the effects of radiotherapy on the ovary and the uterus the effects of radiotherapy on the ovary and...

The Effects of The Effects of Radiotherapy on the Ovary Radiotherapy on the Ovary

and the Uterusand the Uterus

PRIMER WORKSHOP LATINOAMERICANO

SOBRE FALLA OVÁRICA SECUNDARIA A LOS TRATAMIENTOS DEL CÁNCER

Montevideo, Uruguay Nov. 2006

Tom KelseyTom Kelsey

University of St AndrewsUniversity of St Andrews

Lunes 27 de NoviembreLunes 27 de Noviembre Primer Workshop LatinoAmericanoPrimer Workshop LatinoAmericano 22

My ColleaguesMy Colleagues

• Hamish WallaceHamish Wallace• Angela ThomsonAngela Thomson

– Royal Hospital for Sick ChildrenRoyal Hospital for Sick Children– Edinburgh, ScotlandEdinburgh, Scotland

• Frank SaranFrank Saran– Royal Marsden HospitalRoyal Marsden Hospital– London London


The OvaryThe Ovary

• The Faddy-Gosden ModelThe Faddy-Gosden Model– of decline in ovarian reserveof decline in ovarian reserve

• Calculation of the LDCalculation of the LD5050

• Prediction of ovarian failure after Prediction of ovarian failure after radiotherapyradiotherapy– for populations and for individuals for populations and for individuals

• Effective sterilising dosesEffective sterilising doses


The Faddy-Gosden ModelThe Faddy-Gosden Model

• Based on many sources Based on many sources • Histological studiesHistological studies

– Block 1952, Gougeon Block 1952, Gougeon et alet al. 1984, . 1984, Richardson Richardson et alet al. 1987. 1987

– model agrees with Baker 1963model agrees with Baker 1963• Distribution of menopausal agesDistribution of menopausal ages

– Trelour 1981Trelour 1981– model agrees with van Noord model agrees with van Noord et alet al. .

19971997



• Population at birth about 700,000Population at birth about 700,000• Steady exponential decline until 10 Steady exponential decline until 10

years before menopauseyears before menopause– similar proportion lost each yearsimilar proportion lost each year

• Accelerated decline thereafterAccelerated decline thereafter• Population at menopause about Population at menopause about

1,0001,000


Calculation of the LDCalculation of the LD5050

• First estimated as < 4 GyFirst estimated as < 4 Gy– Wallace Wallace et alet al. 1989. 1989– using an over-simple model of follicle using an over-simple model of follicle

population declinepopulation decline– and self-reporting of ovarian failureand self-reporting of ovarian failure

• Likely to be an over-estimateLikely to be an over-estimate– but a useful first approximationbut a useful first approximation



• Recalculated in 2003Recalculated in 2003– using the Faddy-Gosden modelusing the Faddy-Gosden model– and improved clinical techniques for and improved clinical techniques for

determining age at ovarian failuredetermining age at ovarian failure

• Same methodology usedSame methodology used– assume that each individual conforms assume that each individual conforms

to the Faddy-Gosden modelto the Faddy-Gosden model– estimate fraction of population estimate fraction of population

remaining after a known dose of RTremaining after a known dose of RT



• LDLD5050 now estimated at < 2 Gy now estimated at < 2 Gy– 0.15 Gy for mice0.15 Gy for mice– 50 Gy for monkeys50 Gy for monkeys

• AssumptionsAssumptions– rate of decline not affected after rate of decline not affected after

radiationradiation– individuals close to the Faddy-Gosden individuals close to the Faddy-Gosden

model before and after treatmentmodel before and after treatment– likely age of ovarian failure without likely age of ovarian failure without

treatment is 50-51 yearstreatment is 50-51 years


Prediction of Ovarian Prediction of Ovarian FailureFailure

• We know the age at treatmentWe know the age at treatment– we have a good model for follicle declinewe have a good model for follicle decline– we have good data on ages of we have good data on ages of

menopausemenopause• We can estimate the dose received We can estimate the dose received

by the least-affected ovaryby the least-affected ovary– using iso-dose charts based on CT scansusing iso-dose charts based on CT scans– improved using conformal radiotherapyimproved using conformal radiotherapy– we have a good estimate of the LDwe have a good estimate of the LD5050



• We can use these to predict the age We can use these to predict the age of ovarian failure after a known dose of ovarian failure after a known dose at a known ageat a known age

• We also assume that We also assume that latelate menopause corresponds to menopause corresponds to highhigh follicle population at birthfollicle population at birth– and that and that earlyearly menopause corresponds menopause corresponds

to a to a lowlow follicle population at birth follicle population at birth


Trelour, 1981Trelour, 1981distribution ofdistribution ofages at menopauseages at menopause

Faddy-GosdenFaddy-Gosdensolutions for early,solutions for early,average & lateaverage & latemenopausemenopause



• Taken together, we can estimate Taken together, we can estimate the effects of treatmentthe effects of treatment– given the dose and age at treatmentgiven the dose and age at treatment– we supply expected age of ovarian we supply expected age of ovarian

failurefailure– together with ranges that account for together with ranges that account for

variations in follicle populationvariations in follicle population– which we can’t measure directlywhich we can’t measure directly


Prediction for IndividualsPrediction for Individuals• We would like to give more specific We would like to give more specific

advice to children & familiesadvice to children & families• But we can’t assess the population But we can’t assess the population

before treatmentbefore treatment– and our assumptions need not be and our assumptions need not be

validvalid• We can be reasonably confidentWe can be reasonably confident

about calculating a sterilising doseabout calculating a sterilising dose– immediately reduce the population to immediately reduce the population to

fewer than 1,000fewer than 1,000 follicles follicles


19 Gy will19 Gy willsterilisesteriliseat 7 yearsat 7 years

11 Gy 11 Gy willwillsterilise sterilise atat42 years42 years


Prediction for IndividualsPrediction for Individuals• We may be able to do betterWe may be able to do better

– by using ovarian volume as a surrogate by using ovarian volume as a surrogate indicator of ovarian reserveindicator of ovarian reserve

– in combination with hormonal indicatorsin combination with hormonal indicators• AMH, FSH, inhibin-B, etc.AMH, FSH, inhibin-B, etc.

– genetic indicatorsgenetic indicators• strong evidence from study on twins, de strong evidence from study on twins, de

Bruin Bruin et alet al. 2001. 2001

– ovarian indicatorsovarian indicators• antral follicle counts, Broekmans antral follicle counts, Broekmans et alet al. 2004 . 2004


Prediction for IndividualsPrediction for Individuals• Strong correlation between ovarian Strong correlation between ovarian

volumes and follicle populationsvolumes and follicle populations– Pavlik Pavlik et alet al. 2000 data on ovarian . 2000 data on ovarian

volumesvolumes– Faddy-Gosden modelFaddy-Gosden model

• Both for the average case and the Both for the average case and the high volume - high population casehigh volume - high population case– very good agreement with a separate very good agreement with a separate

study on age-related ovarian volumestudy on age-related ovarian volume– Flaws Flaws et alet al. 2000. 2000


r = 0.97r = 0.97

r = 0.96r = 0.96


Future ResearchFuture Research

• Ovarian volumeOvarian volume– time in cycle, contraception, left & time in cycle, contraception, left &

rightright– longitudinal studylongitudinal study– relation to hormonal, genetic & other relation to hormonal, genetic & other

indicatorsindicators• Clinical factorsClinical factors

– better assessment of ovarian failurebetter assessment of ovarian failure– accurate estimate of dose to ovariesaccurate estimate of dose to ovaries


Future ResearchFuture Research

• Validation (or revision) of existing Validation (or revision) of existing resultsresults– use CCSS data to test LDuse CCSS data to test LD5050

calculationscalculations– Childhood Cancer Survivor StudyChildhood Cancer Survivor Study– large follow up study, N = 3390large follow up study, N = 3390– good protocol informationgood protocol information– including AA regimes (chemotherapy)including AA regimes (chemotherapy)– self-reported ovarian failureself-reported ovarian failure


The UterusThe Uterus

• Much fewer quantitative resultsMuch fewer quantitative results• Normal uterine function is well Normal uterine function is well

documenteddocumented– and can be assessed using TV ultrasoundand can be assessed using TV ultrasound

• We know that RT can increase uterine We know that RT can increase uterine volume and endometrial thicknessvolume and endometrial thickness– and change shape from tubular to pear-and change shape from tubular to pear-

shaped shaped



• TBI (14.4 Gy) is known to cause TBI (14.4 Gy) is known to cause uterine disfunctionuterine disfunction– reduction in length & blood flowreduction in length & blood flow– Holm Holm et alet al. 1999. 1999

• Excess risk of low birthweightExcess risk of low birthweight– Green, 2001Green, 2001

• Ovum donation can lead to pregnancyOvum donation can lead to pregnancy– high risk of miscarriage, Larsen high risk of miscarriage, Larsen et alet al. .

20002000



• Chemotherapy does not appear to Chemotherapy does not appear to affect uterine functionaffect uterine function– Critchley, Thomson & Wallace 2004Critchley, Thomson & Wallace 2004

• Further work is needed to quantify Further work is needed to quantify the effects of radiotherapy on the effects of radiotherapy on uterine functionuterine function


ConclusionsConclusions

• LDLD5050 of 2 Gy for the human oocyte of 2 Gy for the human oocyte– Wallace, Thomson & Kelsey 2003Wallace, Thomson & Kelsey 2003

• Prediction of ovarian failure after RTPrediction of ovarian failure after RT• Effective Sterilising DoseEffective Sterilising Dose

– Wallace, Saran, Thomson & Kelsey 2005Wallace, Saran, Thomson & Kelsey 2005

• Individual assessment via ovarian Individual assessment via ovarian volumevolume– Wallace & Kelsey 2004Wallace & Kelsey 2004


ConclusionsConclusions

• More work needed to improve modelsMore work needed to improve models– and justify assumptionsand justify assumptions– and consider uterine functionand consider uterine function

• Aim is to provide high-quality Aim is to provide high-quality information to children, their families information to children, their families and their clinical teamsand their clinical teams– minimise the late-effects of treatments minimise the late-effects of treatments

for cancer during childhoodfor cancer during childhood

the effects of radiotherapy on the ovary and the uterus the effects of radiotherapy on the ovary and...

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