(P 06) GONADOTOXICITY RISK EVALUATION AND REPRODUCTIVE OUTCOMES IN YOUNG ADULTS WITH SOFT TISSUE AND BONE SARCOMA TREATED WITH CHEMOTHERAPY AND/OR RADIATION THERAPY: A SINGLE CENTER RETROSPECTIVE STUDY

Objective: With improved survivorship care, evaluation of late effects of cancer treatment has assumed increasing importance, particularly for patients (pts) with cancer diagnosed at younger ages like onco-hematologic neoplasms and sarcomas. The risk of gonadotoxicity has been well established within increasing cumulative doses of chemotherapy (CT) with alkylating agents as well as direct radiotherapy (RT) to the gonads. A cyclophosphamide equivalent dosing (CED) score to standardize cumulative dosing across protocols using various alkylating agents via a mathematical calculation was developed in a pediatric population (Green et al, 2014). Platinum agents are not currently included in this formula. Risk of infertility is commonly classified as low (< 20%), intermediate (21%-80%), or high (>80%). PanCareLIFE Consortium and the International Late Effects of Childhood Cancer Guideline Harmonization Group have recommended sperm cryopreservation for male pts; oocyte and embryo cryopreservation in female pts. Ovarian tissue cryopreservation is considered experimental, and there is conflicting evidence to support gonadotropin-releasing hormone agonists (GnRHa) and other means of ovarian function suppression for fertility preservation, but these could be considered if other strategies are not feasible. Data on gonadotoxicity from CT and RT for sarcoma are scarce, and commonly reported for adolescents and young adults (AYA) up to the age of 25 years. As the age for first child advances, better assessment and prevention of gonadotoxicity in young adults up to the age of 40 years treated for sarcoma is therefore of utmost importance.

Methods: We retrospectively reviewed all consecutive pts aged < 40 years that received platinum (Plt) or ifosfamide (Ifo) based chemotherapy at Istituto Oncologico Veneto for bone (BS) or soft tissue sarcoma (STS) from January 2000 to June 2021. Date of diagnosis, age at diagnosis, histological data, site of primary tumour, chemotherapy regimens, response to treatment were retrieved by a prospectively maintained database. Fertility-related discussion and acceptance of fertility preservation, data of semen samples, menstrual cycle, use of hormone replacement therapy, eventual pregnancies were collected from electronic health records. CED was calculated through the equation: CED (mg/m2)=1·0 (cumulative cyclophosphamide dose [mg/m2]) + 0·244 (cumulative ifosfamide dose [mg/m2]) + 0·857 (cumulative procarbazine dose [mg/m2]) + 14·286 (cumulative chlorambucil dose [mg/m2]) + 15·0 (cumulative carmustine dose [mg/m2]) + 16·0 (cumulative lomustine dose [mg/m2]) + 40 (cumulative melphalan dose [mg/m2]) + 50 (cumulative thiotepa dose [mg/m2]) + 100 cumulative chlormethine dose [mg/m2]) + 8·823 (cumulative busulfan dose [mg/m2]). Exposure was categorized in three groups: low CED < 4000 mg/mq; intermediate CED 4000-8000 mg/mq; high CED >8000 mg/mq. Platinum exposure was categorized in higher or lower than 500 mg/mq.

Results: Out of 218 young patients, fifty-nine pts were eligible for the analysis, after excluding pts presenting with metastatic disease upfront or who developed metastases in first year after diagnosis. Thirty-seven (62.7%) were male. Median age at diagnosis was 26 years (range 15-39). Diagnosis was STS in 39 pts and BS in 20 pts. Pts’ and disease characteristics are reported in Table 1.
Fertility related discussion was conducted with 46 pts (78%) and 35 pts underwent fertility preservation strategies (76%), eleven pts declined. Thirteen female pts received GnRHa, one pt estroprogestinic pill. All but two pts received CT, nineteen pts in neoadjuvant setting, eighteen pts in adjuvant setting, twenty pts both in neoadjuvant and adjuvant setting. Twenty-eight pts were irradiated in lower abdomen, pelvis or upper thigh. Detailed data on CT regimens are reported in Table 1.
Of all patients treated with CT, Epirubicin and Ifosfamide was the regimen in 28 pts (49.1%), the others received either osteosarcoma-like regimens (combinations of Cisplatin, Doxorubicin, Methotrexate and Ifosfamide) or Ewing-like regimens (combinations of Ifosfamide-Cyclophosphamide-Vincristine-doxorubicin-Dactinomycin-Etoposide). One pt with sacral Ewing sarcoma underwent autologous peripheral stem cell transplantation with Busulphan and Melphalan conditioning regimen. Out of 22 female pts, thirteen (59%) had resumption of menstrual cycle (MC), six amenorrhoeic pts were placed in hormone replacement therapy (HRT), 2 pts experimented amenorrhea without HRT, for 1 pt data is not known. Median age was 23 years for pts who have resumed MC and 22 years for amenorrhoic pts. Details are reported in Table 2. One pt in the high CED group and one in the intermediate CED group had spontaneous full-term uneventful pregnancies.
For male pts, post CT semen samples were available in 11 cases. Abnormal findings were present in 9 pts (4 oligospermia, 3 teratospermia, 2 azoospermia). Results are reported in Table 3.

Conclusion: Chemotherapy regimens for treatment of young pts with STS and BS involve the frequent use of high doses of cisplatin and alkylating agents, sometimes in addition to RT with risk of gonadal irradiation. Our data confirm the lack of a clear threshold for risk of menstrual/semen disorders, and consequent possible higher risk of infertility. Long-term fertility issues associated to the treatment for sarcoma should be discussed in all adults in fertile age, along with providing essential information on fertility preservation strategies. Prospective studies on refining risk classification as well as risk associated with platinum exposure in young adults with sarcoma, along with prevention and management of gonadotoxicity are needed.

Table 1 abstract Fertility.doc

Table 2 abstract fertility.docx

Table 3 abstract Fertility.doc