Surgery and Beyond: The Evolution of Oncofertility

In the 1950s, the first surgical procedure salvaging female fertility in a cancer patient involved an ovarian transposition surgery in Louisiana. This required the repositioning of ovaries outside the radiation field while maintaining native blood supply. Since then, the field of oncofertility has grown immensely encompassing a multidisciplinary approach to fertility requiring the expertise of the primary surgeon/oncologist, the reproductive endocrinologist that would work to optimize fertility in this setting, and the maternal–fetal medicine specialist that would monitor the higher-risk pregnancy to follow. Oncofertility encompasses two umbrellas of surgical management to maintain functional reproductive organs, and at times, the two overlap. This includes: (1) procedures for the primary surgical management of a gynecological malignancy affecting a specific reproductive organ(s) and (2) procedures that salvage fertility in the midst of another treatment such as gonadotoxic chemotherapy or localized radiation for any malignancy affecting the pelvic region.

In gynecology, many of the women affected by a primary diagnosis of a pelvic malignancy are well into their reproductive years. Women aged 35–45 are at risk of being diagnosed with over 50% of cervical cancers, 7% of ovarian cancers, and 5% of uterine cancers. This imposes a big impact on live births, considering that as of 2020, approximately 20% of all pregnancies occur after age 35. This edition will go over the currently available procedures established to salvage fertility of pelvic malignancies and their accompanying oncologic and reproductive outcomes.

For early-stage cervical cancers, fertility options are surgical. This includes procedures to excise the affected portion of the cervix via cervical conization, simple vs radical vaginal trachelectomy, radical abdominal trachelectomy, or radical laparoscopic/robotic trachelectomy. In the late 1980s, Dargent established the radical vaginal trachelectomy as the first fertility-sparing procedure for cervical cancer in France. By 1994, he had published the first article describing the procedure and short-term outcomes. Over time and for the appropriate candidate, the procedure evolved to be less radical by omitting removal of the parametria and keeping any unaffected cervical tissue. Under guidance from new prospective trials, cervical cancers are now being treated with cervical conization as a safe and effective strategy for tumors ≤2 cm with low-risk features. For tumors greater than 2 cm, abdominal radical trachelectomy remains the preferred fertility-sparing modality to obtain wider parametrial margins, though pregnancy rates may be lower. For patients who do require a radical trachelectomy procedure, minimally invasive modalities such as laparoscopy or robotics do not appear to increase risk of recurrence or worsen survival, unlike the significantly increased risk noted with minimally invasive radical hysterectomy. Neoadjuvant therapy with subsequent fertility-sparing surgery is being actively studied as a potential strategy for expanding fertility candidacy to a broader number of patients.

In lower-risk uterine cancers, fertility-sparing is largely accomplished via medication that acts to reverse the cancerous effects on the uterine lining. This is accomplished through locally or systemically delivered hormonal modulating therapy that can prevent further cancer formation and revert the presence of active cancer. The primary medication used is progesterone, which can help revert the effects of excess estrogen causing cancerous cells. Other anti-hormonal medications such as tamoxifen and everolimus have been used in conjunction to optimize the effects of reversal. If this reversal is confirmed and durable, fertility can then be pursued by redacting the active treatment. Evidence for focal resection of intrauterine lesions using resectoscopic techniques has been reported with some success. New age weight-loss medications such as GLP-1 agonists are being actively studied for their potential primary and secondary prevention of uterine cancers. Whole uterine transposition surgeries were described as early as 2017, when Dr. Ribiero performed the first case in a young patient with colorectal cancer out of Brazil. The uterus was mobilized along with the ovaries to the mid-abdomen. It was temporarily connected to the umbilicus, allowing it to be utilized as an outflow tract for menses and was subsequently re-anastomosed to the pelvis once primary surgery and radiation were undertaken. Even if eventual hysterectomy is pursued, fertility can also be maintained through egg/embryo harvesting either before or after surgery pending ovarian removal. If radiation/adjuvant therapy is anticipated in addition to surgery, ovaries can be explanted and frozen, repositioned, or transpositioned outside of the radiation field for later egg/embryo harvesting. In 1999, the first ovarian orthotopic tissue reimplantation was described. Live births have been reported for both orthotopic and heterotopic reimplantation, although the latter can carry higher risk due to native tissue distortion from localized treatment such as radiation.

For ovarian cancers, the surgical approach is highly variable based on histotype, and surgical salvage can be difficult, as removal of all reproductive organs can have a prognostic and therapeutic effect. In patients with non-epithelial subtypes, such as granulosa cell, removal of a single ovary can be considered, leaving the other ovary and uterus in-situ. If both ovaries are to be removed, cryopreservation of the ovarian tissue can be undertaken for later reimplantation. However, this has to be weighed against the theoretical risk of cancer recurrence with reimplantation. In those patients requiring bilateral ovarian excision, presurgical egg/embryo harvesting can also be undertaken when malignancy is suspected.

Several medical and surgical options are currently available to patients desiring fertility preservation, and many continue to evolve as treatment strategies become more advanced. It can be difficult to alter surgical approaches and techniques at the expense of worsening oncologic outcomes. Therefore, the biggest area for exploration will be within neoadjuvant or adjuvant therapies by which surgical candidacy can be optimized. This would allow a growing number of patients to qualify for fertility preservation that may not have traditionally done so with surgery alone. The future may one day include whole organ preservation with or without the need for reimplantation and even the potential of cloning of reproductive tissue.