Version May 2024
INTRODUCTION — A gynecologic malignancy is estimated to complicate four to eight of every 100,000 pregnancies [1-4]. Unfortunately, the data on the effects of antineoplastic drugs administered during pregnancy have largely been derived from case reports, small case series, and collected reviews of pregnant women treated for a variety of cancers. There are even less data on long-term outcomes in offspring.
This topic will address the administration of chemotherapy for women diagnosed with ovarian cancer in pregnancy. In order to optimize treatment outcomes, a pregnant woman with a diagnosis of ovarian cancer should be managed by a multidisciplinary team that includes experts in the fields of maternal-fetal medicine, gynecologic oncology, pediatrics, and pathology.
The clinical manifestations and diagnosis of ovarian cancer in pregnancy and surgical management of this disease are reviewed separately. (See "Adnexal mass: Evaluation and management in pregnancy".)
GENERAL PRINCIPLES — Concerns about the administration of cytotoxic chemotherapy during pregnancy arise because chemotherapy preferentially kills rapidly proliferating cells, and the fetus represents a rapidly proliferating cell mass. Individual chemotherapeutic agents have resulted in adverse effects including intrauterine growth restriction, prematurity, and low birth weight in the infants [5]. Chemotherapy may also cause fetal toxicities similar to those observed in the mother (eg, bone marrow suppression).
The risks of spontaneous abortion, fetal death, and major malformations vary depending on the agent used and the trimester of pregnancy. These risks must be weighed against the benefits of immediate versus delayed (ie, postdelivery) chemotherapy for the mother. Ethical considerations of treatment during pregnancy have emphasized the role of patient autonomy and the concept of beneficence and nonmaleficence for both the mother and fetus [6].
Although previous data suggested that the administration of chemotherapy increased the risk of fetal malformations, most data suggest this is not the case. It is now believed that the impact of chemotherapy during pregnancy is predominantly dependent on when treatment is administered:
●During the first four weeks of gestation (first two weeks post conception) the embryo is undifferentiated. Fetal exposure to cytotoxic agents at this point results in "all or none" phenomena: either the pregnancy is lost or it continues with no apparent adverse effect [5,7].
●Organogenesis occurs during weeks 5 to 10 weeks of gestation. The administration of cytotoxic drugs, particularly antimetabolites (eg, fluorouracil and methotrexate) and alkylating agents (eg, busulfan, chlorambucil, cyclophosphamide), during this period carries an increased risk of fetal malformations. In a review of the literature, rates of adverse pregnancy outcomes (APOs) for anti-neoplastic agents in single and combination therapy were 33, 27, and 25 percent for the first, second, and third trimesters. Rates of congenital malformations (included in the APOs) were 16, 8, and 6 percent for the first, second, and third trimesters [8]. The majority of stillborn infants and infants with chromosomal or congenital abnormalities occur when chemotherapy is administered in the first trimester.
●When chemotherapy is delivered to the mother during the second and third trimesters of pregnancy, the risk of fetal malformation is lower. First trimester exposure poses a larger and more permanent risk to the fetus. Administration of chemotherapy within three weeks of anticipated delivery or beyond 35 weeks of gestation may induce neonatal myelosuppression and complicate delivery due to adverse effects of treatment on bone marrow reserves. This includes potential complications such as bleeding, sepsis, and death. Additionally, neonatal toxicity may be higher if chemotherapy is administered peripartum because placental drug clearance is generally more effective than either hepatic and/or renal drug clearance in the neonate [9].
OVARIAN CANCER DURING PREGNANCY — There are several different histologic types of malignancy that can arise within the ovary including epithelial ovarian cancer (EOC), ovarian germ cell tumors, and sex-cord stromal tumors. In some series of women presenting with an ovarian malignancy while pregnant, germ cell tumors predominate, while others report a higher frequency of EOC. The indications and medical treatment of ovarian cancer during pregnancy by histologic type is discussed below. (See "Adnexal mass: Evaluation and management in pregnancy", section on 'Malignant neoplasms'.)
EPITHELIAL OVARIAN CANCER
Indications — Following surgery, the indications for adjuvant treatment of epithelial ovarian cancer (EOC) are similar for pregnant and nonpregnant women. However, administration of chemotherapy during the first trimester should be avoided. We recommend chemotherapy for:
●Women with early-stage EOC (table 1) if any of the following high-risk features is present: stage IA/IB, grade 2/3; stage IC or II (any histology); serous or clear cell carcinoma (stage IA, IB, IC, or II)
●Women with stage III or IV EOC
Regimen — As with nonpregnant women, we recommend the use of a platinum drug plus taxane for women with EOC in pregnancy because, in general, this combination results in the best survival outcomes. For women diagnosed during pregnancy, we prefer carboplatin to cisplatin because it is a better tolerated agent and reduces the risk of long-term side effects (eg, renal and neurotoxicity). Although there are few data to guide the use of taxanes in pregnancy, it has been used to treat breast cancer in pregnancy without apparent adverse events [10-12]. We prefer paclitaxel rather than docetaxel because it is generally less myelotoxic.
Targeted therapy has been incorporated into treatment regimens for nonpregnant women, eg, poly(ADP-ribose) polymerase inhibitors, which have the capacity to cross the placenta. Large molecules (for example, monoclonal antibodies) can cross the placenta and reach the fetus after 14 weeks. Animal data has demonstrated potential embryotoxicity and risk of adverse fetal outcomes with these agents (table 2) [13]. Angiogenesis inhibitors, eg, bevacizumab, a humanized anti-vascular endothelial growth factor antibody, are teratogenic and induce intrauterine growth restriction, pregnancy loss, and skeletal malformation in animal models [14]. Therefore, these agents should not be used until after delivery.
All women with EOC in pregnancy should be informed of the limited data on maternal and fetal outcomes associated with treatment. In one of the largest cohort studies of pregnant women with all types of cancer treated at multiple institutions, 84 were exposed to taxanes and 74 were exposed to platinum-based chemotherapy [15]. Both drugs were associated with an increased risk of delivery of a small for gestational age infant: platinum odds ratio (OR) 3.12, 95% CI 1.45-6.70 and taxanes OR 2.07, 95% CI 1.11-3.86. However, it was not possible to determine whether these findings were related to in-utero drug exposure or to other factors, such as effects of other medications, maternal stress, lack of adequate gestational weight gain, and other prenatal factors.
Administration — Patients can be treated with single agent carboplatin or a combination of carboplatin and a taxane. A decision should be made on an individual basis taking into account potential risks and benefits of treatment.
Intraperitoneal therapy — In the absence of a larger experience, we do not administer intraperitoneal (IP) chemotherapy in these patients. There is only one case report of a woman with ovarian cancer treated with IP therapy for four cycles during pregnancy. She underwent a cesarean section at 37 weeks; the baby was male and had bilateral congenital talipes equinovarus [16]. The role of IP therapy for advanced ovarian cancer is discussed separately. (See "First-line chemotherapy for advanced (stage III or IV) epithelial ovarian, fallopian tube, and peritoneal cancer", section on 'Women with optimally cytoreduced disease'.)
Timing of chemotherapy
Early-stage disease — For pregnant women with high-risk, early-stage EOC, we suggest initiation of chemotherapy following completion of the first trimester. The approach is similar to the treatment of nonpregnant women with early-stage EOC. (See 'Indications' above and "Adjuvant therapy of early-stage (stage I and II) epithelial ovarian, fallopian tube, or peritoneal cancer", section on 'Choice of adjuvant treatment'.)
For women who prefer not to receive treatment during pregnancy due to concerns for fetal safety, it may be reasonable to delay adjuvant chemotherapy until after delivery. The evidence to support this comes from two studies that evaluated the impact of a treatment start delay [17]. In these trials, 271 nonpregnant women with high-risk stage I EOC were randomly assigned treatment with adjuvant cisplatin versus observation (trial 1) or P-32 (trial 2). In both trials, women who were not treated with cisplatin received cisplatin at the time of relapse. The main results were:
●Administration of cisplatin reduced the risk of relapse in both trials (compared with observation, hazard ratio [HR] 0.35, 95% CI 0.14-0.89; compared with P-32, HR 0.39, 95% CI 0.19-0.77).
●There was no difference in five year overall survival (88 and 82 percent with cisplatin or observation; HR 1.15, 95% CI 0.44-2.98; 81 and 79 percent with cisplatin or P-32; HR 0.72, 95% CI 0.72, 95% CI 0.37-1.43).
Advanced-stage disease — Women with advanced disease should begin chemotherapy as soon as they are out of the first trimester and have recovered from surgery. We generally prefer to initiate treatment in two to four weeks after surgery for ovarian cancer. The approach to treatment is similar to that for nonpregnant women with advanced EOC. Although dose-dense (weekly) paclitaxel has been reported to improve progression-free survival, other groups have been unable to duplicate these data [18,19]. (See "First-line chemotherapy for advanced (stage III or IV) epithelial ovarian, fallopian tube, and peritoneal cancer", section on 'Women with suboptimally cytoreduced disease' and "First-line chemotherapy for advanced (stage III or IV) epithelial ovarian, fallopian tube, and peritoneal cancer", section on 'Women with optimally cytoreduced disease'.)
GERM CELL TUMORS — Most germ cell ovarian malignancies occur in young women and are limited to one ovary [3]. Maximal surgical cytoreduction is usually undertaken initially. (See "Treatment of malignant germ cell tumors of the ovary" and "Approach to surgery following chemotherapy for advanced testicular germ cell tumors".)
Despite being diagnosed at a relatively early stage, we recommend adjuvant chemotherapy for most women with completely resected malignant ovarian germ cell tumors except those with stage IA dysgerminoma (table 1) or stage I grade one immature teratoma. When indicated, chemotherapy should be delayed at least until completion of the first trimester of pregnancy [20-22]. The most commonly used regimen is bleomycin, etoposide, and cisplatin (BEP (table 3)). (See "Ovarian germ cell tumors: Pathology, epidemiology, clinical manifestations, and diagnosis" and "Treatment of malignant germ cell tumors of the ovary".)
In other series, use of etoposide during pregnancy has been associated with growth restriction and neonatal bone marrow suppression [5,7]. Etoposide is teratogenic in mice and rats at doses much lower than the human dose and should not be used in the first trimester. A consensus report suggested paclitaxel-carboplatin or cisplatin-vinblastine-bleomycin as alternatives to BEP in pregnancy [23].
Timing of chemotherapy — Given that germ cell neoplasms are exquisitely sensitive to platinum-based chemotherapy, several investigators have published case reports addressing a treatment delay until after the completion of the pregnancy [24-26]. A summary of findings is presented below:
●One case report documents a woman with a yolk sac (endodermal sinus) tumor that was surgically resected at 19 weeks of gestation [24]. The pregnancy was allowed to continue and BEP was not initiated until after the baby was delivered at 36 weeks. At a follow-up of 27 months, there was no evidence of recurrence disease.
●Another report described a patient with a yolk sac tumor resected at 22 weeks of gestation, after which the pregnancy was allowed to continue [25]. Unfortunately, at 34 weeks she was found to have tumor regrowth. After secondary debulking and delivery of the infant, the mother was successfully treated with BEP and was without evidence of disease 39 months after her last treatment with chemotherapy.
These reports suggest that delaying adjuvant chemotherapy may increase the risk of recurrence, although without an apparent risk to long-term recurrence free survival. Given the low quality of the data, however, a decision on the timing of adjuvant chemotherapy for women with a germ cell tumor should take into account the individual circumstances and preferences of the mother.
TUMORS OF LOW MALIGNANT POTENTIAL — Tumors of low malignant potential have an excellent prognosis and management is the same as that for nonpregnant patients [27]. In general, treatment is surgical and most patients do not require adjuvant chemotherapy. (See "Borderline ovarian tumors".)
SEX CORD-STROMAL TUMORS — Most of these tumors are limited to one ovary, of low malignant potential and/or slowly progressive. The benefit of postoperative treatment for women with stage 1B to IV disease (table 1) is unclear and practice is variable. Therefore, we suggest oophorectomy alone for disease diagnosed during pregnancy. The decision for chemotherapy, if any, can be deferred to the postpartum period. (See "Sex cord-stromal tumors of the ovary: Epidemiology, clinical features, and diagnosis in adults".)
BREASTFEEDING — Cytotoxic agents may reach significant levels in breast milk and thus breastfeeding while on chemotherapy is generally contraindicated [28]. The United States National Library of Medicine Drugs and Lactation Database (LactMed) is an excellent resource for information on transfer of specific drugs into human milk and possible effects on the infant or on lactation, if known. Possible adverse effects include immune suppression, impaired growth, or association with carcinogenesis [29]. We agree with the World Health Organization’s recommendation against nursing while receiving chemotherapy [30].
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Ovarian, fallopian tube, and peritoneal cancer".)
SUMMARY AND RECOMMENDATIONS
●The development of a gynecologic cancer during pregnancy is a rare event, affecting 4 to 8 pregnancies in 100,000. (See 'Introduction' above.)
●The risks of chemotherapy administration during pregnancy depend on the specific drugs used and the gestational age of the fetus (table 2). (See 'General principles' above.)
●Early delivery to avoid fetal exposure to chemotherapy is reasonable provided the fetus is ≥34 weeks of gestation and/or fetal lung maturity can be documented. In this setting, the risks of prematurity are relatively low. (See "Adnexal mass: Evaluation and management in pregnancy".) Prematurity can be associated with impaired cognitive development, and therefore iatrogenic prematurity should be avoided when possible.
●If chemotherapy is indicated, we recommend instituting platinum-based chemotherapy during pregnancy rather than waiting until after delivery (Grade 1B). We recommend delaying administration until at least the second trimester in order to minimize the potential for fetal injury (Grade 1B). (See 'General principles' above.)
●For women with epithelial ovarian cancer in pregnancy, we recommend platinum-based therapy (Grade 1B). Patients should be informed of the limited data on maternal and fetal outcomes associated with platinum and/or taxane therapy.
●For most women with germ cell tumors, we recommend adjuvant platinum-based combination chemotherapy (Grade 1B). However, women with stage IA dysgerminomas or stage I grade 1 immature teratomas have a good prognosis. We recommend not treating these patients with chemotherapy (Grade 1A). (See "Treatment of malignant germ cell tumors of the ovary".)
●Oophorectomy is the standard treatment for tumors of low malignant potential and sex cord stromal tumors diagnosed during pregnancy. These patients should not receive chemotherapy in pregnancy. (See 'Sex cord-stromal tumors' above.)
آیا می خواهید مدیلیب را به صفحه اصلی خود اضافه کنید؟
