Proton Radiotherapy to Preserve Fertility and Endocrine Function: A Translational Investigation

Abstract

Photon radiation therapy (x-ray radiation therapy [XRT] and gamma-ray radiation therapy [GRT]) of tumors close to ovaries causes reproductive and endocrine sequelae due to ovarian primordial follicle depletion. Given its finite range, proton radiation therapy (PRT) can 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-Müllerian hormone (AMH) levels (a biomarker of ovarian function) and primordial follicle survival after invivo mouse pelvic GRT versus PRT. One hundred twenty-four 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 after treatment, and the total number of surviving primordial follicles was counted. Multivariable linear mixed-effects modeling was used to assess the relationship between radiation therapy modality and dose on AMH and primordial follicle survival. For ovaries beyond the SOBP, ovarian function (P = .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 after treatment were reduced for all groups: 1.8 Gy GRT (βAMH = -4.9 ng/mL; βOPF = -728.2/animal), 1.8 Gy (relative biological effectiveness [RBE] = 1.1) PRT (βAMH = -5.1 ng/mL; βOPF = -728.2/animal), 0.2 Gy GRT (βAMH = -2.5 ng/mL; βOPF = -595.1/animal), and 0.2 Gy (RBE = 1.1) PRT (βAMH = -3.0 ng/mL; βOPF = -555.4/animal) relative to sham controls (all differences P < .001). This study uses 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 proposes that proton therapy is much safer than photon radiation therapy to protect ovarian follicles with the same dose, and it supports further testing of proton therapy for abdominopelvic tumors in young women.