MOLECULAR AND CLINICAL ONCOLOGY 3: 367-374, 2015 Fertility following treatment of high‑grade malignant bone and soft tissue tumors in young adults MANABU HOSHI, MASATSUGU TAKAMI, MAKOTO IEGUCHI, MASANARI AONO, JUN TAKADA, NAOTO OEBISU, TADASHI IWAI and HIROAKI NAKAMURA Department of Orthopedic Surgery, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan Received July 28, 2014; Accepted November 18, 2014 DOI: 10.3892/mco.2014.474 Abstract. This study was conducted to investigate marriage Introduction and fertility in long-term survivors with high-grade bone and soft tissue tumors following chemotherapy. We Over the last few years, with the advances in multidisciplinary reviewed issues related to fertility in 47 patients (24 men therapy, including neoadjuvant chemotherapy (1,2), radiation and 23 women) who had survived for >5 years. The median therapy (3) and limb-preserving surgery (4,5), the prognosis of age at diagnosis was 18.0±8.9 years and the mean duration high-grade bone and soft tissue tumors has markedly improved, of follow-up 11.0 years. We investigated the proportions of with a corresponding increase in the number of long-term married subjects (number of married/total number of subjects) survivors. This increase has generated new problems in the and fertile subjects (number who had fathered or conceived form of latent treatment-related adverse effects (6). Although offspring/total number of subjects), the interval between first several types of cancer occur predominantly in the elderly, a delivery and last chemotherapy, type of delivery, congenital number of cancers arise prior to or during the reproductive deformities in the offspring and the association between age. For example, high-grade bone and soft tissue tumors, such cumulative dose of chemotherapeutic agents and subsequent as osteosarcoma, Ewing's sarcoma and synovial sarcoma, most reproduction. The final proportions of married and fertile commonly occur in adolescents and young adults. Similar to subjects following sarcoma treatment were 36.2% (17/47) and healthy individuals, young survivors of such cancers would 29.8% (14/47), respectively. Two subjects had fathered and expect to get married and parent their own offspring (7). 8 had conceived a total of 15 offspring. The proportion of Amputation or limb-preserving surgery are now routinely fertile men was significantly lowercompared to that of women. performed on patients with high-grade bone and soft tissue The mean interval between the last chemotherapy and the first tumors arising in the extremities. Limb-preserving surgery delivery was 9.5 years. Of the 10 first births, 6 were normal with a wide margin has achieved positive outcomes; however, transvaginal deliveries and 4 were caesarean sections (1 was loss of limb function remains an unsolved problem. Marriage a medical termination due to lung metastases, 1 was due to is an important goal for patients, from the physical as well as infected amniotic fluid caused by uterine myomas and 2 were the psychological perspective (8). However, chemotherapeutic performed due to abnormal rotation of the fetus). No offspring agents may cause gonadal toxicity and long-term impairment presented with congenital deformities. Fertile men had received of fertility, with infertility being one of the major long-term smaller cumulative chemotherapeutic agent doses, particularly adverse effects of chemotherapy. A number of studies have of ifosfamide, compared to those who had not fathered any addressed gonadal toxicity following chemotherapy for hema- offspring. In conclusion, infertility occurs more frequently in tological malignancies and testicular and breast cancers (9-11); men compared to women following intensive chemotherapy. however, only a limited number of studies have addressed All the patients should be offered counseling regarding the marriage and fertility in long-term survivors of high-grade potential risk of infertility prior to cancer treatment. bone and soft tissue sarcomas (12-15). In this study, we aimed to investigate specific issues, such as the effect of the treat- ment of high-grade bone and soft tissue tumor on marriage and fertility of long-term survivors, whether it is safe for these patients to father or conceive offspring, the optimal interval between the completion of the last chemotherapy and concep- tion and whether the cumulative dose of chemotherapeutic Correspondence to: Dr Manabu Hoshi, Department of Orthopedic agents are associated with subsequent fertility. Surgery, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-Machi, Abeno-Ku, Osaka 545-8585, Japan Materials and methods E-mail: [email protected] Patients. Between September, 1985 and December, 2013, Key words: marriage, fertility, childbirth, chemotherapy, sarcoma 272 patients aged <40 years at diagnosis were treated for high-grade bone and soft tissue tumors at Osaka City 368 HOSHI et al: FERTILITY FOLLOWING CHEMOTHERAPY FOR SARCOMA University Hospital (Osaka, Japan). The inclusion criteria for (0.7 mg/m2; days 1-2). Subsequently, following pretreatment this study were male or female patients who had been diag- with busulfan (4 mg/kg/day; days 1-4) and L-phenylalanine nosed with high-grade malignant bone or soft tissue tumors, mustard (70 mg/m2; days 1-3), the patients also received adju- received chemotherapy and survived for >5 years after the vant peripheral blood stem cell transplantation. initial treatment; a total of 47 patients fulfilled these criteria. Patients with high-grade soft tissue sarcomas received The patients comprised 24 men and 23 women, with a median DOX and IFM-based chemotherapy. The preoperative chemo- age at diagnosis ± standard deviation (SD) of 18.0±8.9 years therapy consisted of DOX (30 mg/m2 i.v.; days 1-2) and IFM (range, 4-40 years). The median age ± SD at the last follow-up (2 g/m2 i.v.; days 1-5) repeated three times at 3-week intervals. was 33.0±9.5 years. The mean duration of the follow-up was Following tumor resection, two courses of the same regimen 11.0 years (range, 5.0-28.0 years). The mean interval from administered preoperatively were given at 3-week inter- the last chemotherapy to the last follow-up was 10.1 years vals (20). (range, 0.1-27.3 years). For patients with relapse in pulmonary or other sites, The study protocol was approved by the Institutional Ethics second-line chemotherapy comprised IFM (1,800 mg/m2/day; Review Board of Osaka City University Graduate School of days 0-4), carboplatin (400 mg/m2/day; days 0-1) and ETP Medicine. (100 mg/m2/day; days 0‑4) with some modifications (21). Treatment. In this series, the treatment protocol for patients Classification by marriage. The proportion of married with high-grade bone and soft tissue sarcomas consisted of subjects was defined as number of married/total number of preoperative chemotherapy, wide resection and postoperative subjects and was investigated to clarify whether treatment chemotherapy. Various surgical procedures, including amputa- exerted an effect on achieving marriage. To assess the true tion, rotationplasty and reconstruction with tumor prostheses, effect of treatment, the ‘true marriage proportion’ was calcu- were performed. When the only option was amputation, this lated from the difference in the proportion of patients already was performed after providing a full explanation and receiving married at presentation and at the final follow‑up. Theassocia - the patient's informed consent. tions between the proportion of married patients and gender The chemotherapeutic protocols for high-grade osteo- (male vs. female), age [<20 vs. ≥20 years (in Japan, individuals sarcoma were as follows: Between 1985 and 1996 (16), aged ≥20 years are officially considered to be adults)], type of chemotherapy was administered preoperatively for an tumor (bone vs. soft tissue tumor) and surgical procedure were average of 3.5 months and postoperatively for 7.2 months. also investigated. The surgical procedures were classified as Adriamycin (DOX) was administered intravenously (i.v.) amputation or limb preservation groups at the last follow-up. at a dose of 40-60 mg/m2 every 2-3 weeks. Methotrexate One patient who had undergone rotationplasty was classified (MTX) was administered i.v. at a dose of 200-300 mg̸kg into the amputation group. every 2 weeks. Cisplatin (CDDP) was administered i.v. at a dose of 100-130 mg/m2 every 3 weeks. The patients were Classification by fertility. The fertility of the 47 patients was divided into six groups according to the protocols of preopera- also investigated. Childbirth was selected as the end-point of tive chemotherapy they had received: Group 1 had received fertility, as it was considered important to ascertain whether DOX-DOX-MTX-MTX, group 2 DOX-CDDP-DOX, group 3 the offspring, particularly the first‑born, of subjects who had CDDP-CDDP-MTX-MTX, group 4 CDDP-CDDP-CDDP, received chemotherapy were normal. The proportion of fertile group 5 MTX-MTX-CDDP-CDDP and group 6 MTX-MTX- subjects was defined as the number of patients fathering or CDDP+DOX-MTX-MTX-CDDP-DOX. Postoperative conceiving offspring/total number of patients. As some chemotherapy was repeated twice, using the same protocols as patients already had children prior to treatment, the data for the preoperative chemotherapy. on fertility at the final follow‑up did not represent the true Between 1997 and 2004, intensive doses of chemotherapy proportion of fertile subjects. To determine the true effect of were administered according to the OOS-D protocol (17), chemotherapy on fertility, the ‘true fertility proportion’ was which was based on the T10 and T12 protocols with modi- calculated as the difference between the proportion of patients fications (1,2). Two cycles of DOX 90 mg/m2 plus CDDP with offspring at presentation and with offspring at the final 120 mg/m2 and ifosfamide (IFM) 15 g/m2 were administered follow-up.