1. The Effects of Radiotherapy on the Ovary and the Uterus The Effects of Radiotherapy on the Ovary and the Uterus PRIMER WORKSHOP LATINOAMERICANO SOBRE FALLA OVÁRICA SECUNDARIA A LOS TRATAMIENTOS DEL CÁNCER Montevideo, Uruguay Nov. 2006 Tom Kelsey Tom Kelsey University of St Andrews

2. Lunes 27 de NoviembrePrimer Workshop LatinoAmericano2 My Colleagues Hamish WallaceHamish Wallace Angela ThomsonAngela Thomson –Royal Hospital for Sick Children –Edinburgh, Scotland Frank SaranFrank Saran –Royal Marsden Hospital –London

3. Lunes 27 de NoviembrePrimer Workshop LatinoAmericano3 The Ovary The Ovary The Faddy-Gosden ModelThe Faddy-Gosden Model –of decline in ovarian reserve Calculation of the LD 50Calculation of the LD 50 Prediction of ovarian failure after radiotherapyPrediction of ovarian failure after radiotherapy –for populations and for individuals Effective sterilising dosesEffective sterilising doses

4. Lunes 27 de NoviembrePrimer Workshop LatinoAmericano4 The Faddy-Gosden Model The Faddy-Gosden Model Based on many sourcesBased on many sources Histological studiesHistological studies –Block 1952, Gougeon et al. 1984, Richardson et al. 1987 –model agrees with Baker 1963 Distribution of menopausal agesDistribution of menopausal ages –Trelour 1981 –model agrees with van Noord et al. 1997

5. Lunes 27 de NoviembrePrimer Workshop LatinoAmericano5 The Faddy-Gosden Model

6. Lunes 27 de NoviembrePrimer Workshop LatinoAmericano6 The Faddy-Gosden Model Population at birth about 700,000Population at birth about 700,000 Steady exponential decline until 10 years before menopauseSteady exponential decline until 10 years before menopause –similar proportion lost each year Accelerated decline thereafterAccelerated decline thereafter Population at menopause about 1,000Population at menopause about 1,000

7. Lunes 27 de NoviembrePrimer Workshop LatinoAmericano7 Calculation of the LD 50 Calculation of the LD 50 First estimated as < 4 GyFirst estimated as < 4 Gy –Wallace et al. 1989 –using an over-simple model of follicle population decline –and self-reporting of ovarian failure Likely to be an over-estimateLikely to be an over-estimate –but a useful first approximation

8. Lunes 27 de NoviembrePrimer Workshop LatinoAmericano8 Calculation of the LD 50 Calculation of the LD 50 Recalculated in 2003Recalculated in 2003 –using the Faddy-Gosden model –and improved clinical techniques for determining age at ovarian failure Same methodology usedSame methodology used –assume that each individual conforms to the Faddy-Gosden model –estimate fraction of population remaining after a known dose of RT

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11. Lunes 27 de NoviembrePrimer Workshop LatinoAmericano11 Calculation of the LD 50 Calculation of the LD 50 LD 50 now estimated at < 2 GyLD 50 now estimated at < 2 Gy –0.15 Gy for mice –50 Gy for monkeys AssumptionsAssumptions –rate of decline not affected after radiation –individuals close to the Faddy-Gosden model before and after treatment –likely age of ovarian failure without treatment is 50-51 years

12. Lunes 27 de NoviembrePrimer Workshop LatinoAmericano12 Prediction of Ovarian Failure Prediction of Ovarian Failure We know the age at treatmentWe know the age at treatment –we have a good model for follicle decline –we have good data on ages of menopause We can estimate the dose received by the least-affected ovaryWe can estimate the dose received by the least-affected ovary –using iso-dose charts based on CT scans –improved using conformal radiotherapy –we have a good estimate of the LD 50

13. Lunes 27 de NoviembrePrimer Workshop LatinoAmericano13 Prediction of Ovarian Failure Prediction of Ovarian Failure

14. Lunes 27 de NoviembrePrimer Workshop LatinoAmericano14 Prediction of Ovarian Failure Prediction of Ovarian Failure We can use these to predict the age of ovarian failure after a known dose at a known ageWe can use these to predict the age of ovarian failure after a known dose at a known age We also assume that late menopause corresponds to high follicle population at birthWe also assume that late menopause corresponds to high follicle population at birth –and that early menopause corresponds to a low follicle population at birth

15. Lunes 27 de NoviembrePrimer Workshop LatinoAmericano15 Trelour, 1981 distribution of ages at menopause Faddy-Gosden solutions for early, average & late menopause

16. Lunes 27 de NoviembrePrimer Workshop LatinoAmericano16 Prediction of Ovarian Failure Taken together, we can estimate the effects of treatmentTaken together, we can estimate the effects of treatment –given the dose and age at treatment –we supply expected age of ovarian failure –together with ranges that account for variations in follicle population –which we can’t measure directly

17. Lunes 27 de NoviembrePrimer Workshop LatinoAmericano17

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19. Lunes 27 de NoviembrePrimer Workshop LatinoAmericano19 Prediction for Individuals Prediction for Individuals We would like to give more specific advice to children & familiesWe would like to give more specific advice to children & families But we can’t assess the population before treatmentBut we can’t assess the population before treatment –and our assumptions need not be valid We can be reasonably confident about calculating a sterilising doseWe can be reasonably confident about calculating a sterilising dose –immediately reduce the population to fewer than 1,000 follicles

20. Lunes 27 de NoviembrePrimer Workshop LatinoAmericano20 19 Gy will sterilise at 7 years 11 Gy will sterilise at 42 years

21. Lunes 27 de NoviembrePrimer Workshop LatinoAmericano21 Prediction for Individuals Prediction for Individuals We may be able to do betterWe may be able to do better –by using ovarian volume as a surrogate indicator of ovarian reserve –in combination with hormonal indicators AMH, FSH, inhibin-B, etc.AMH, FSH, inhibin-B, etc. –genetic indicators strong evidence from study on twins, de Bruin et al. 2001strong evidence from study on twins, de Bruin et al. 2001 –ovarian indicators antral follicle counts, Broekmans et al. 2004antral follicle counts, Broekmans et al. 2004

22. Lunes 27 de NoviembrePrimer Workshop LatinoAmericano22 Prediction for Individuals Prediction for Individuals Strong correlation between ovarian volumes and follicle populationsStrong correlation between ovarian volumes and follicle populations –Pavlik et al. 2000 data on ovarian volumes –Faddy-Gosden model Both for the average case and the high volume - high population caseBoth for the average case and the high volume - high population case –very good agreement with a separate study on age-related ovarian volume –Flaws et al. 2000

23. Lunes 27 de NoviembrePrimer Workshop LatinoAmericano23 r = 0.97 r = 0.96

24. Lunes 27 de NoviembrePrimer Workshop LatinoAmericano24 Future Research Ovarian volumeOvarian volume –time in cycle, contraception, left & right –longitudinal study –relation to hormonal, genetic & other indicators Clinical factorsClinical factors –better assessment of ovarian failure –accurate estimate of dose to ovaries

25. Lunes 27 de NoviembrePrimer Workshop LatinoAmericano25 Future Research Validation (or revision) of existing resultsValidation (or revision) of existing results –use CCSS data to test LD 50 calculations –Childhood Cancer Survivor Study –large follow up study, N = 3390 –good protocol information –including AA regimes (chemotherapy) –self-reported ovarian failure

26. Lunes 27 de NoviembrePrimer Workshop LatinoAmericano26 The Uterus Much fewer quantitative resultsMuch fewer quantitative results Normal uterine function is well documentedNormal uterine function is well documented –and can be assessed using TV ultrasound We know that RT can increase uterine volume and endometrial thicknessWe know that RT can increase uterine volume and endometrial thickness –and change shape from tubular to pear- shaped

27. Lunes 27 de NoviembrePrimer Workshop LatinoAmericano27 The Uterus TBI (14.4 Gy) is known to cause uterine disfunctionTBI (14.4 Gy) is known to cause uterine disfunction –reduction in length & blood flow –Holm et al. 1999 Excess risk of low birthweightExcess risk of low birthweight –Green, 2001 Ovum donation can lead to pregnancyOvum donation can lead to pregnancy –high risk of miscarriage, Larsen et al. 2000

28. Lunes 27 de NoviembrePrimer Workshop LatinoAmericano28 The Uterus Chemotherapy does not appear to affect uterine functionChemotherapy does not appear to affect uterine function –Critchley, Thomson & Wallace 2004 Further work is needed to quantify the effects of radiotherapy on uterine functionFurther work is needed to quantify the effects of radiotherapy on uterine function

29. Lunes 27 de NoviembrePrimer Workshop LatinoAmericano29 Conclusions LD 50 of 2 Gy for the human oocyteLD 50 of 2 Gy for the human oocyte –Wallace, Thomson & Kelsey 2003 Prediction of ovarian failure after RTPrediction of ovarian failure after RT Effective Sterilising DoseEffective Sterilising Dose –Wallace, Saran, Thomson & Kelsey 2005 Individual assessment via ovarian volumeIndividual assessment via ovarian volume –Wallace & Kelsey 2004

30. Lunes 27 de NoviembrePrimer Workshop LatinoAmericano30 Conclusions More work needed to improve modelsMore work needed to improve models –and justify assumptions –and consider uterine function Aim is to provide high-quality information to children, their families and their clinical teamsAim is to provide high-quality information to children, their families and their clinical teams –minimise the late-effects of treatments for cancer during childhood

31. Lunes 27 de NoviembrePrimer Workshop LatinoAmericano31