Radiation Oncology/Toxicity/Ovary

Ovarian Tolerance

• Also please see Toxicity/Pelvis

• Ovary contains a fixed pool of primordial oocytes, maximal at 5 months gestational age
• Oocytes decrease in a biexponential fashion, culminating in menopause (average age 50-51)
• Rate of decrease accelerates ~ age 37 years, when ~25,000 primordial oocytes remain
• At menopause, ~1,000 oocytes remain
• Radiosensitivity of the human oocyte is <2 Gy
• Estimated sterilizing dose decreases with increasing age, because the remaining oocyte population is becoming depleted with age
• Time-dependency
  • Acute ovarian failure (AOF): loss of ovarian function during or shortly after cancer therapy
  • Premature menopause: retention of ovarian function after cancer therapy, but development of menopause <40

• Childhood Cancer Survivor Study (1970-1986)
  • 2009 PMID 19364965 -- "Fertility of female survivors of childhood cancer: a report from the childhood cancer survivor study." (Green DM, J Clin Oncol. 2009 Jun 1;27(16):2677-85. Epub 2009 Apr 13.)
    • Retrospective. 5,149 female CCCS 5-year survivors not surgically sterile and cohort of 1,441 randomly selected female siblings
    • Outcome: RR for ever being pregnant 0.81 (SS)
    • Negative predictors: hypothalamic/pituitary RT dose >=30 Gy (RR 0.61), ovarian/uterine RT dose >5 Gy (RR 0.56) or RT dose >10 Gy (RR 0.18), treatment with lomustine or cyclophosphamide, or summed alkylating agent dose (AAD) 3-4
    • Conclusion: Fertility decreased among female pediatric cancer survivors
  • 2009 PMID 19364956 -- "Ovarian failure and reproductive outcomes after childhood cancer treatment: results from the Childhood Cancer Survivor Study" (Green DM, J Clin Oncol. 2009 May 10;27(14):2374-81. Epub 2009 Apr 13.)
    • Retrospective. 3,390 eligible survivors for acute ovarian failure; 2,819 survivors and comparison 1,065 siblings for premature menopause. Excluded those who received CSI >30 Gy, hypothalamic/pituitary tumors, bilateral oophorectomy
    • Acute ovarian failure (self-reported amenorrhea): 6.3%. Predictors older age, Hodgkin's, abdominal/pelvic RT (especially doses >20 Gy to ovary, associated with >70% AOF), exposure to procarbazine or cyclophosphamide
    • Premature nonsurgical menopause: 8% vs 0.8% sibings (SS). Predictors age, ovarian RT, increasing alkylating agent dose, and Hodgkin's disease. If both alkylating agents and abdominal/pelvic RT, incidence almost 30%
    • Pregnancy outcome: 1,915 patients reported 4,029 pregnancies. If uterine RT >5 Gy, offspring small for gestational age (18% <10th percentile, SS). No difference in rate of congenital malformations
    • Conclusion: Survivors should generally be reassured, though some women may have shortened fertile life span

• Edinburgh
  • Ovarian failure dose; 2005 PMID 15936554 -- "Predicting age of ovarian failure after radiation to a field that includes the ovaries." (Wallace WH, Int J Radiat Oncol Biol Phys. 2005 Jul 1;62(3):738-44.)
    • Effective sterilising dose estimated using CT planning. Defined as 97.5% likelihood of failing immediately after treatment'
    • Effective sterilising dose: At birth 20.3 Gy, at 10 years 18.4 Gy, at 20 years 16.5 Gy, at 30 years 14.3 Gy.
    • Conclusion: Model developed to predict age of ovarian failure, as a function of age and dose
  • Oocyte tolerance; 2003 PMID 12525451 -- "The radiosensitivity of the human oocyte." (Wallace WH, Hum Reprod. 2003 Jan;18(1):117-21.)
    • Used data from ovarian failure after TBI in 6 patients to estimate oocyte LD50
    • Outcome: LD(50) = 1.99 Gy
    • Conclusion: Oocyte tolerance is <2 Gy