Reproductive Consequences of Cancer Treatment

in Childhood

18 September 2012

Jeanette Falck Winther, MD, DMSc Head of Research Group

Childhood Cancer Survivorship Survivorship Unit

Danish Cancer Society Research Center Copenhagen, Denmark

Dedicated to childhood cancer survivors and their children and to all children who are fighting cancer

European Cancer Rehabilitation & Survivorship Symposium 2012

Context

The treatment of children and young adults with cancer has been a great

success

but

There are concerns about ill effects that cancer treatment may have on

children born to cancer survivors

Radiation and many cancer drugs may produce trans-generational germ cell mutations leading to genetic

disease in the next generation

In genetic counseling, in the area of mutagenicity of the human gonad, the ultimate concern is hereditary disease

Does cancer treatment induce damage of human germ cells?

Does it cause actual disease in the offspring,

- or mutational events of no clinical significance?

These concerns are voiced by

geneticists

pediatric oncologists

and other specialists in this field

- but also by the former childhood

cancer patients themselves

Will I be able to have children of my own? Will my children be healthy? Will they have birth defects or malignancies?

Laboratory studies of germ-cell mutagenesis

Decades of experimental research have shown that both chemicals and ionizing radiation are potent germ-cell mutagens in mice

However, no environmental exposure has been proven to cause new heritable disease in human beings

”There is now a growing consensus that the inability to detect human germ-cell mutagens is due to technological limitations in the detection of random de novo mutations rather than biological differences between animal and human susceptibility”

Wyrobek et al, Environ Mol Mutagen, 2007

Genetic effects in Japanese atomic bomb survivors

55,000 children born to survivors

• Untoward pregnancy outcomes (major congenital malformations, and/or stillbirths and/or neonatal deaths)

• Cytogenetic abnormalities

• Numeric aberrations (sex-aneuploidy or Down)

• Structural abnormalities (translocations)

• Sex of child

• Childhood cancer

• Death of offspring

• Growth and development

• Protein mutations

• DNA microarray-based comparative genomic hybridization

Schull et al, J Rad Prot, 2003

Neel et al, Teratology, 1999

Various indicators of possible genetic damage - markers of potential damage to germ cells

Results of the first population-based studies

Cohort studies

• Pregnancy outcomes (spontaneous and induced abortions and stillbirths)

• Sex ratio

• Chromosomal abnormalities

• Congenital malformations

• Hospitalizations

Case-cohort study

• Genetic disease (including chromosomal

abnormalities, congenital

malformations, stillbirths,

and neonatal deaths)

Pregnancies by age

Age at pregnancy

10 15 20 25 30 35 40 45 50

Nu

mb

er

of

pre

gn

an

cie

s

1

10

100

1000

10000

Population

Sisters

Survivors

Figure 2

Log-frequency distribution of 34,560 pregnancies among female cancer survivors

and sisters and population comparison women, by age at pregnancy

Winther et al, JCO, 2008

Pregnancy outcomes after childhood cancer

Female Survivors (1,479 pregnancies)

Sisters (5,092 pregnancies)

Population comparisons

(27,989 pregnancies)

% PR (95% CI) % PR % PR (95%CI)

Livebirths 69.1 0.97 (0.94-1.01) 70.2 1 (ref.) 69.8 0.98 (0.96-1.00)

Abortions 31.8 1.06 (0.97-1.15) 30.4 1 (ref.)

30.9 1.03 (0.99-1.08)

Stillbirths 0.3 1.1 (0.4- 2.9) 0.3 1 (ref.)

0.3 1.1 (0.6-1.8)

Proportion ratios (PR) of pregnancy outcome among childhood cancer survivors and comparison groups

(sisters as referent)

Spontaneous abortion

Risk of spontaneous abortion (PR) among childhood cancer survivors (sisters as referent)

Number of pregnancies

Number of miscarriages

PR (95% CI)

Sisters 5,092 304 1 (ref.)

Population Comparisons

27,989 1,718 0.98 (0.87-1.11)

Survivors 1,479 109 1.23 1.00-1.52

Wilms 58 10 3.0 (1.6-5.5)

Radiotherapy

No 1,006 63 1.1 (0.8-1.4)

Yes 457 44 1.6 (1.2-2.2)

High dose irradiation to the pituitary gland and the ovary and uterus

and risk of spontaneous abortion

Ovary/uterus: low low high Pituitary gland: low high low

This slight excess risk may have resulted from uterine damage after high-dose pelvic radiation (a non-heritable somatic effect) - although radiation-induced germinal mutations or decreased hypothalamic-pituitary-ovarian function could not be ruled out

First and second-trimester terminations, by indication

Survivors did not have more induced abortions - most occurring during the first trimester in all three cohorts Survivors were not more likely than comparisons to elect a second-trimester abortion because of physical or mental conditions (< 2% of all induced abortions; §2; §3.1, §3.4 and §3.6 combined) – or fetal abnormality (< 1%; §3.3)

Winther et al, JNCI, 2009

Induced abortions

Indication by section of The Danish Abortion Act

Survivors Sisters Population comparison

group

n % n % n %

Total 292 (100) 961 (100) 5 505 (100)

First-trimester termination

§1 By week 12 271 (92.8) 902 (93.9) 5 131 (93.2)

Second-trimester termination 7 (2.4) 29 (3.0) 174 (3.2)

§2 Danger to woman’s life 0 2 8

§3.1 §3.2 §3.3 §3.4 §3.5 §3.6

Deterioration of woman’s health Criminal act Abnormal fetus Physical or mental suffering Young age or immaturity Serious strain

1 0 2 2 0 2

7 0 9 0 4 7

42 2

45 2

15 55

§6 Below age 18 0 0 4

§7.1 Without Danish residence 0 0 1

Unknown 15 (5.1) 34 (3.5) 222 (4.0)

Sex ratio in offspring

The first population-based study to investigate whether radiotherapy received by childhood cancer patients affected the sex ratio of their offspring

The sex ratio for male (0.99) and female survivors (1.00) was similar and did not differ significantly from that in the Danish population (1.06)

Radiotherapy did not influence the sex ratio of the children

No dose-related changes over categories of estimated parental radiation dose to gonads

Winther et al, Br J Cancer, 2003

Chromosomal abnormalities in offspring

Adjusted* proportion of live-born children with abnormal karyotypes in survivor families and in the sibling families * Exclusion of hereditary cases and inclusion of prenatally

diagnosed and terminated cases (after correction for expected viability)

Winther et al, Am J Hum Genet, 2004

2,630 offspring of

4,676 survivors

5,504 offspring of 6,441 siblings

Chromosomal abnormality

5.5 (0.21%) 11.8 (0.21%)

Congenital malformations in offspring

Adjusted prevalence proportion ratios (PPRs) and hazard ratios (HRs) of congenital malformations registered at birth and at any age, respectively, among offspring of childhood cancer survivors in comparison with offspring of siblings Malformations slightly more prevalent in offspring of survivors and in offspring of irradiated (PPR 1.2) to non-irradiated (1.0) survivors. No dose-response

Winther et al, Clin Genet, 2009

1,715 offspring of 3,963 survivors

6,009 offspring of

5,657 siblings

RR (95% CI)

Congenital malformations at birth

44 (2.6%) 140 (2.3%) 1.1 (0.8-1.5)

Congenital malformations at any age*

96 (5.6%) 301 (5.0%) 1.1 (0.9-1.4)

*median follow-up 8.2 yrs; range 0-25

Hospitalization in offspring

Winther et al, Int J Cancer 2010

The probability for offspring of survivors of being hospitalized before a given age in childhood – overall and for selected diagnostic groups (infections and respiratory diseases shown) - was remarkably close to that in the comparison groups (siblings’ offspring and a population comparison offspring group) 6-fold excess risk in offspring of being hospitalized for cancer

Cohort Survivors offspring

pop. comparison Siblings offspring

Age

A case-cohort study relating adverse prenancy outcomes to radiation dose to gonads

• Patterned largely on the genetic studies of

Japanese atomic bomb survivors

• Computation of the gonadal doses made it possible to interpret the epidemiological results in light of dose–response evaluations

Measurement in anthropomorphic phantoms

Winther et al, Int J Clin Oncol 2012

Phantom is set up and treated in same way as patient and radiation doses to organs are estimated

Risk of genetic disease among of the children of cancer survivors, by radiation dose to ovary,

uterus or testes of survivor parent

Organ dose (cGy) of

survivor parent Cases Subcohort

Members Adjusted

RR 95% P-

Value

Offspring Offspring

No (%) No. (%)

Female cancer survivor

Ovarian min dose 0.96

0 (non-irradiated) 52 (69) 306 (68) 1.00 referent > 0 - 0 - 0 -

Summary of findings (I)

• No evidence that radiotherapy or chemotherapy causes adverse pregnancy outcomes that could conceivably be related to inherited germline mutations

• No indications of an altered sex ratio among the offspring

• No increases in the risks for chromosome aberrations, congenital malformations, or hospitalizations, except for cancer in offspring due to familial cancer syndromes

• Further confirmed in the case-cohort study, in which mutagenic doses of chemotherapy and radiotherapy to the gonads were not associated with genetic defects in the children of cancer survivors

Summary of findings (II)

• High radiation doses to the uterus in young girls, however, seemed to be linked to serious adverse pregnancy outcomes, such as spontaneous abortions and neonatal death in premature immature infants

This increased risk of fetal death in females (but not in conceptuses of males) treated

with ionizing radiation to the pelvis in infancy and childhood is probably

attributable to radiation damage to the infantile uterus, either connective tissue or

vascular supply, and not to germ line mutation

Failure to detect human germ cell mutagenic effects…

• may be a consequence of inadequate study size, too low exposure, failure to measure the appropriate outcome

• or perhaps – the phenomenon that the mammalian organism can eliminate serious chromosome abnormalities or lethal mutations early in pregnancy and, therefore, result in surviving offspring that have a normal or background incidence of birth defects or genetic disease

Draper, Radiation Protection Dosimetry, 2008

Brent, Health Physics, 2007

Genetic counselling

”Your child had a spontaneous change or mutation in the egg or sperm that led to her

It is nothing you did or did not do during your pregnancy or before conception

– it just happens”

This explanation is in line with the fact that

No environmental agent has been proved to cause germ cell mutations

that manifest as hereditary disease in the offspring

Mulvihill JJ, J Community Genet, 2012