Student The College of New Jersey Ewing, New Jersey, United States
Introduction: Two online calculators exist to predict primary ovarian insufficiency (POI) in pediatric cancer survivors based on age of radiation treatment and dose of radiation. Prediction models allow healthcare providers to anticipate health adversities, like delayed puberty or infertility, following radiation treatment. The Wallace-Kelsey Model is a mechanistic model utilizing a natural non-growing follicle (NGF) depletion double gaussian curve and a radiosensitivity of the human oocyte to estimate the age of ovarian insufficiency. The Childhood Cancer Survivor Study (CCSS) Model is a logistic regression statistical model based on clinical outcomes of childhood cancer survivors. The two models have large discrepancies making it difficult for providers to accurately counsel patients and their families. The Wallace-Kelsey model can be tuned to better match the CCSS model by changing the LD50 from 2 Gy to 7 Gy. Increased understanding of the effects of radiation on pediatric cancer survivors provides better counseling and access to options for patients requiring radiation therapy. The need for an analytical POI calculator that matches with patient outcomes remains prevalent.
Materials and
Methods: Each group has implemented a web-based calculator as a resource for physicians. The Wallace-Kelsey calculator takes the patients' age and dose of radiation therapy and provides an estimate of the age of POI diagnosis. The CCSS calculator takes chemo and radiation doses, the patient's age of radiation therapy, and whether or not the patient had a stem cell transplant to provide a percent risk of POI for each age between 21 and 40. To make an equivalent comparison, an assumption was made that no chemotherapy or stem cell transplant would be considered. Since the Wallace-Kelsey calculator is based on the mean follicle depletion curve, the output age was taken to be 50% risk at that age. To directly compare the two online calculators, the CCSS model was converted to a mechanistic model by using the age for which 50% risk occurred for each dosage. The two models’ outputs were compared for each radiation treatment age, considering only output ages for which the CCSS model is valid. To fit the Wallace-Kelsey model to the CCSS model, potential LD50s evaluated were 4 to 9 Gy, based on a prior estimation of an LD50 of 4 Gy. All differences were considered using a normalized root mean square error.
Results, Conclusions, and Discussions: Large discrepancies exist between the Wallace-Kelsey and CCSS prediction models (Figure). The Wallace-Kelsey model requires less radiation dose to produce POI than the CCSS model. Both models span approximately 7 Gy in the range of interest but do not overlap. The CCSS model shows that sparing 3 Gy of radiation to the less exposed ovary can be the difference between a relatively normal fertility window and no chance of normal pregnancy. The models are most similar at age 16 (NRMSE =1.780), and most different at age 1(NRMSE = 2.413). Following the trialing of different LD50 values (Figure 2), an LD50 of 8 Gy minimized the root mean square error for ages 1-7 and 7 Gy minimized for ages 8-21.
The Wallace-Kelsey model does not match the CCSS model. For a ten-year-old patient treated with 13 Gy of radiation to the less effected ovary, the CCSS model predicts a POI diagnosis at age 39. The Wallace-Kelsey model under the same conditions predicts POI at age 15. The updated model with LD50 of 7 Gy predicts 35, a far closer estimate. The Wallace-Kelsey model was developed based on an LD50 of 2 Gy. The cohort used to determine this value was women with leukemia treated with total body irradiation and chemotherapy including alkylating agents and cytosine (n = 8). Both alkylating agents and cytosine have been shown to have gonadotoxic effects. Because of this, there is a possibility that Wallace and Kelsey have overestimated the effect of radiation on the oocytes. A future study should include a re-evaluation of the LD50 with a large cohort of patients with various radiation-treated pediatric malignancies.
Acknowledgements (Optional): St Jude Department of Radiation Oncology
