Proton radiotherapy to preserve fertility and endocrine function: a translational investigation Proton therapy spares ovarian function and reserve in mice.

Abstract Purpose Photon radiotherapy (x-ray radiotherapy, XRT and gamma-ray radiotherapy, GRT) of tumors close to ovaries causes reproductive and endocrine sequelae due to ovarian primordial follicle depletion. Given its finite range, proton radiotherapy (PRT) may preserve ovarian function when ovaries are positioned distal to the spread-out Bragg peak (SOBP) in tumors of the abdominopelvic region. This study compared anti-Mullerian hormone (AMH) levels (a biomarker of ovarian function) and primordial follicle survival following in vivo mouse pelvic GRT vs. PRT. Methods 124 female prepubertal mice received sham, GRT or PRT with ovaries positioned at various depth with respect to the proton SOBP, with single doses of 1.8 or 0.2 Gy. AMH was measured at baseline, 1-, 3-, and 8-weeks post-treatment, and the total number of surviving primordial follicles was counted. Multivariable linear mixed-effects modeling was used to assess the relationship between radiotherapy modality and dose on AMH and primordial follicle survival. Results For ovaries beyond the SOBP, ovarian function (p=0.5) and ovarian primordial follicle (OPF) (p=1.0) were spared relative to sham controls. For ovaries in the SOBP plateau, ovarian function and primordial follicle reserve 8-weeks post-treatment were reduced for all groups: 1.8 Gy GRT (sAMH = -4.9 ng/ml, sOPF = -728.2/animal), 1.8 Gy (relative biological effectiveness, RBE =1.1) PRT (sAMH = -5.1 ng/ml, sOPF = -728.2/animal), 0.2 Gy GRT (sAMH = -2.5 ng/ml, sOPF = -595.1/animal), and 0.2 Gy (RBE = 1.1) PRT (sAMH = -3.0 ng/ml, sOPF = -555.4/animal) relative to sham controls (all differences p Conclusions This study used an animal model to demonstrate the safety of proton therapy in sparing fertility. Ovaries positioned beyond the SOBP during PRT maintain ovarian reserve, suggesting that a proton beam has no energy and exit dose beyond SOBP. This study proposed that proton therapy is much safer than photon radiotherapy to protect ovarian follicles with the same dose, and supports further testing of proton therapy for abdominopelvic tumors in young women.