Cancer in Pregnancy

1. Cancer in Pregnancy irena.nulman@sickkids.ca 416 813 7887 www.motherisk.org 416 813 6780 press 9

2. Disclosure Irena Nulman holds the Canadian Breast Cancer Foundation (CBCF) Grant

4. Reproduction Today • Women delay childbearing (older age at conception) • High-risk pregnancies • CVD, Diabetes, Obesity, Infections (HIV) • IVF (available modern obstetric care) • Organ transplant • Age-dependent malignancies and cancer survivors • Exposure to diagnostic and treatment procedures during gestation is unavoidable

5. Cancer in Women • Is the second leading cause of mortality in women of childbearing age • In Canada 9% of cancers is diagnosed in ages 20 to 44; 2/3 are women • Breast, cervical, lymphoma, thyroid, and melanoma the most prevalent

7. Cancer in Pregnancy • Cancer in pregnancy is not common, but is not a rare disorder anymore • Cancer in pregnancy increased from 1/1550 in 1990 to 1/1180 in 2004 and is on the rise • Complicates up to 0.02% of pregnancies annually • Termination of a cancer pregnancy is not always an option

8. Cancer in Pregnancy, con’t • Associated with anxiety and stress • Creates a conflict between optimal maternal care and fetal safety • Fetal risk of cancer treatment should be weighed against maternal risk if treatment is delayed • Women decline treatment because of fear of teratogenicity even in life - threatening conditions

9. Teratology Domains 1st Trimester 2nd Trimester 3rd Trimester Death 1st Trimester 2nd Trimester 3rd Trimester Postnatal CNS Development

10. Malformations • Major Structural and/or functional deficits for which medical or surgical intervention is necessary or a defect that can impair the child’s future lifestyle The baseline risk for general population is 1 – 3%, 5%, 7% • Minor Morphologic traits of no serious medical or cosmetic consequence, but might signify a major malformation complex

11. Factors Modifying Teratogenic Risks • Dose, rate, duration of administration, interaction with other environmental factors may modify action of a teratogen • Genetic characteristics of maternal/fetal enzymatic bouquet (individual drug handling) • Time of exposure during gestation

12. Critical Windows of Vulnerability • All or none period (preimplantation 8-14 days) • Gastrulation period is the most central to all of teratology - 3weeks PC • Cell proliferation and migration • Medial and lateral growth is developing • Axes of neural tubes are associated with genetic expression, interruption of proliferation in this period can cause detrimental long-term outcomes • Organogenesis (up to 12 weeks) • Synapse formation and Myelination continue throughout childhood and adolescence

13. Behavioral Teratology • Behavioral Teratology is a science of neurocognitive effects or impairments of prenatal origin • The long-term continuous development of the CNS have consequences for vulnerability to adverse conditions Even small interference with the process of CNS development may have a profound impact across the life span of an individual

15. “It is not birth, marriage or death, but gastrulation which is truly the most important time in your life” Lewis Wolpet, 1938

16. Cancer Management • Risk/benefit model should be used to individualize and optimize maternal treatment • Most cytotoxic drugs cross the placenta and reach the fetus • Decision-making is complicated by medical, ethical, religious and psychological considerations

17. Cancer Management, con’t • Provision of clear information on all potential effects on mother and fetus • Avoidance of assumptions about women's pregnancy intentions • Discuss breastfeeding • Address sexual activity and future reproductive health.

18. Cancer Management, con’t • Dispel misconception about cancer therapy in pregnancy • Reach optimal as in non-pregnant women anti-cancer regimen protecting the fetus • Involve multidisciplinary team: oncologist, hematologist, obstetrician/gynecologist, toxicologist, perinatologist, psychologist, psychiatrist, social workers, and spiritual advisors • Provide support in complex treatment decisions, often in absence of definitive evidence

19. Challenges • Limited knowledge due to : • High rates of pregnancy termination • Decision not to treat during critical periods of fetal development • Multiple protocols • Multiple-drug regiments limits the ability to estimate the individual drug safety • Pregnancy physiological changes and long-term outcomes

20. Challenges con’t • Outcomes confounded by concomitant therapies and co-morbidities • Associated with stress - a known teratogen • Misperception of reproductive risk/safety of antineoplastic agents (patients and care providers) • Evidence-based information should be used in decision making

21. Challenges con’t • No RCTs • Case reports • Small retrospective studies using different methodologies (under-powered, association vs. causality) • Registries: limited by a lack of a denominator, control group, unknown treatment compliance, and possible selection and recall biases • Consensus guidelines

22. Outcomes • Death, Malformations • Prematurity, Impaired growth - IUGR • Fetal/neonatal myelosuppression • Metastases to placenta and fetus • Long-term outcomes • Cognitive and behavioral • Childhood cancers • Fertility

23. Diagnostic Radiation Deterministic Effects • Conservative safe threshold: 5 cGy • Likely safe clinical threshold: 10-20 cGy • Fetal dose depends on: • Cumulative dose, size of radiation field • Distance from field to fetus • If fetus 30cm away from field edge, dose may only be 4-20 cGy • Equipment type

24. Non-ionizing Radiation: MRI • FDA: Fetal safety not established • Most research has not found adverse effects • Acoustic damage (Baker et al 1994) • Contrast media • Preference should be given to Gadobenate dimeglumine or Gadoterate meglumine • Gadolinium – nephrogenic systemic sclerosis

25. Diagnostic Procedures & Fetal Risk Estimated fetal ionizing radiation dose from common diagnostic procedures

27. Risk of Childhood Cancer • Diagnostic Radiation • Oxford Survey of Childhood Cancer, nationwide case-control study (Doll, Br J Radiol 1997) • OR: 1.39 (95% CI 1.30 -1.49) • Population-based study of 1.8 million of mother-child pairs exposed to CT or radionuclide imaging in Ontario between 1991 – 2008 (Ray, PLoS Med 2010) • The rate of testing increased from 1.1 to 6.3 per 1000 pregnancies • Median duration of follow-up of 8.9 years • 1.13 per 10.000 in exposed group vs 1.56 per 10.000 in unexposed • A crude hazard ratio of 0.69 (95%CI 0.26-1.82) • The absolute annual risk remains about 1 in 10.000, considering the upper confidence limit of 1.8 times that of unexposed, the authors did not exclude that exposure to CT or radionuclide imaging is carcinogenic

28. Childhood Cancer cont’ • A case-control study (Rajaraman, BMJ 2011) • 2690 cases and 4858 matched controls, 305 children exposed to 319 procedures • A slight, non- stat. sig. increase risk (OR 1.14 (95% CI 0.90 -1.45) for all cancers • For leukemia OR 1.36 (95% CI 0.91 -2.02) • Exposure to diagnostic x-rays in early infancy was associated with small, non- significant excess risk for all cancers and leukemia, but increased risk of lymphoma OR 5.14 (95% CI 1.27-20.78) • Conclusion: indicate a possible risk of cancer from radiation • Results for lymphoma need to be replicated • Caution use of diagnostic radiation during pregnancy and in children in very young age • No evidence of increased risk with in utero exposure to ultrasound

29. Surgery • 0.5-2% of pregnant women in North America undergo non-obstetric surgery • Mazze and Kallen (1989)- 5404 women • No overall increased risk of malformations • Increased risk of neural tube defect in subgroup who had surgery at gestational age 4-5 weeks (n=572) • These effect were not found in subsequent studies • Cohen-Kerem et al. (2005) review of 12,452 pregnancy • No increase in malformation rates • Risk of miscarriages was comparable to baseline

30. Radiotherapy • Common misbelieve that any dose of radiation is teratogenic • Not completely contraindicated • First and second trimester radiotherapy can be considered • Fetal dose during first and second trimester not as high as during the third trimester • Shielding reduces fetal dose up to 50-75%

31. Chemotherapy Outcomes • 1st trimester exposure • Malformations – 10 to 20%; 6% when folate antagonists were excluded • 2 and 3 trimester exposure (n=376) • Fetal death – 5% • Neonatal growth – 1% • Premature delivery – 5% • IUGR – 7% • Myelosuppression – 4% (Cardonic, Lancet Oncol 2004) • High rates of prematurity, regardless time of exposure

32. Chemotherapy Outcomes con’t • American registry, 2nd and 3 trimester exposure (n=152) • 1 fetal death • 1 neonatal death • Malformations rates - 3.8% • IUGR - 7.6% • Transient myelosuppression – 2 neonates (Cardonick , Am J Clin Oncol 2010)

33. Chemotherapy Outcomes con’t • 2nd and 3rd trimester exposure • Chemotherapy exposed 117 vs 58 controls • 17.9% of low birth weight in chemotherapy group vs 8.6% in controls • Most infants were of mothers treated for hematological cancer Van Calsteren, J Clin Oncol 2010

34. Breast Cancer • The choice to accept chemotherapy rather than delay it until after pregnancy may significantly impact the woman’s survival • Delaying treatment by 3-6 months can increase the risk for metastases • Pregnant BC patients who receive comparable chemotherapy to non-pregnant BC patients have same survival when controlling for stage at diagnosis • Termination of pregnancy does not improve survival of BC women

35. BC in Pregnancy: Recommendations of an international consensus meetingEur J Cancer, 2010 • Efficient treatment of BCP is possible • BCP treatment should adhere to standardized protocols of non-pregnant patients and should be discussed by a multidisciplinary team • Surgery can be performed in all 3 trimesters • Radiation – 1st and 2nd trims, considering fetal dose • Deliveries should not be induced before 37 weeks • Patient should be included in a registry in order to promote research for further knowledge (International study on cancer in pregnancy: http://www.cancerinpregnancy.org) • Termination of pregnancy does not improve maternal prognosis

36. Metastases • 87 patients with placental or fetal metastases were reported, melanoma - most common (31%) • In placental melanomas patients, 22% of the fetuses were affected as well • Poor outcome in mothers, fatal in infants was reported • Placentas of women with malignancies known to affect placenta should be carefully examined grossly and by a pathologist • Neonates delivered with placental metastases should be considered high-risk population and monitored Alexander et al, J Clin Oncol 2003

37. Long-term Neurodevelopmental Outcomes • Neurocognitive outcomes of 111 children • No adverse effects, but formal tests often lacking Nulman et al. (2001) • Neurocognitive outcomes of 84 children, treatment for maternal hematological cancer • Formal tests employed • Did not differ from controls on school performance or standardized IQ test • Neurodevelopment of 12 second generation children reported Aviles and Neri (2001)

38. Long-term cognitive and cardiac outcomes after prenatal exposure to chemotherapy in children aged 18 months or older: an observational study • Multicentre observational cohort of 236 cycles of chemotherapy (adjusted for maternal weight gain) in 70 children • Anthracyclines were the most common agents (53 patients) • Children were assessed at birth, age 18 months, and ages 5-6, 8-9, 11-12, 14-15, or 18 years • Bayley or IQ tests, electro/echo cardiography, and audiometry were performed, and general health was documented Frédéric Amant, Lancet, 2012

39. Frédéric Amant, Results • 40 children achieved 96.8 on Bayley MDI scores • IQ scores for 13 children born at term were 103.1 • 27 preterm children scored 94.6 • Fetal exposure to chemotherapy was not associated with increased CNS, cardiac, auditory, or other pediatric morbidity morbidity • Prematurity was commonand was associated with impaired cognitive development • IQ increased by 11.6 points (95% CI 6·0–17·1) for each additional month of gestation (p<0·0001) • Iatrogenic preterm delivery should be avoided when possible

40. Pregnancy outcome and child neurodevelopment following in utero exposure to maternal cancer. Division of Clinical Pharmacology and Toxicology, The Hospital for Sick Children, University of Toronto

41. The Cohort The cohort was recruited from the prospectively collected Motherisk database and other Cancer Centers in Ontario. • GROUP 1: Mother-child pairs exposed to chemotherapy and/or radiation during pregnancy • GROUP 2: Mother-child pairs exposed to maternal cancer and surgery alone, who served as controls.

42. Objective • To define cognitive developmental and pediatric outcomes of children exposed in utero to maternal malignancy and its treatment

43. Results • 24 mother – child pairs (aged 3 to 12) were assessed. • 15 - exposed to chemotherapy and/or radiation and • 9 were exposed to surgery only.

44. Children’s Characteristics (mean + SD)

45. Children’s Cognitive Outcome (mean + SD)

46. Results • Three children were exposed to radiation during the first trimester, one of which was also exposed to chemotherapy throughout pregnancy. Their Full-Scale IQ were: 112,124, 87 (maternal IQ=62).

47. Summary • Child’s physical and neurological development was within population norms for both groups. • Shorter gestations and low birth weights among controls were due to planned deliveries in order to start treatment. • In the assessed cohort, children between groups were no different in the main outcome (IQ), which were also no different than population norms. • This finding is reassuring for the patients who need treatment for maternal malignancy during pregnancy.

48. Concluding Remarks • Cancer in pregnancy can be successfully treated in collaboration with multidisciplinary team • State - of the art treatment management should be provided • Individualization of treatment and effective psychological support is imperative • Risks of most diagnostic procedures and surgery is small

49. Concluding Remarks • Serious concerns should be given to iatrogenic prematurity • Associated with increased child mortality, morbidity and neurocognitive impairments • 1st trimester pharmaco/chemotherapies are associated with normal outcomes in up to 80% of pregnancies • Individual differences in drug handling (including pharmacogenetics)

50. Concluding Remarks • If MM rates following chemotherapy in 2 and 3 trimester are above the baseline • Understand the confounding of stress, maternal disorder, and other factors • Radiotherapy not completely contraindicated • May be considered in 1and 2 trimester and if the tumor is far from the fetus • Appropriate fetal protection should be employed • Breast feeding should be considered based on individual drug safety/kinetics and neonatologist –breastfeeding experts consult http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?LACT