diagnosis in pregnancy with a higher incidence of breast, uterine, cervical, and ovarian involvement, perhaps related to increased vascularity.[81] The current standard therapy is CHOP-rituximab, with consideration of the addition of involved field radiotherapy for localized disease.[83]

Treatment delay is rarely advisable in the first trimester but may be a consideration in some patients with relatively indolent disease clinically. A recommended option has been a therapeutic abortion followed by standard chemotherapy.[81] However, experience with CHOP-based regimens in the first trimester suggests the risk of teratogenicity is low; Aviles reported no adverse fetal outcome 17 mothers with aggressive NHL treated in the first trimester with CHOP-bleomycin or similar regimens.[8] This suggests that CHOP-based chemotherapy, preferably without an alkylator initially, is a reasonable consideration during the first trimester when treatment is required without delay and termination is not acceptable. Prompt administration of CHOP-rituximab chemotherapy is recommended in the second trimester. Reduced intervals between cycles (e.g., each 2 weeks versus the standard 3 weeks) is commonly used in nonpregnant women[84] but is not currently advised in pregnancy, as there are no data on this approach.

An important issue is the safety of rituximab during pregnancy. This agent has been shown in a number of randomized studies to improve outcome in aggressive CD20+ NHL and represents a major therapeutic advance.[83] Administration of rituximab during organogenesis in monkeys had no obvious adverse effect on embryo or fetal development apart from the expected pharmacologic effect of B cell depletion, as IgG is known to cross the placental barrier.[85] The available literature in human pregnancy is limited. Two reports of exposure to rituximab without chemotherapy in the first trimester have described delivery of healthy, normal babies with no immunologic deficits. [22] [23] Four reports of CHOP (or CHOP-like)-rituximab chemotherapy in the second trimester described delivery in all cases of healthy babies with subsequent normal immunologic reconstitution. [24] [25] [26] [27] Two babies had detectable rituximab levels at birth with severe B lymphopenia but subsequently achieved normal immunologic status at 3 to 4 months without infectious sequelae in the interim. [26] [27] One report of rituximab in the third trimester described no toxicity apart from asymptomatic transient neonatal neutropenia.[28] The approved product information states that rituximab should not be given to a pregnant woman unless the potential benefit outweighs the potential risk. A reasonable position is to recommend rituximab as part of combination chemotherapy during pregnancy, as in the author's opinion, the available evidence suggests that the maternal benefits outweigh the fetal risk.

Acute Leukemia

The presence of acute leukemia and/or its treatment has been associated with increased incidence of premature birth, stillbirths, and intrauterine growth retardation, particularly early in pregnancy.[35]Contributing factors other than chemotherapy include sepsis, anemia, and disseminated intravascular coagulation. Treatment is generally required without delay, irrespective of gestational age, as delay may increase both fetal and maternal mortality.

The most common acute leukemia in adults is acute myeloid leukemia, for which the usual chemotherapy is cytarabine (with at least one high-dose course) and an anthracycline such as daunorubicin or idarubicin. Acute lymphoblastic leukemia in adults is less common; induction treatments are less standard and more complex than in acute myeloid leukemia but generally include cyclophosphamide, vincristine, adriamycin, and steroids. Consolidation treatments in acute lymphoblastic leukemia characteristically include high-dose methotrexate. The risk of teratogenicity appears to be confined to the first trimester, particularly with methotrexate, other antimetabolites, thioguanine, and alkylating agents.[35] Cytarabine has been associated with limb malformations after first trimester exposure.[18] Other chemotherapy drugs such as vincristine, anthracyclines, and prednisolone appear to be relatively safe. Aviles and colleagues reported the outcome of 29 pregnancies that were complicated by acute leukemia: acute myeloid leukemia in 19 patients and acute lymphoblastic leukemia in the remainder.[8] All were treated with standard antileukemic protocols; 11 received chemotherapy during the first trimester. No congenital abnormalities were observed, there was no evidence of intrauterine growth retardation, and no excess of complications was seen in long-term follow-up in the children.

General principles of management include the following:

  

   

In the first trimester, a therapeutic abortion is probably the recommendation of choice, particularly in acute myeloid leukemia, owing to concern of the teratogenicity of the optimal chemotherapy. Methotrexate is absolutely contraindicated.

  

   

In the second and third trimesters, it is reasonable to treat with standard regimens without inducing an abortion, as there are no convincing data that the relevant chemotherapy is teratogenic at this time. However, the mother needs to be counseled about the fetal risks from maternal sepsis, anemia, and coagulopathy. High-dose methotrexate is inadvisable, and the administration of high-dose cytarabine is arguably best deferred until after birth, as there is minimal experience with this schedule during pregnancy.

  

   

If possible, delivery should be scheduled not to coincide with severe neutropenia and thrombocytopenia. It is recommended to maintain platelets at greater than 30 to 50 × 109/L, especially around time of delivery, to allow for regional anesthesia and to maintain hemoglobin at greater than 9.8 g/dL, as perinatal complications increase as the hemoglobin declines. [82] [86] Neonatal blood counts should be checked at delivery. Neonates are at risk of transient myelosuppression and cardiomyopathy after administration of idarubicin.[11]

  

   

Following are some specific points:

  

   

Use of prednisolone rather than dexamethasone is recommended owing to concern of repeated fetal exposure to dexamethasone and adverse neurologic sequelae.[82] Steroids may increase the risk of diabetes owing to increased insulin resistance in pregnancy.

  

   

L-asparaginase is commonly used in acute lymphoblastic leukemia protocols. Limited experience suggests this drug does not pose a major risk to the fetus when used beyond the first trimester. However, L-asparaginase has been associated with thromboembolism related to reduced levels of antithrombin III.[87] The risk may be higher in pregnancy, which is a hypercoagulable state. Consideration should be given to prophylactic infusion of antithrombin III concentrates if L-asparaginase is administered during pregnancy or in the first 6 weeks thereafter.

  

   

Acute promyelocytic leukemia is optimally treated with all-trans-retinoic acid, usually in combination with an anthracycline.[88] Retinoic compounds are teratogenic in animals, which has led to FDA approval of a centralized pregnancy risk management program for isoretinoin preparations. First trimester acute promyelocytic leukemia should be managed with a therapeutic abortion followed by chemotherapy that includes all-trans-retinoic acid. However, there are a number of reports of safe and effective use of all-trans-retinoic acid in the second trimester and beyond. [89] [90] Arsenic is another agent active in acute promyelocytic leukemia. There are no data on the effect of therapeutic doses of arsenic in pregnancy, but epidemiologic studies in women with chronic exposure to arsenic found in drinking water reported an increase in stillbirths and an increase in spontaneous abortions.[91] These observations would argue strongly against the use of arsenic in pregnancy at any stage.

Chronic Leukemias

Of the chronic leukemias, chronic myeloid leukemia (CML) is the condition that is most likely to require treatment in pregnancy. Imatinib is now the treatment of choice in newly diagnosed CML.[92]Imatinib is teratogenic in rats (but not rabbits) during organogenesis at ≥100 mg/kg, doses that are equivalent to >800 mg/day in adults based on body surface area.[93] Defects include exencephaly, encephalocele, and skull bone abnormalities with fetal loss in all animals. Postimplantation loss occurred at doses ≥45 mg/kg, approximately equivalent to 400 mg/day. The product information from Novartis recommends that imatinib not be used in pregnancy.

A recent publication reported on 180 cases of women who were exposed to imatinib during pregnancy.[17] Timing of exposure by trimester was known in 146 cases; of these, 71% involved exposure in the first trimester. Outcome data were known for 125 cases (63%): normal live infant (n = 63; 50%), elective termination (n = 35; 28%, including three following identification of fetal abnormalities), fetal abnormality (n = 12; 10%), and spontaneous abortion (n = 18; 14%). The fetal abnormalities included bony defects similar to those seen in animal models as well as an excess incidence of exomphalos. No data was presented on crucial issues such as the relationship of dose to the incidence and nature of fetal abnormalities or whether abnormalities were confined to first trimester exposure.

The MD Anderson group reported the outcome of CML in 10 women in whom imatinib was discontinued immediately after pregnancy was identified.[94] Six patients had an increase in Philadelphia-positive metaphases during pregnancy. All resumed imatinib after the abortion or birth, and nine achieved complete hematologic remission with varying levels of cytogenetic response with a median follow-up of 18 months (5 to 40 months).

Within the caveats of this limited experience, the following guidelines are suggested:

  

   

In the first trimester, cease imatinib immediately. Counsel that there might be an increased risk of spontaneous abortion and fetal abnormalities, although the risk is probably not high enough at 400 mg/day to recommend termination of the pregnancy. There is no meaningful experience at doses in excess of 400 mg/day. Monitor CML, and institute treatment with leukapheresis or interferon if therapy is required. Interferon is thought to be safe in all trimesters.[95] Hydroxyurea is teratogenic at high doses in animals but has not been associated with major malformations in human pregnancies, even with first trimester exposure.[96] Consider reintroduction of imatinib at 400 mg/day in the second and third trimesters if CML is poorly controlled with these other measures and the mother's health is compromised.

  

   

In the second and third trimesters, cease imatinib and commence interferon if therapy is required, but consider resumption as described previously.

  

   

Postpartum, resume imatinib as quickly as practical. It should not be administered to women who are breast-feeding.

OTHER CONSIDERATIONS

Therapeutic Abortion

The decision by the mother or parents whether to continue with the pregnancy or to have a therapeutic abortion will depend on ethical, moral, and religious issues as well as the medical situation. Some of the parental considerations include willingness to assume a possible risk of fetal toxicity either directly from chemotherapy or radiation or indirectly from maternal complications of therapy, the impact on prognosis of delaying effective chemotherapy until the second trimester if a termination is not performed and there is unwillingness to accept risks to the fetus of chemotherapy in the first trimester, overall maternal prognosis and the ability to care for the child, and the effect of treatments on future fertility.

Therapeutic Radiation

Radiation therapy is commonly used in the treatment of patients with breast cancer, cervical cancer, and lymphoma, and systemic iodine 131 is often used for treatment of thyroid cancer. The use of radiation therapy is addressed in the sections devoted to these cancers. Radiation is extremely important for palliation of cancer-related symptoms and has been carefully used during pregnancy without fetal harm.

Subsequent Pregnancy

There is no evidence that a subsequent pregnancy increases the risk of recurrence of any malignancy in the mother, including hormone-responsive breast cancer, or the risk of fetal anomalies. Standard practice has been to defer pregnancy for 2 to 3 years, as the relapse risk is highest during this period, but recommendations need to be individualized on the basis of each patient's circumstances.

Transfer of Maternal Disease to the Fetus

Placental involvement has been documented, albeit rarely, in a variety of malignancies, but only a handful of cases of active transfer of malignancy to the fetus have been described; most have been melanoma. It is reasonable to counsel the mother that, apart perhaps from melanoma, the risk is minimal.

CONCLUSION

The care of the pregnant woman with cancer is complicated by unique issues such as the teratogenicity of staging procedures as well as chemotherapy and radiotherapy, the altered maternal physiology affecting drug metabolism, the impact of treatment on subsequent fertility, and the emotional trauma experienced by the mother (and her partner) in making decisions about the well-being of herself and the unborn child. Appropriate management of these issues necessitates the coordinated effort of a multidisciplinary team including hemato-oncologists, surgeons, nurses, psychologists, obstetricians, and pediatricians.

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