Predictors Of Premature Ovarian Failure (Pof) In Young Women With Locally Advanced Rectal Cancer (Larc) Treated With Pelvic Radiation Therapy (Rt)

Pelvic RT is standard of care for patients with LARC. POF in pre-menopausal women is a possible side effect of this treatment. The predicted rise in rectal cancer in 2030 is 124% for patients 20-34 and 6% for patients 35-49 yrs. The purpose of our study was to evaluate the clinical and dosimetric predictors of POF in women younger than 50 years, treated with pelvic RT for LARC, including those who underwent ovarian transposition (OT). We retrospectively reviewed the medical records of women younger than 50 treated with pelvic RT for LARC at our institution between 2001-2019. Clinical [date of last menstrual period], and hormonal data [FSH, LH, and estradiol levels] were used to determine ovarian function. The ovaries and uterine body/fundus were contoured on the simulation scans by a single dosimetrist, and dose volume histograms were generated. Association of factors with POF was evaluated using Cox regression and optimal dosimetry cut-offs were based on maximum log rank statistic. The study identified 76 women who were premenopausal at time of RT. Median age at RT was 43 years [range 20-49]. Fertility preservation [FP] referral was done for 53% of the women, and 34% underwent OT. Neoadjuvant, concurrent and adjuvant chemotherapy was administered in 74%, 91%, and 34% of women respectively. Median RT dose was 50Gy in 25 fractions. Intensity modulated RT was used in 61% and 39% had 3D-RT. Only 26% had preservation of ovarian function, all in the OT group, and 1 woman carried a high-risk pregnancy 15 years after end of treatments, with premature birth at 25 weeks. Ovarian function was preserved in 77% of women who underwent OT. Median time from start of RT to POF was 17 days [7-54 days], and those patients did not resume menses >1 year after competing treatments. Compared to patients who underwent OT, those who haven’t had significantly higher means of ovarian doses (p<0.001): maximum dose [Right (R): 47.1 vs. 2.7 Gy, Left (L): 46.9 vs. 5.8 Gy], minimum dose [R: 40.6 vs. 0.5 Gy, L: 30.6 vs. 0.8 Gy], and mean dose [R: 45.1 vs. 1.1 Gy, L: 43.7 vs. 1.5 Gy]. Uterine doses were similar [medians >40Gy in both groups]. On univariable analysis, OT (HR: 0.05) and age at RT (HR: 1.18) were significantly associated with POF (p <0.001). At the optimal threshold for ovarian doses, patients with mean R ovarian dose >5.322 Gy had L>4.90 and bilateral >4.12 Gy and were significantly associated with higher risk of POF (HR 16.9, p<.001). However, on multivariable analysis, only OT remained independently associated with risk of POF. RT modality and chemotherapy had no significant effect. OT significantly reduced the risk of POF in our cohort, and should be considered in premenopausal women undergoing pelvic RT. Even with OT, ovarian doses approached 6Gy in some patients. We are currently investigating the role of protons therapy in further sparing the ovaries and uterus.