The Effects of Radiotherapy on the Ovary and the Uterus

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

2. My Colleagues • Hamish Wallace • Angela Thomson • Royal Hospital for Sick Children • Edinburgh, Scotland • Frank Saran • Royal Marsden Hospital • London Primer Workshop LatinoAmericano

3. The Ovary • The Faddy-Gosden Model • of decline in ovarian reserve • Calculation of the LD50 • Prediction of ovarian failure after radiotherapy • for populations and for individuals • Effective sterilising doses Primer Workshop LatinoAmericano

4. The Faddy-Gosden Model • Based on many sources • Histological studies • Block 1952, Gougeon et al. 1984, Richardson et al. 1987 • model agrees with Baker 1963 • Distribution of menopausal ages • Trelour 1981 • model agrees with van Noord et al. 1997 Primer Workshop LatinoAmericano

5. The Faddy-Gosden Model Primer Workshop LatinoAmericano

6. The Faddy-Gosden Model • Population at birth about 700,000 • Steady exponential decline until 10 years before menopause • similar proportion lost each year • Accelerated decline thereafter • Population at menopause about 1,000 Primer Workshop LatinoAmericano

7. Calculation of the LD50 • First 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-estimate • but a useful first approximation Primer Workshop LatinoAmericano

8. Calculation of the LD50 • Recalculated in 2003 • using the Faddy-Gosden model • and improved clinical techniques for determining age at ovarian failure • Same methodology used • assume that each individual conforms to the Faddy-Gosden model • estimate fraction of population remaining after a known dose of RT Primer Workshop LatinoAmericano

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11. Calculation of the LD50 • LD50 now estimated at < 2 Gy • 0.15 Gy for mice • 50 Gy for monkeys • Assumptions • 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 Primer Workshop LatinoAmericano

12. Prediction of Ovarian Failure • We 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 ovary • using iso-dose charts based on CT scans • improved using conformal radiotherapy • we have a good estimate of the LD50 Primer Workshop LatinoAmericano

13. Prediction of Ovarian Failure Primer Workshop LatinoAmericano

14. Prediction of Ovarian Failure • We 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 birth • and that early menopause corresponds to a low follicle population at birth Primer Workshop LatinoAmericano

15. Trelour, 1981 distribution of ages at menopause Faddy-Gosden solutions for early, average & late menopause Primer Workshop LatinoAmericano

16. Prediction of Ovarian Failure • Taken 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 Primer Workshop LatinoAmericano

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19. Prediction for Individuals • We would like to give more specific advice to children & families • But we can’t assess the population before treatment • and our assumptions need not be valid • We can be reasonably confidentabout calculating a sterilising dose • immediately reduce the population to fewer than 1,000follicles Primer Workshop LatinoAmericano

20. 19 Gy will sterilise at 7 years 11 Gy will sterilise at 42 years Primer Workshop LatinoAmericano

21. Prediction for Individuals • We 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. • genetic indicators • strong evidence from study on twins, de Bruin et al. 2001 • ovarian indicators • antral follicle counts, Broekmans et al. 2004 Primer Workshop LatinoAmericano

22. Prediction for Individuals • Strong 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 case • very good agreement with a separate study on age-related ovarian volume • Flaws et al. 2000 Primer Workshop LatinoAmericano

23. r = 0.97 r = 0.96 Primer Workshop LatinoAmericano

24. Future Research • Ovarian volume • time in cycle, contraception, left & right • longitudinal study • relation to hormonal, genetic & other indicators • Clinical factors • better assessment of ovarian failure • accurate estimate of dose to ovaries Primer Workshop LatinoAmericano

25. Future Research • Validation (or revision) of existing results • use CCSS data to test LD50 calculations • Childhood Cancer Survivor Study • large follow up study, N = 3390 • good protocol information • including AA regimes (chemotherapy) • self-reported ovarian failure Primer Workshop LatinoAmericano

26. The Uterus • Much fewer quantitative results • Normal uterine function is well documented • and can be assessed using TV ultrasound • We know that RT can increase uterine volume and endometrial thickness • and change shape from tubular to pear-shaped Primer Workshop LatinoAmericano

27. The Uterus • TBI (14.4 Gy) is known to cause uterine disfunction • reduction in length & blood flow • Holm et al. 1999 • Excess risk of low birthweight • Green, 2001 • Ovum donation can lead to pregnancy • high risk of miscarriage, Larsen et al. 2000 Primer Workshop LatinoAmericano

28. The Uterus • Chemotherapy does not appear to affect uterine function • Critchley, Thomson & Wallace 2004 • Further work is needed to quantify the effects of radiotherapy on uterine function Primer Workshop LatinoAmericano

29. Conclusions • LD50 of 2 Gy for the human oocyte • Wallace, Thomson & Kelsey 2003 • Prediction of ovarian failure after RT • Effective Sterilising Dose • Wallace, Saran, Thomson & Kelsey 2005 • Individual assessment via ovarian volume • Wallace & Kelsey 2004 Primer Workshop LatinoAmericano

30. Conclusions • More 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 teams • minimise the late-effects of treatments for cancer during childhood Primer Workshop LatinoAmericano

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