Reproductive Consequences of

(1)

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

(2)

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

(3)

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

(4)

- 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?

(5)

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

(6)

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

(7)

Various indicators of possible genetic damage

- markers of potential damage to germ cells

(8)

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)

(9)

Pregnancies by age

Age at pregnancy

10 15 20 25 30 35 40 45 50

Number of pregnancies

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

(10)

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)

(11)

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)

(12)

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

(13)

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)

(14)

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

(15)

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%)

(16)

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

(17)

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

(18)

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

(19)

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 - <50 21 (28) 124 (29) 1.12 0.52 - 2.38

≥ 50 2 (3) 12 (3) 1.04 0.17 - 6.25

Uterine dose 0.07

≥ 50 11 (13) 26 (6) 2.30 0.95 - 5.56

Male cancer survivor

Testicular dose 0.72

≥ 50 4 (7) 28 (7) 1.12 0.44 - 2.88

No association between genetic disease in offspring and parental treatment with radiotherapy or with alkylators

- or with preconception radiation doses to gonads

An association between uterine dose and malformations, stillbirth and neonatal death, taken together, in children of female survivors overall (p=0.07) - and in those of mothers with highest doses

(20)

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

(21)

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

(22)

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 ’biological filtration’ – 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

(23)

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