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Practice Guidelines Chemotherapy during pregnancy L. Heyns, K. Van Calsteren, S.N. Han, M. Mhallem Gziri, P. Augustijns, F. Amant When a pregnant woman is diagnosed with cancer, treatment with chemotherapy can be life-saving for the mother but might put the foetal development at risk. Haematologic malignancies constitute approximately 20% of all cancers during pregnancy. Depending on the type of cancer and the stage of disease at diagnosis, chemotherapy cannot always be delayed until postpartum. Uncomplicated use of chemotherapy during pregnancy has been reported, especially during the second and third trimester, however firm data on long term maternal and foetal outcome are lacking. It appears from preclinical studies that the placenta functions as a barrier and protects the foetus from cytotoxic effects. In clinical practice, ABVD, R-CHOP and IFN-α are used for treatment of haematologic cancer during pregnancy. Imatinib-mesylate is not recommended during pregnancy. Currently the same dosages of chemotherapeutic agents are administered to pregnant and non-pregnant patients. Albeit, gestational changes in haemodynamics and drug pharmacokinetics render optimal chemotherapeutic dosage during pregnancy uncertain. In this review, we discuss transplacental passage of chemotherapeutical agents, the toxicity in the three trimesters of pregnancy, pharmacokinetics of chemotherapy during pregnancy and the use of chemotherapeutical agents for haematologic malignancies. (Belg J Hematol 2011;2:101-6) Introduction The diagnosis of cancer during pregnancy is relatively uncommon and its incidence is estimated to be about 1 per 1,000 pregnant women.1 The majority of patients have a solid tumour, haematologic malignancies represent almost 18% of cancer during pregnancy.2 Hodgkin disease (HD) and high grade non-Hodgkin lymphomas (NHL) have a peak incidence in the second to fifth decade of life and can thus be diagnosed in pregnant women. HD is significantly more common than NHL, with an incidence of 10 to 50 per 100,000 pregnancies.2 NHL is rarely reported during pregnancy; however, the HIV epidemic which increases the risk of developing NHL 150-fold, along with the trend to delay childbearing, can make it more frequent in future.3 The occurrence of leukaemia during pregnancy is very rare with an estimated incidence of 1 per 100,000 pregnancies annually. The epidemiology of leukaemia in pregnant women reflects the relative frequency in the general population. Most leukaemias are acute, two thirds myeloid (AML) and one third lymphatic (ALL). Chronic myeloid leukaemia (CML) is found in less than 10% of leukaemias during pregnancy.4 The coincidence of pregnancy and cancer presents complex therapeutic problems requiring a multidisciplinary approach. Although the treatment options for the non-pregnant patient with cancer have Authors: L. Heyns MSc, K. Van Calsteren MD PhD, S.N. Han MD, M. Mhallem Gziri MD, P. Augustijns PhD, F. Amant MD PhD, Department of Gynecological Oncology Please send all correspondence to: F. Amant MD PhD, UZ Gasthuisberg Leuven, Department of Gynecological Oncology, UZ Leuven, Belgium. Herestraat 49, 3000 Leuven, Belgium, tel: 0032 16 344 252, email: [email protected] Conflict of interest: The authors have nothing to disclose and indicate no potential conflict of interest. F. Amant is Sr. Clinical Investigator for the Research Fund-Flanders. Key words: cancer, chemotherapy, haematology, pregnancy Belgian Journal of Hematology 101 Volume 2, Issue 3, September 2011 3 been extensively examined, the current knowledge and treatment of the pregnant patient with cancer is based on anecdotical cases, small series with relatively short follow up periods and mostly retrospective data. The care of a pregnant patient with a malignancy necessitates a difficult balance of trying to cure the mother while minimising the effects on the foetus. With the use of cytotoxic agents during pregnancy, concerns arise with regard to the teratogenicity and long term effects for the foetus. The purpose of this review is to evaluate the available data on the use of chemotherapy during pregnancy, including trimester of exposure, changes in drug metabolism during pregnancy and the placental properties to minimise the foetal exposure to chemotherapeutical agents. Transplacental passage The foetoplacental unit renders prenatal chemotherapy administration possible. The placenta provides a link between the circulations of two distinct individuals but also acts as a barrier to protect the foetus from xenobiotics in the maternal blood. Since placental transfer of drugs from the maternal to the foetal side primarily occurs by passive diffusion, the physicochemical properties of the drugs, such as lipid solubility, polarity and molecular weight, the concentration gradient over the placenta and the properties of the placenta determine the rate of transfer across the placenta.5 Low molecular weight, lipid soluble, non-ionised drugs can easily cross the placenta.6 Drug binding to plasma proteins will reduce placental transfer, due to the larger structure of the complex that has been formed. Only a few groups conducted transplacental studies (Table 1). Gaillard et al. and Grohard et al. examined transplacental transfer of epirubicin and doxorubicine respectively by in vitro placental perfusion of term human placenta’s. They found limited transfer to the foetus for both antracyclines.7,8 Van Calsteren et al. examined the transplacental materno-foetal transfer of different drugs in a mouse model and a baboon model. In the mouse model, important variations were found between different chemotherapeutical agents. High transfer was found for carboplatin, an intermediate transfer for cytarabine, a limited transfer for anthracyclines and vinblastin and undetectable levels of paclitaxel in the foetal plasma.9 In the baboon model, FEC, ABVD were administered to pregnant Belgian Journal of Hematology baboons and maternal and foetal bloodsamples were taken simultaneously. Low transfer was found for doxorubicin, epirubicin, vinblastin and (4-OH)CP, the active metabolite of cyclofosphamide.10 Remarkable was the fact that all P-glycoprotein substrates revealed a limited transfer stressing the importance of ATPbinding cassette proteins in the protection of the foetus from chemotherapeutics. Also supportive treatment can interact with these proteins and may possibly affect the transfer of chemotherapeutical agents to the foetal compartment. To date these interactions have not yet been examined and supportive treatment can be given according to general recommendations.11 Granulocyte colony stimulating factors and erythropoietin can also be used safely during pregnancy. Corticoids can be used after the first trimester of pregnancy, though prednisolone and hydrocortisone are preferred over beta- and dexamethasone.12 Chemotherapy exposure in utero Short term outcome Chemotherapeutical agents are toxic for cells since they cause chromosomal breaks, gene mutations, aneuploidy and cell cycle disruption. Therefore their administration during pregnancy generates important concerns regarding the effects on the developing foetus. The organogenesis, until the tenth week after conception, is the most vulnerable period of pregnancy. Since cytotoxic therapy may interfere with organogenesis, teratogenic effects will be maximal at this time of pregnancy and chemotherapy administration is contraindicated.1 Including a safety period, it is strongly recommended to wait until 14 weeks to initiate chemotherapy. The risk of congenital malformations when chemotherapy is administered after the first trimester is about 3%, which approaches the baseline population risk.13 During the second and third trimester, chemotherapy is considered relatively safe; however, cases of intrauterine growth restriction, in utero and neonatal death, haematopoietic suppression and preterm delivery have been reported. Chemotherapy exposure in the last 3-4 weeks before the delivery should be avoided, since haematological toxicity can put the mother as well as the foetus at risk for infections and bleeding complications during delivery.12 In order to evaluate the association of adverse events in the mother and Volume 2, Issue 3, September 2011 102 Practice Guidelines Table 1. Transplacental passage of chemotherapeutical agents. Drug MOUSE 9 BABOON 10, 33 PERFUSION MODEL 7,8 % transfer (mean + SD) % transfer (mean + SD) % transfer (mean + SD) daunorubicin 13.3 + 3.5 epirubicin 4.8 + 3.8 4.0 + 1.6 3.66 + 1.07 doxorubicin 5.1 + 0.6 7.5 + 3.2 2.96 + 0.75 ND 1.6 + 0.8 paclitaxel docetaxel vinblastine ND 13.8 + 5.8 18.5 + 15.5 carboplatinum 117.0 + 38.9 57.5 + 14.2 cytarabine 56.7 + 22.6 (4-OH)CP 25.1 + 6.3 SD=standard deviation, ND=not detectable, (4-OH)CP=(4-hydroxy-)cyclophosphamide. the foetus, Aviles et al. reviewed the literature and found 1,395 cases which documented the use of chemotherapy for haematological malignancies during pregnancy.14 Congenital malformations were reported in 5,8% of all newborns. Malformations in hands, toes, extremities and hypospadias were most frequently encountered. Based on these findings, they concluded that chemotherapy could be administered safely during second and third trimester of pregnancy. Van Calsteren et al. reported on 215 patients with cancer diagnosed during pregnancy.15 In the group of patients who were treated with chemotherapy during pregnancy, an increase in small for gestational age (SGA) children (birth weight below tenth percentile) was observed. Most of them are from mothers with haematological tumours, suggesting that the impact on foetal growth might be related to specific cancer types and treatments. In general, the incidence of congenital malformations was not increased and the malformations that were reported are also seen in the normal population. Long term outcome Long term follow up studies are scarce. Only 2 series have been described with a follow up till schoolage. Hahn et al. described 57 patients who were treated for breast cancer during pregnancy.16 The results were obtained by interviewing the parents and teachers by telephone or email. Respiratory problems were the most important neonatal complications (N=10). One child suffered from a subarachnoidal bleeding and three congenital anomalies were registered. Forty children were Belgian Journal of Hematology 103 followed until the age of 2 till 157 months, 43% of them had no medical problems. Medical problems that were reported included allergy, eczema (20%), asthma (10%) and upper respiratory interactions. Two of the 18 children who went to school needed special attention. One need to underline that many described problems on the short term are associated with prematurity. Aviles et al. described a series of 84 children from mothers with haematological malignancies who received chemotherapy during pregnancy.17 They reported that all children had a normal birth weight, a normal learning and educational performance, no congenital, neurological or psychological abnormalities and no malignancies. Pharmacokinetics during pregnancy Changes in maternal physiology and morphology associated with pregnancy alter the absorption, distribution, metabolism and excretion of drugs and make it very difficult to predict pharmacokinetics of chemotherapy during pregnancy. These changes include an increase in distribution volume due to increased blood volume, body fat and the development of an extra (amniotic) fluid compartment.18 The higher oestrogen and progesterone levels affect the activity and expression of metabolising enzymes. Depending on which metabolic enzymes are involved, a higher or lower rate of metabolism will be seen.19 Also, renal blood flow and glomerular filtration rate are increased during pregnancy, leading to enhanced elimination of drugs and lower steady state concentrations.20 These changes begin in early gestation but are most Volume 2, Issue 3, September 2011 3 pronounced in the third trimester of pregnancy. Most anticancer drugs have a wide inter-individual pharmacokinetic variability and a narrow therapeutic window, which may be increased in pregnancy. In the absence of pharmacokinetically based dosing guidelines for pregnancy, physicians use drug dosage recommendations derived from studies conducted in nonpregnant women. However, since the gestational changes are not taken into account, anticancer drugs levels might reach subtherapeutic or toxic levels.21 A recent study compared pharmacokinetics of doxorubicin, epirubicine, paclitaxel and docetaxel between the pregnant and the non-pregnant state.22 For all drugs tested, a decreased plasma drug exposure (area under the curve and maximal plasma concentration), an increased distribution volume and clearance were observed in pregnancy. These data underline the importance of further research to translate the differences in plasma levels into alterations in tumour concentration and treatment efficacy. Clinical importance for haematology Standard treatment as a combination scheme of doxorubicin-bleomycin-vinblastine-dacarbazine (ABVD) for HD; cyclophosphamide-vincristinedoxorubicin-prednisone with or without rituximab (R-CHOP) for NHL and high dose combination schemes including vincristine, methotrexate, an anthracycline, cyclophosphamide and cytarabine for leukaemia have been described during pregnancy.23 Based on different case reports, ABVD and (R)-CHOP regimens seems to be safe when given during second or third trimester. A recent review of the literature yielded no foetal adverse events when ABVD was given after the first trimester. One intra-uterine foetal death (3%) occurred during third trimester.24 In one patient who received CHOP during pregnancy, transitory lymphopaenia in the newborn has been reported, albeit without congenital malformations.25 Since rituximab is an antibody of the IgG isotype, it is likely to cross the placental barrier and interact with foetal B cells. One case report compared maternal and foetal rituximab concentrations and B cells. Although at birth rituximab concentrations were similar in mother and child and the foetal B cells were severely diminished (1% of normal) at birth, B cells recovered after 6 weeks, to reach a normal level at 12 weeks. No further adverse events or malformations were seen during 16 months follow up.26 For this reason, Belgian Journal of Hematology rituximab, seems to be safe and without significant consequences for the foetus.26 Administration of imatinib mesylate, a tyrosine kinase inhibitor, during the first trimester is associated with a considerable risk of congenital anomalies and spontaneous abortions, while late exposure does not have the same impact. It has been reported that the concentration of imatinib mesylate and its active metabolite were higher in the placenta than in the maternal blood, while they were low or undetectable in the umbilical cord.27 Although these findings suggest limited placental transfer of imatinib mesylate in late pregnancy it should not be the treatment of choice because of the high risk for malformations during first trimester.23 Interferon-alpha (IFN-α), an immune modulator, does not cross the placenta to a great extent due to its high molecular weight (19kDa) and does not inhibit DNA synthesis in the foetus. No foetal malformations were reported when interferon was administered as monotherapy. All reported cases of pregnant women with chronic myelogenous leukaemia (CML), treated with interferon, resulted in healthy babies and normal maternal outcomes. Given the available pre-clinical and clinical data, interferon can be safely administered throughout pregnancy and it is the treatment of choice for patients diagnosed with CML in pregnancy.28 Hydroxyurea is a cytotoxic drug, which inhibits DNA synthesis and is capable of crossing the placenta. Several cases of hydroxyurea administration during pregnancy have been reported. Hydroxyurea treatment should be avoid in first trimester and could be given to patients who cannot tolerate interferon therapy during second or third trimester.29 No data are available yet for administration of alemtuzumab during pregnancy. Given that alemtuzumab is a large molecule with a molecular weight of (150 kDa), it is unlikely to cross the placental and reach the foetus. Cytarabine, an antimetabolite that is used in combination with other chemotherapeutical agents for the treatment of acute leukaemia, carries a significant risk to the foetus. A review of 93 cases of pregnant women exposed to cytarabine alone or in combination with other chemotherapeutical agents reported 4 cases of limb malformations associated with first trimester exposure. Administration in second and third trimester was associated with transient neonatal cytopaenias in 5 cases, intrauterine Volume 2, Issue 3, September 2011 104 Practice Guidelines Key messages for clinical practice 1. Cancer complicates 1 in 1,000 pregnancies. 2. A multidisciplinary approach is mandatory. 3. Chemotherapy during the first trimester results in increased rates of congenital malformations but it can be administered safely from the second trimester onwards. 4. In absence of pharmacokinetic data, during pregnancy the same dosages of chemotherapy are administered as in non-pregnant women. 5. The placenta partially protects the foetus against most of the chemotherapeutic agents. foetal death in 6 cases, intrauterine growth retardation in 12 cases and 2 cases of neonatal deaths from severe infections.1 For these reasons, the use of cytarabine in the first trimester is not advised and termination of pregnancy is strongly preferred. Antracyclines are an integral part of regimens used for treatment of many malignancies besides leukaemias, including lymphomas, breast- and lungcancer and soft tissue sarcomas. Idarubicin is more lipophilic compared to other anthracylines and placental transfer is more likely to occur. Therefore, idarubicin may be associated with higher rates of adverse foetal outcomes and should be avoided during pregnancy. Doxorubicin has widely studied for breast cancer during pregnancy and its use is considered relatively safe throughout pregnancy.16 Since doxorubicin seems to be as effective as the other anthracyclines for the treatment of leukaemia, it is the preferred anthracycline during pregnancy.23 First trimester exposure to all trans retinoic acid (ATRA), a vitamin A derivative, carries an 85% risk of teratogenicity, including severe neurological and cardiovascular malformations. The administration of ATRA alone or in combination with an anthracycline during the second and third trimesters has been reported in several case-reports.23 These limited data suggest that ATRA seems to be safe and well tolerated when given after first trimester, however close foetal cardiac monitoring is mandatory throughout pregnancy.30 Methotrexate, a folate antagonist, is highly teratogenic. First trimester methotrexate exposure is associated with an increased risk of miscarriage. And Belgian Journal of Hematology 105 also exposure to high dose methotrexate after the first trimester is associated with cranial dysostosis, delayed ossification, hypertelorism, wide nasal bridge, micrognatia, anomalies of external ears and cleft palate.31 The risk for foetal malformations diminishes as pregnancy advances. However, termination of pregnancy is recommended for patients prior to the twentieth week of gestation. After the twentieth week, a modified anti-ALL treatment, without methotrexate, may be used.28 Conclusion Pregnant women diagnosed with cancer require an individualised treatment, established by a multidisciplinary team. Most chemotherapeutic agents are assigned to Food and Drug Administration pregnancy category D and carry a product label warning about the potential risk to the foetus. However, depending on the type of malignancy, clinical stage of disease and health status of the mother, it may not always be possible to delay chemotherapy until postpartum. Available research data demonstrate short term safety data for several chemotherapy regimens in the second and third trimester of pregnancy. However, in the absence of firm long term outcome data, a certain prudence should be taken into account. In absence of valid data, currently standard doses of drugs adjusted to continuing weight gain during pregnancy are used. Although pregnancy induces physiological changes, it is unknown if the pregnant patient is optimally treated compared to the nonpregnant patients. More extensive studies are required Volume 2, Issue 3, September 2011 3 for accurate prediction of pharmacokinetics of chemotherapeutical agents in pregnancy. Besides the changes in pharmacokinetics in pregnant women, the placental transfer of drugs leading to a potential toxicity to the foetus are a major concern in the treatment of a pregnant patient with chemotherapy. The placenta acts as a barrier between the mother and the foetus, mostly low molecular weight and lipophilic drugs pass through the barrier. Ongoing research is continued in order to collect more data on pharmacokinetics and the maternal and foetal outcome.32 Van Gemert W, et al. Cancer during pregnancy: an analysis of 215 patients emphasizing the obstetrical and the neonatal outcomes. J Clin Oncol 2010;28:683-9. 16. Hahn KM, Johnson PH, Gordon N, Kuerer H, Middleton L, Ramirez M, et al. Treatment of pregnant breast cancer patients and outcomes of children exposed to chemotherapy in utero. Cancer 2006;107:1219-26. 17. Aviles A, Neri N. Hematological malignancies and pregnancy: a final report of 84 children who received chemotherapy in utero. Clin Lymphoma 2001;2:173-7. 18. Krauer B, Krauer F, Hytten FE. Drug disposition and pharmacokinetics in the maternal-placental-fetal unit. Pharmacol Ther 1980;10:301-28. 19. Anderson GD. Pregnancy-induced changes in pharmacokinetics: a mechanistic-based approach. Clin Pharmacokinet 2005;44:989-1008. 20. Dawes M, Chowienczyk PJ. Drugs in pregnancy. Pharmacokinetics in References pregnancy. Best Pract Res Clin Obstet Gynaecol 2001;15:819-26. 1. Cardonick E, Iacobucci A. Use of chemotherapy during human pregnancy. 21. Frederiksen MC. Physiologic changes in pregnancy and their effect on Lancet Oncol 2004;5:283-91. drug disposition. Semin Perinatol 2001;25:120-3. 2. Ward FT, Weiss RB. Lymphoma and pregnancy. Semin Oncol 1989;16:397-409. 22. Van Calsteren K, Verbesselt R, Ottevanger N, Halaska M, Heyns L, 3. Pentheroudakis G, Pavlidis N. Cancer and pregnancy: poena magna, not Van Bree R, et al. Pharmacokinetics of chemotherapeutic agents in anymo re. Eur J Cancer 2006;42:126-40. pregnancy: a preclinical and clinical study. Acta Obstet Gynecol Scand 4. Caligiuri MA, Mayer RJ. Pregnancy and leukemia. Semin Oncol 2010;89:1338-45. 1989;16:388-96. 23. Shapira T, Pereg D, Lishner M. How I treat acute and chronic leukemia in 5. Gedeon C, Koren G. Designing pregnancy centered medications: drugs pregnancy. Blood Rev 2008;22:247-59. which do not cross the human placenta. Placenta 2006;27:861-8. 24. Azim HA Jr, Pavlidis N, Peccatori FA. Treatment of the pregnant mother 6. Garland M. Pharmacology of drug transfer across the placenta. Obstet with cancer: a systematic review on the use of cytotoxic, endocrine, targeted Gynecol Clin North Am 1998;25:21-2. agents and immunotherapy during pregnancy. Part II: Hematological tumors. 7. Gaillard B, Leng JJ, Grellet J, Ducint D, Saux MC. [Transplacental passage Cancer Treat Rev 2010;36:110-21. of epirubicin]. J Gynecol Obstet Biol Reprod (Paris) 1995;24:63-8. 25. Friedrichs B, Tiemann M, Salwender H, Verpoort K, Wenger MK, 8. Grohard P, Akbaraly JP, Saux MC, Gimenez S, Robert J, Brachet-Liermain Schmitz N. The effects of rituximab treatment during pregnancy on a neonate. A, et al. [Transplacental passage of doxorubicin]. J Gynecol Obstet Biol Haematologica 2006;91:1426-7. Reprod (Paris) 1989;18:595-600. 26. Decker M, Rothermundt C, Hollander G, Tichelli A, Rochlitz C. Rituximab 9. Van Calsteren K, Verbesselt R, Van Bree R, Heyns L, De Bruijn E, De Hoon plus CHOP for treatment of diffuse large B-cell lymphoma during second J, et al. Substantial variation in transplacental transfer of chemotherapeutic trimester of pregnancy. Lancet Oncol 2006;7:693-4. agents in a mouse model. Reprod Sci 2011;18:57-63. 27. Russell MA, Carpenter MW, Akhtar MS, Lagattuta TF, Egorin MJ. Imatinib 10. Van Calsteren K, Verbesselt R, Beijnen J, Devlieger R, De Catte L, mesylate and metabolite concentrations in maternal blood, umbilical cord Chai DC, et al. Transplacental transfer of anthracyclines, vinblastine, blood, placenta and breast milk. J Perinatol 2007;27:241-3. and 4-hydroxy-cyclophosphamide in a baboon model. Gynecol Oncol 28. Rizack T, Mega A, Legare R, Castillo J. Management of hematological 2010;119:594-600. malignancies during pregnancy. Am J Hematol 2009;84:830-41. 11. Gralla RJ, Osoba D, Kris MG, Kirkbride P, Hesketh P J, Chinnery LW, 29. Thauvin-Robinet C, Maingueneau C, Robert E, Elefant E, Guy H, Caillot et al. Recommendations for the use of antiemetics: evidence-based, clinical D, et al. Exposure to hydroxyurea during pregnancy: a case series. Leukemia practice guidelines. American Society of Clinical Oncology. J Clin Oncol 2001;15:1309-11. 1999;17:2971-94. 30. Fadilah SA, Hatta AZ, Keng CS, Jamil MA, SinghS. Successful treatment 12. Amant F, Van Calsteren K, Halaska MJ, Beijnen J, Lagae L, Hanssens M, of acute promyelocytic leukemia in pregnancy with all-trans retinoic acid. et al. Gynecologic cancers in pregnancy: guidelines of an international Leukemia 2001;15:1665-6. consensus meeting. Int J Gynecol Cancer 2009;19 Suppl 1:S1-12. 31. Ebert U, Loffler H, Kirch W. Cytotoxic therapy and pregnancy. Pharmacol 13. Dolk H, Loane M, Garne E. The prevalence of congenital anomalies in Ther 1997;74:207-20. Europe. Adv Exp Med Biol 2010;686:349-64. 32. Kanker en zwangerschap. Available at www.cancerinpregnancy.org 14. Aviles A. Hematological malignancies and pregnancy. A brief review. 33. Van Calsteren K, Verbesselt R, Devlieger R, De Catte L, Chai DC, Van Rev Recent Clin Trials 2009;4:131-9. Bree R, et al. Transplacental Transfer of Paclitaxel, Docetaxel, Carboplatin, and 15. Van Calsteren K, Heyns L, De Smet F, Van Eycken L, Gziri MM, Trastuzumab in a Baboon Model. Int J Gynecol Cancer 2010;20:1456-64. Belgian Journal of Hematology Volume 2, Issue 3, September 2011 106