Fertility preservation with proton therapy – Pelvic Cancers

Every year, numerous girls and young adult women are diagnosed with cancer, facing the challenges of both a life-threatening illness and treatment-related hazards to their future fertility, hormone production, and psychosocial-sexual well-being. This is primarily an issue in cancers and tumours affecting the pelvis and lower spine which include gynecological cancers, soft tissue and bone sarcomas, chordomas and ependymomas. In view of this, there is a critical need for innovative radiation techniques to limit ovarian harm in women with abdominopelvic malignancies.

Photons utilized in conventional x-ray radiation (XRT) that attenuate and scatter through and beyond the target. Because of this "exit" dosage, XRT aiming targeting cancers in the pelvis, abdomen, or lower spinal column will invariably deliver radiation to the ovaries. Advanced methods, such as intensity-modulated radiotherapy (IMRT), are now utilized to decrease high-dose exposure to neighboring healthy tissues, but as a result, low- and moderate-dose radiation is administered to a much broader region.

Another strategy to radiation involves the use of protons, which can greatly preserve healthy tissue due to the fact that protons have a set maximum penetration depth, known as the Bragg peak, at which the bulk of their energy is released over a few millimeters. Beyond the spread-out Bragg peak (SOBP), a proton beam has no energy and gives no "exit" dosage, hence using Proton therapy (PT) instead of XRT can result in a significant reduction in toxicity to surrounding healthy tissue.

Germ cells in reproductive organs are highly vulnerable to chemotherapy and radiation therapy, frequently resulting in premature ovarian insufficiency (POI) owing to follicle death. As a result, the primordial follicle might be used as a sensitive marker of radiation-induced degradation in the distal proton spread-out Bragg peak or from secondary neutrons.

In a recently published article, Gross et al (1) found that when mouse ovaries were bombarded with either XRT/GRT or PRT, the ovarian follicles were destroyed depending on the strength of the radiation. In addition, the ovaries in the middle of the SOBP plateau had the most significant ovarian damage. Ovarian follicles were retained in the mouse when PRT was used and the ovaries were positioned enough beyond the SOBP. The major findings of the animal study were also duplicated using ex vivo whole-ovary irradiation and precise determination of ovary location relative to the SOBP. PT did not cause unintended harm beyond the SOBP in this investigation, with intact primordial follicles in the ovary (Gross et al). This indicates the role of PT addressing abdominopelvic malignancies in young women, though more clinical research is needed.

My team’s experience in ovarian preservation using proton therapy at APCC has been on similar lines. The images above represent the proton therapy plan of a thin built young lady suffering from a sacral chordoma.

Chordomas require a high dose of radiation, 70 Gy or more while the ovaries should receive less than 2-3 Gy. PT allowed ovarian function preservation in this patient, in spite of a thin anteroposterior separation, 16-17 cm and the fact that only the right ovary could be transposed anteriorly.

The patient’s ovarian function was maintained normally post treatment and happily, ovarian follicles were noted on MRI in both the transposed right ovary as well as the left ovary, which was close to the target but outside the SOBP.

Reference:

Gross, J. P., Kim, S.-Y., Gondi, V., Pankuch, M., Wagner, S., Grover, A., Luan, Y., & Woodruff, T. K. (2021). Proton Radiotherapy to Preserve Fertility and Endocrine Function: A Translational Investigation. In International Journal of Radiation Oncology*Biology*Physics (Vol. 109, Issue 1, pp. 84–94). Elsevier BV. https://doi.org/10.1016/j.ijrobp.2020.07.2320