Chemotherapy in pregnancy

1. Cancer in Pregnancy
Noha El-Baghdady
Clinical Pharmacy Assistant Lecturer
MTI University

2. Cancer in pregnancy
• Introduction
• Epidemiology
• Pharmacokinetic changes
• Chemotherapy in the different trimesters
• Breast cancer management in pregnancy
• Lymphoma management in pregnancy

3. Epidemiology
• Cancer is the 2nd most common cause of death during the
reproductive years.
• The incidence of cancer in pregnancy is a rare event (1 to 2 cases per
1000 pregnancies)
• The numbers have increased in recent years because of the increase
in maternal age at the time of the 1st pregnancy.
Esposito S, Tenconi R, Preti V, Groppali E, Principi N. Chemotherapy against cancer during pregnancy.
Medicine (Baltimore). 2016;95(38):e4899.

4. Incidence of most common malignancies diagnosed in
pregnant women
Type of cancer Incidence *
Breast Cancer 10-30 : 100,000
Lymphoma 10-60: 100,000
Leukemia 1:100,000
Cervical Cancer 10:100,000
Ovarian cancer 10:100,000
Thyroid cancer 3.6-14:100,000
*Malignant tumors per pregnancies
Esposito et al. Medicine (2016)

5. Pharmacokinetic changes in pregnancy
Normal physiological changes in pregnancy
Increased
plasma volume
Enhanced renal
clearance
Faster hepatic
metabolism
Decreased
albumin
concentration
Third space
formed by the
amniotic fluid.

6. Pharmacokinetic changes during pregnancy
The teratogenicity of any drug depends on
• The timing of exposure
• The dose
• The characteristics affecting placental transfer “High lipid solubility,
low molecular weight, and loose binding to plasma proteins favor
transfer of drugs from mother to fetus.”
E.x: Most drugs with MW< 600 KDa are capable of crossing the
placenta “Chemotherapy agents have a MW of 250-400 Kda”
• Genetic predispositions

7. Transplacental passage of chemotherapeutical
agents
Drug
% transfer (mean + SD)
mouse
% transfer (mean + SD)
BABOON
% transfer (mean + SD)
PERFUSION MODEL
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
paclitaxel ND 1.6 + 0.8
docetaxel ND
vinblastine 13.8 + 5.8 18.5 + 15.5
cytarabine 56.7 + 22.6
SD=standard deviation, ND=not detectable
Mazin et.al. Belg J Hematol 2011

8. Pharmacokinetic changes in pregnancy
• Most of the available data on the teratogenic risks of chemotherapy
are based on case reports and retrospective series.
• No pharmacokinetic studies have been performed to examine the
treatment regimens outcome in pregnancy.

9. Chemotherapy in pregnancy
The administration of chemotherapy cannot be delayed until the end of
pregnancy due to potential impact on maternal survival.

10. Chemotherapy in pregnancy
Dose and Regimen
• Despite the fact that pregnancy may alter the pharmacokinetics of these
agents, doses should not vary from those used outside pregnancy.
• To date, chemotherapy should generally be dosed according to actual body
weight of the pregnant women and dose adjustments will be according
weight changes during treatment.
• Weekly chemotherapeutic schedules are generally preferred, as close
monitoring of adverse events is more feasible.
Ngu, Siew Fei, and Hextan Y.S. Ngan. 2016. “Chemotherapy in Pregnancy.” Best Practice and Research: Clinical Obstetrics and Gynaecology 33: 86–101.
Zagouri, Flora et al. 2016. “Cancer in Pregnancy: Disentangling Treatment Modalities: Table 1.” ESMO Open 1(3): e000016.

11. Cardonick E et al. Lancet Oncol 2004;5(5):283-291

12. The all-or-non period
• (8 to 14 days) from conception.
• Teratogenic insult during this phase may disrupt the processes of
implantation, causing miscarriages.
• If implantation is successful, the fetus will usually survive intact.
“This is because the undifferentiated embryo contains totipotent cells
during this period, which can repair and recover damaged tissue.”
• No congenital defects unless the exposure continues after this phase.

13. First trimester
• The period about 2 to 8 weeks post-conception.
• The first trimester is the period of organogenesis of the fetus
and the most sensitive period of drug exposure “Due to rapidly
dividing and differentiating tissues, which are prone to
irreversible damage.
• High risk of miscarriage and congenital malformations.
• Malformations risk (10% to 20%) VS 1.3% in the third trimester.
• When folate antagonists excluded, the risk of fetal
malformations may decline to about 6% .
Pregnancy termination!!

14. Fetal phase
• From the end of embryonic period until term.
• It involves the growth and functional maturation of formed organs
and systems.
• Teratogens exposure during this later part of pregnancy increases the
risks of perinatal complications such as intrauterine growth restriction
(IUGR), low birth weight, and functional defects of several organs.
“Generally, the risk of teratogenesis with cancer treatment is estimated
to be lower than in animal studies”

15. Second and third trimester
A review of 376 fetuses exposed to chemotherapy in utero, most after
organogenesis, reported complications of:
• Fetal death (5%)
• Neonatal death (1%)
• IUGR (7%)
• preterm birth (5%)
• transient myelosuppression (4%)
Cardonick, Elyce, and Audrey Iacobucci. 2004. “Use of Chemotherapy during Human Pregnancy.” Lancet
Oncology 5(5): 283–91.

16. Second and third trimester
• 66 patients exposed to cytotoxic
treatment (chemotherapy and/or
radiotherapy) during the second and
third trimesters
• 109 Pregnant patients without
cytotoxic treatment in the second and
third.
• The incidence of major and minor malformations was not increased compared with the background risk.
• The rate of low birth weight was higher in the treatment group (24.2%) compared to the group without
cytotoxic treatment (9.2%).
Cardonick, Elyce, Aniqa Usmani, and Sadia Ghaffar. 2010. “Perinatal Outcomes of a Pregnancy Complicated by Cancer, Including Neonatal
Follow-up after in Utero Exposure to Chemotherapy: Results of an International Registry.” American Journal of Clinical Oncology: Cancer
Clinical Trials 33(3): 221–28.

17. Second and third trimester
An analysis of 157 neonates exposed to chemotherapy during
pregnancy after the first trimester.
• One case of intrauterine fetal death and one case of neonatal death.
• Congenital anomaly (3.8%)
• IUGR (7.6%)
• Spontaneous premature birth (5.8%)
• Two infants suffered from transient myelosuppression.
Cardonick, Elyce, Aniqa Usmani, and Sadia Ghaffar. 2010. “Perinatal Outcomes of a Pregnancy Complicated by Cancer, Including Neonatal
Follow-up after in Utero Exposure to Chemotherapy: Results of an International Registry.” American Journal of Clinical Oncology: Cancer
Clinical Trials 33(3): 221–28.

18. The second and third trimesters
• Generally, patients could be advised to continue with the pregnancy
and start chemotherapy.
• In late third trimester, the risks should be weighed against the risks of
prematurity.
• It is a standard practice to establish fontal well-being using ultrasound
monitoring when chemotherapy is given.

19. Delivery
• Diagnosis after 32-35 weeks gestation, it may be reasonable to deliver the
baby before initiating chemotherapy due to risk of spontaneous delivery
before recovery of bone marrow.
• Delay delivery for 2 to 3 weeks following administration of chemotherapy
to minimize the risk of maternal and neonatal myelosuppression and will
facilitate fetal drug clearance via the placenta.
Koren G, Carey N, Gagnon R, Maxwell C et al. Cancer chemotherapy and pregnancy. J Obstet Gynaecol Can 2013; 35: 263-80.
Buekers TE, Lallas TA. Chemotherapy in pregnancy. Obstet Gynecol Clin North Am 1998; 25: 323-9.

20. Main effects of chemotherapy during pregnancy on embryo and
fetus development
Period of pregnancy Impact on embryo or fetus
Impact on the perinatal
period
Long term effect
First 4 weeks
Either pregnancy loss or no
adverse effect
Not known Not known
From 4 weeks to the
end of 1st trimester
Malformations in 7%–17% of
children born to mothers
receiving a single drug and 25%
in case of combination therapy
Not known Not known
Second or third
trimester
Case reports of reversible fetal
heart toxicity for treatment
with anthracyclines, particularly
when trastuzumab is associated
in the regimen
Malformations are as frequent
as in children born to healthy
mothers
Preterm delivery and low
birth weight (11%)
Myelosuppression (1%–
43%, according to time of
therapy suspension)
In general, neuropsychological
development is not affected. When
retard is demonstrated, it is ascribed to
prematurity
Older children frequently have
internalizing behavioral problems
Progressive left ventricular dysfunction
several years after anthracycline
exposure
Esposito et al. Medicine (2016) 95:38

21. Breast feeding
• Limited short-term and long-term safety data regarding chemotherapy
administration during the postpartum period.
• Neonatal neutropenia and thrombocytopenia have been reported in
infants breastfed during maternal chemotherapy with cyclophosphamide.
“Patients advised not to breast feed concomitantly with chemotherapy
administration.”
Azim HA, Jr., Peccatori FA, Pavlidis N. Treatment of the pregnant mother with cancer: a systematic review on the use of cytotoxic, endocrine, targeted
agents and immunotherapy during pregnancy. Part I: Solid tumors. Cancer Treat Rev 2010; 36: 101-9.
Amato D, Niblett JS. Neutropenia from cyclophosphamide in breast milk. Med J Aust 1977; 1: 383-4
Ito S. Drug therapy for breast-feeding women. N Engl J Med 2000; 343: 118-26.

22. Targeted anticancer therapies
• Most of the literature available regarding exposure during pregnancy
is on the Imatinib and Rituximab .
1- Imatinib
• 180 female with chronic myeloid leukaemia treated with imatinib
(data were available for 125 women, all congenital malformations
were associated with 1st trimester exposure)
Pye SM, Cortes J, Ault P, Hatfield A et al. The effects of imatinib on pregnancy outcome. Blood 2008; 111: 5505-8.

23. Targeted anticancer therapies
2- Rituximab
231 patients with lymphoma or autoimmune diseases (outcome data were
available for 153 women)
Cardiac malformation (1)
Talipes (1)
Neonatal death (1)
First trimester miscarriage (33)
Chakravarty EF, Murray ER, Kelman A, Farmer P. Pregnancy outcomes after maternal exposure to rituximab. Blood 2011; 117: 1499-506

24. Supportive care
Ondansentron + metoclopramide
Safe during pregnancy (most accumulated data and two prospective RCTs)
Erythropoietin
Not crossing placenta
No reported teratogenic effects
GCSF
Crosses the placenta
category C
Use only in absolute need for protracted febrile neutropenia

25. Supportive care
Antibiotics
Many options could be used
Bisphosphonates
Should be avoided, as they remain in mineralised bone for several years.
However, in a review on 78 pregnant women exposed to bisphosphonates,
no increased maternal or fetal morbidity was recorded.
Zagouri, Flora et al. 2016. “Cancer in Pregnancy: Disentangling Treatment Modalities: Table 1.” ESMO Open 1(3): e000016.

26. Breast Cancer in Pregnancy

27. Definition
Gestational or pregnancy-associated breast cancer is defined as
“breast cancer that is diagnosed during pregnancy, in the first
postpartum year, or any time during lactation.”

28. Incidence
• Breast cancer is the most common cancer in pregnant and
postpartum women.
• Occurs in about 1 in 3,000 pregnant women.
• The average patient is between the ages of 32 years and 38 years.

29. Breast Cancer in pregnancy
• Surgery is the first line of treatment for breast cancer in pregnancy;
with modified radical mastectomy being the treatment of choice for
operable disease.
• Radiation therapy is, in general, contraindicated in pregnancy, due to
an increased risk of fetal malformations and associated delays in
neurocognitive development.
• Chemotherapy as adjuvant treatment has also been shown to be
beneficial in patients with high-risk breast cancer; however,
chemotherapy agents are contraindicated in the first trimester of
pregnancy.

30. Managing Breast Cancer in Pregnancy Time
Time of diagnosis Surgical treatment Adjuvant treatment After Delivery
1st trimester Modified radical mastectomy or
lumpectomy with axillary node
dissection
2nd trimester adjuvant
chemotherapy
± Radiation
± Hormone therapy
2nd trimester/early 3rd Modified radical mastectomy or
lumpectomy with axillary node
dissection
± Adjuvant
chemotherapy
± Radiation
± Hormone therapy
±Adjuvant chemotherapy
Late 3rd trimester Modified radical mastectomy or
lumpectomy with axillary node
dissection
Adjuvant chemotherapy
±Radiation
±Hormone therapy
Keyser, C P T Erin A et al. 2012. “Pregnancy-Associated Breast Cancer.” 5(2): 94–99.

31. Anthracyclins
• Anthracycline-based regimens are the most studied during pregnancy
and remain the first choice.
• There is no particular preference given for one regimen over another
(e.g. AC, FAC, FEC, EC), hence the choice should be made based on
the local practice in the non-pregnant setting.
Cardiotoxicity risk
None of the studies has shown an increased risk of fetal cardiotoxicity
secondary to in-utero exposure to an anthracycline-based regimen

32. Taxanes
• Data from animal models have shown that transplacental transfer of
both paclitaxel and docetaxel is minimal.
• A systemic overview of 50 breast cancer patients treated with taxanes
has shown adequate pregnancy outcomes. The same data were
shown in 15 in European – based registries and 12 patients reported
in the American-based registries
Zagouri F, Sergentanis TN, Chrysikos D et al. Taxanes for breast cancer during pregnancy: a systematic review. Clin
Breast Cancer 2013; 13: 16–23

33. Taxanes
• The use of taxanes during pregnancy recommended in cases where
they are clinically indicated or the use of anthracyclines is
contraindicated.
Taxol doses
Out of pregnancy, weekly paclitaxel (80mg/m2) or 3-weekly docetaxel
(100mg/m2) are the most effective schedules.
During pregnancy,
The weekly doses would allow close pregnancy monitoring
It is also associated with a better overall toxicity profile
No need for high dose steroid premedication or prophylactic use of
granulocyte colony stimulating factor (GCSF).

34. Hormone therapy
• The use of tamoxifen during pregnancy is contraindicated at any time
during the course of pregnancy as it has been shown to be associated
with fetal malformation.
Braems G, Denys H, De Wever O et al. Use of tamoxifen before and during pregnancy. Oncologist 2011;
16: 1547–1551.

35. Targeted therapy
• Trastuzumab crosses the placenta at increased levels starting in the second
trimester.
• Consistent observations have been made of an apparent high risk of oligo-
anhydramnios secondary to exposure to trastuzumab during the second and third
trimesters.
Hence, in patients with HER2-positive disease, trastuzumab or any other HER2-
targeted agent should be postponed until after delivery.
Pentsuk N, van der Laan JW. An interspecies comparison of placental antibody transfer: new insights into developmental toxicity testing of monoclonal antibodies. Birth
Defects Res Part B Dev Reprod Toxicol 2009; 86: 328–344.
Azim HA Jr, Azim H, Peccatori FA. Treatment of cancer during pregnancy with monoclonal antibodies: a real challenge. Expert Rev Clin Immunol 2010; 6: 821–826.
Zagouri F, Sergentanis TN, Chrysikos D et al. Trastuzumab administration during pregnancy: a systematic review and meta-analysis. Breast Cancer Res Treat 2013; 137: 349–
357.

36. ESMO Clinical Practice Guidelines for systemic management of patients diagnosed
with breast cancer during pregnancy according to gestational age at diagnosis and
breast cancer subtype
Breast cancer subtype Recommendations
Endocrine- sensitive
Hormonal agents (LHRH, tamoxifen) are contraindicated during pregnancy.
Early (i.e. adjuvant, neoadjuvant)
(i) If node-positive, and/or signs of aggressive disease (i.e. luminal-B), wait until second
trimester and start anthracycline-based chemotherapy. Patients diagnosed in the third
trimester could be counselled on a case-by-case basis and in some of them treatment
could be deferred until delivery.
(ii) If node-negative, low proliferative disease (i.e. luminal-A), observe until delivery, then
start hormonal therapy.
Metastatic
(i) Wait until the second trimester and start an anthracycline-based regimen.

37. ESMO Clinical Practice Guidelines for systemic management of patients diagnosed
with breast cancer during pregnancy according to gestational age at diagnosis and
breast cancer subtype
Breast cancer subtype Recommendations
HER2-positive
HER2-targeted agents are contraindicated during pregnancy.
Early (i.e. adjuvant, neoadjuvant)
(i) Wait until second trimester and start anthracycline- based chemotherapy until
delivery. Taxanes could be added in sequence during pregnancy if needed,
(ii) Trastuzumab to be added following delivery.
(iii) Patients diagnosed in the third trimester could start chemotherapy until W 34
and aim to deliver at term.
Metastatic
(i) If chemotherapy and/or trastuzumab need to be urgently started during the first
trimester, discuss pregnancy termination. Otherwise, follow the procedure as in the
early setting.

38. ESMO Clinical Practice Guidelines for systemic management of patients diagnosed
with breast cancer during pregnancy according to gestational age at diagnosis and
breast cancer subtype
Breast cancer subtype Recommendations
Triple negative
Early
(i) Wait until the second trimester and start an anthracycline-based chemotherapy
until delivery. Taxanes could be added in sequence during pregnancy if needed.
(ii) Patients diagnosed in the third trimester could start chemotherapy until W34 and
aim to deliver at term.
Metastatic
(i) If chemotherapy needs to be urgently started during the first trimester, discuss
pregnancy termination. Otherwise, follow the procedure as in the early setting.
Asymptomatic

40. Lymphoma in Pregnancy

41. Lymphoma in Pregnancy
Incidence : Lymphoma 1:1000-6000
Hodgkin’s lymphoma
• In the first trimester, pregnancy termination should be considered
• In 2nd and 3rd trimester, The (ABVD) is the recommended therapy
after the first trimester of gestation, without significant fetal
complications been reported.

42. Lymphoma in Pregnancy
Non-Hodgkin’s lymphoma (NHL)
• Aggressive non-Hodgkin’s lymphoma (NHL), immediate treatment is
mandatory.
• In the first trimester of gestation pregnancy, termination should be
considered
• In 2nd and 3rd trimester : (CHOP) is the standard chemotherapy
regimen, without significant increased fetal morbidity.

43. Lymphoma in Pregnancy
Rituximab, on the basis of the data of a retrospective analysis that evaluated the
outcomes of 253 pregnancies with exposure to rituximab during pregnancy
• It seems that rituximab administration in the second and third trimesters of
pregnancy seems to be relatively safe.
• a relatively increased risk of neonatal infection and transient B cell depletion
without related infection in the neonates has been documented.
• Rituximab does not cross the placenta early in gestation.
• ESMO do not discourage the administration of rituximab during pregnancy in
patients
• Peccatori FA, Azim HA Jr, Orecchia R, et al. Cancer, pregnancy and fertility: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol
2013;24(Suppl 6):vi160–70.
• Lavi N. An update on the management of hematologic malignancies in pregnancy. Womens Health (Lond Engl) 2014;10:255–66.
• Lishner M, Avivi I, Apperley JF, et al. Hematologic malignancies in pregnancy: management guidelines from an international consensus meeting. J Clin Oncol
2016;34:501–8.

44. Practice tips
• Chemotherapy is not allowed during the 1st trimester
• Chemotherapy is safer to administer during the 2nd and 3rd
• Hormonal treatment should be avoided
• Targeted therapy use should generally be avoided.

45. Practice tips
• Diagnosis in late pregnancy, postpone the chemotherapy
administration after delivery.
• Stop chemotherapy administration for 2 to 3 before delivery to
minimize the risk of myelosuppression.

46. Thank you !