Cancer during pregnancy: short and long term effects on mother and child.

Cancer is the second leading cause of death during the reproductive years and
complicates between 0.06% and 0.10% of all pregnancies. In Europe, this number
translates into 3000 to 5000 new cases of cancer diagnosis during pregnancy
yearly. As women in developed societies defer childbearing to the third or
fourth decade of life, and the incidence of several malignancies rises with
increasing age, this rare co-incidence is likely to become more common.
The most frequently encountered types of cancer in women of childbearing age
are breast cancer, cervical cancer, leukaemia, lymphoma and malignant melanoma.
The maternal prognosis is probably similar to non-pregnant women provided the
same treatment strategies are applied. These include surgery, chemotherapy and
radiotherapy or a combination of these. However, little data exist on the
safety and efficacy of chemotherapy and radiotherapy during pregnancy.

Although several reports address the fetal outcome after prenatal exposure to
chemotherapy or radiotherapy, we are not aware of any prospective study on this
subject. Retrospective data suggest an overall reassuring short term outcome
after prenatal exposure to chemotherapy or radiotherapy, however stillbirth,
premature birth and low birth weight seem to occur more frequently. Also,
neonatal myelosuppression has been reported. Although dose-related
cardiotoxicity after anthracycline-exposure in adults or children is a
well-known problem, the effects of doxorubicin on the developing fetal heart
needs further investigation. On the long term outcome, systematic studies are
lacking. The available studies report on a normal physical, neurological,
psychological, haematological and immunologic outcome, without an increased
occurrence or secondary malignancies, however the children were not examined in
a standardized manner.

In 2004, a multidisciplinary team of clinicians and researchers in the UZ
Leuven hospital started to collaborate on the rare problem of cancer during
pregnancy. The collaboration between gynaecologists, pediatricians,
hematologists, farmacologists, medical oncologists and gynaecological
oncologists resulted in a multicentric, international study, with the main aim
to investigate the effect of cancer and cancer treatment during pregnancy on
the mother and child*s outcome. Participating countries so far are: Austria,
Belgium, Canada, Czech republic, Denmark, France, Greece, Israel, Italy,
Lithuania, Mexico, The Netherlands, Norway, Poland, Portugal, Russian
Federation, Serbia, Spain, Sweden, United Kingdom, United States
(Philadelphia), Switzerland . There is also active collaboration with the
German Breast group which registers women diagnosed with breast cancer during
pregnancy (www.germanbreastgroup.de).

PART 1.1A. Registration study *Cancer during pregnancy*
PART 1.1B Effects of prenatal exposure to cancer treatment on fetal growth.
Part 1.2 Measurement of maternal and paternal anxiety and emotional needs when
confronted with a cancer diagnosis during pregnancy
PART 1.3 Biobank *cancer in pregnancy*
PART 1.4 Study on the pharmacokinetics of chemotherapeutic agents in pregnant
women
PART 2. Long term follow up of children and adolescents in utero exposed to
chemotherapy and/or radiotherapy.

The aim of part 1.1A, Registration study, is to record the incidence and
maternal (obstetrical and oncological) outcome of cancer occurring during
pregnancy. To record the short and long term neonatal outcome. And to record
the incidence and prognosis of women with cancer diagnosed in the first year
postpartum. This study will provide insight in the effect of cancer and cancer
treatment during pregnancy on the mother and child*s outcome.
The aim of part 1.1B The aim is to study the pathophysiology of IUGR which is
associated with cancer treatment during pregnancy.Maternal blood samplings at
approximately 32 weeks of gestation will be taken to determine levels of
circulating hormones, factors of angiogenesis and inflammation. Placental and
umbilical cord biopsies will be collected to examine the morphology and markers
of angiogenesis, inflammation, apoptosis and proliferation

In part 1.2, on psychological impact we aim to identify maternal and paternal
emotional needs when cancer is diagnosed during pregnancy. And to identify the
maternal (and paternal) attitude with regard to oncologic treatment during
pregnancy. We developed a questionnaire on maternal anxieties when cancer is
diagnosed during pregnancy. In future we hope to establish guidelines on how to
emotionally and mentally support the mother and her partner when cancer is
diagnosed during pregnancy. These guidelines should form the basis for the
counseling and psychological treatment of these patients.

In part 1.3, a Biobank is collected, to identify differences in tumor biology
and genetic changes in the tumor in pregnancy-associated cancer, compared to
non-pregnancy-associated cancer. The study hopes to compare 2 subgroups within
pregnancy-associated cancer; women diagnosed with cancer during pregnancy, and
women diagnosed with cancer in the first year postpartum. Permission for
storage of blood -and tissue samples for further research will be requested.
Samples that are aimed for are: blood samples, plasma samples, tumour samples,
placenta samples and cord blood samples. Collected samples will be registered
in a central database and will be available for future research on cancer in
preganancy.

In part 1.4 on Pharmacokinetics, we aim to investigate the difference in
pharmacokinetics of cytotoxic drugs and the therapy related toxicity, compared
between pregnant and non-pregnant patients. And to correlate these results
with outcome (disease free and overall survival, as registered in part I).
Pharmacokinetic parameters will be compared between pregnant and non-pregnant
women including terminal elimination half-life, apparent volume of distribution
and (whole body) clearance. (limited sampling will be applied) Supplemental
blood samples will be taken after the course for determination of total blood
count.

In part II, the long term follow up of the children exposed to chemotherapy
and/or radiotherapy in utero the study investigates differences in: general
health issues, incidence and prevalence of secondary malignancies, neurologic,
cardiologic and sexual development.
At the ages of 6 months, 18 months, 3 years, 6 years, 9 years, 12 years, 15
years and 18 years, the children will be invited to the hospital for a
physical, neurologic and cardiac evaluation..

Burden for registration study part 1.1A: none. The treating physician will be
contacted for information. Risk: none
For part 1.1B: 2 maternal blood samples will be drawn, shortly after delivary.
These will be combined with standard of care blood samples. There is no risk or
burden from umbilical or placental biopsies

Burden for the psychological questionnaire (part 1.2): to fill in the
questionnaire once, will take around 10-15minutes. No risks.

Burden for pharmacokinetics study 1.4: during 1 chemotherapy cycle, 5x 1 blood
sample, either through venapunction or using the existing peripheral or
central line. Risk of hematoma.


Burden for the children (part 2): 8x half a day (at the ages of 6 months, 18
months, 3, 6, 9, 12, 15 and 18 years), No risks or invasive procedures
involved.