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 and fertility in long‑term survivors with high‑grade bone and soft tissue tumors following chemotherapy. We reviewed issues related to fertility in 47 patients (24 men and 23 women) who had survived for >5 years. The median age at diagnosis was 18.0±8.9 years and the mean duration of follow‑up 11.0 years. We investigated the proportions of married subjects (number of married/total number of subjects) and fertile subjects (number who had fathered or conceived offspring/total number of subjects), the interval between first delivery and last chemotherapy, type of delivery, congenital deformities in the offspring and the association between cumulative dose of chemotherapeutic agents and subsequent reproduction. The final proportions of married and fertile subjects following sarcoma treatment were 36.2% (17/47) and 29.8% (14/47), respectively. Two subjects had fathered and 8 had conceived a total of 15 offspring. The proportion of fertile men was significantly lower compared to that of women. The mean interval between the last chemotherapy and the first delivery was 9.5 years. Of the 10 first births, 6 were normal transvaginal deliveries and 4 were caesarean sections (1 was a medical termination due to lung metastases, 1 was due to infected amniotic fluid caused by uterine myomas and 2 were performed due to abnormal rotation of the fetus). No offspring presented with congenital deformities. Fertile men had received smaller cumulative chemotherapeutic agent doses, particularly of ifosfamide, compared to those who had not fathered any offspring. In conclusion, infertility occurs more frequently in men compared to women following intensive chemotherapy. All the patients should be offered counseling regarding the potential risk of infertility prior to cancer treatment.

Correspondence to: Dr Manabu Hoshi, Department of Orthopedic Surgery, Osaka City University Graduate School of Medicine, 1‑4‑3 Asahi‑Machi, Abeno‑Ku, Osaka 545‑8585, Japan E‑mail: [email protected]‑cu.ac.jp

Key words: marriage, fertility, childbirth, chemotherapy, sarcoma

Introduction Over the last few years, with the advances in multidisciplinary therapy, including neoadjuvant chemotherapy (1,2), radiation therapy (3) and limb‑preserving surgery (4,5), the prognosis of high‑grade bone and soft tissue tumors has markedly improved, with a corresponding increase in the number of long‑term survivors. This increase has generated new problems in the form of latent treatment‑related adverse effects (6). Although several types of cancer occur predominantly in the elderly, a number of cancers arise prior to or during the reproductive age. For example, high‑grade bone and soft tissue tumors, such as osteosarcoma, Ewing's sarcoma and synovial sarcoma, most commonly occur in adolescents and young adults. Similar to healthy individuals, young survivors of such cancers would expect to get married and parent their own offspring (7). Amputation or limb‑preserving surgery are now routinely performed on patients with high‑grade bone and soft tissue tumors arising in the extremities. Limb‑preserving surgery with a wide margin has achieved positive outcomes; however, loss of limb function remains an unsolved problem. Marriage is an important goal for patients, from the physical as well as the psychological perspective (8). However, chemotherapeutic agents may cause gonadal toxicity and long‑term impairment of fertility, with infertility being one of the major long‑term adverse effects of chemotherapy. A number of studies have addressed gonadal toxicity following chemotherapy for hematological malignancies and testicular and breast cancers (9‑11); however, only a limited number of studies have addressed marriage and fertility in long‑term survivors of high‑grade bone and soft tissue sarcomas (12‑15). In this study, we aimed to investigate specific issues, such as the effect of the treatment 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 conception and whether the cumulative dose of chemotherapeutic agents are associated with subsequent fertility. Materials and methods Patients. Between September, 1985 and December, 2013, 272 patients aged 5 years after the initial treatment; a total of 47 patients fulfilled these criteria. The patients comprised 24 men and 23 women, with a median age at diagnosis ± standard deviation (SD) of 18.0±8.9 years (range, 4‑40 years). The median age ± SD at the last follow‑up was 33.0±9.5 years. The mean duration of the follow‑up was 11.0 years (range, 5.0‑28.0 years). The mean interval from the last chemotherapy to the last follow‑up was 10.1 years (range, 0.1‑27.3 years). The study protocol was approved by the Institutional Ethics Review Board of Osaka City University Graduate School of Medicine.

(0.7 mg/m 2; days 1‑2). Subsequently, following pretreatment with busulfan (4 mg/kg/day; days 1‑4) and L‑phenylalanine mustard (70 mg/m2; days 1‑3), the patients also received adjuvant peripheral blood stem cell transplantation. Patients with high‑grade soft tissue sarcomas received DOX and IFM‑based chemotherapy. The preoperative chemotherapy consisted of DOX (30 mg/m2 i.v.; days 1‑2) and IFM (2 g/m2 i.v.; days 1‑5) repeated three times at 3‑week intervals. Following tumor resection, two courses of the same regimen administered preoperatively were given at 3‑week intervals (20). For patients with relapse in pulmonary or other sites, second‑line chemotherapy comprised IFM (1,800 mg/m2/day; days 0‑4), carboplatin (400 mg/m 2/day; days 0‑1) and ETP (100 mg/m2/day; days 0‑4) with some modifications (21).

Treatment. In this series, the treatment protocol for patients with high‑grade bone and soft tissue sarcomas consisted of preoperative chemotherapy, wide resection and postoperative chemotherapy. Various surgical procedures, including amputation, rotationplasty and reconstruction with tumor prostheses, were performed. When the only option was amputation, this was performed after providing a full explanation and receiving the patient's informed consent. The chemotherapeutic protocols for high‑grade osteosarcoma were as follows: Between 1985 and  1996 (16), chemotherapy was administered preoperatively for an average of 3.5 months and postoperatively for 7.2 months. Adriamycin (DOX) was administered intravenously (i.v.) at a dose of 40‑60 mg/m 2 every 2‑3 weeks. Methotrexate (MTX) was administered i.v. at a dose of 200‑300 mg̸kg every 2 weeks. Cisplatin (CDDP) was administered i.v. at a dose of 100‑130 mg/m 2 every 3 weeks. The patients were divided into six groups according to the protocols of preoperative chemotherapy they had received: Group 1 had received DOX‑DOX‑MTX‑MTX, group 2 DOX‑CDDP‑DOX, group 3 CDDP‑CDDP‑MTX‑MTX, group 4 CDDP‑CDDP‑CDDP, group 5 MTX‑MTX‑CDDP‑CDDP and group 6 MTX‑MTXCDDP+DOX‑MTX‑MTX‑ CDDP‑DOX. Postoperative chemotherapy was repeated twice, using the same protocols as for the preoperative chemotherapy. Between 1997 and 2004, intensive doses of chemotherapy were administered according to the OOS‑D protocol (17), which was based on the T10 and T12 protocols with modifications (1,2). Two cycles of DOX 90 mg/m 2 plus CDDP 120 mg/m2 and ifosfamide (IFM) 15 g/m2 were administered as neoadjuvant chemotherapy and two cycles of DOX/CDDP and IFM plus two cycles of high‑dose MTX (10‑12 g/m 2) postoperatively. Between 2005 and 2013, caffeine‑assisted chemotherapy was introduced according to the K2 protocol (18). Patients with Ewing's sarcoma received high‑dose intensive chemotherapy, according to the European Ewing Tumor Working Initiative of National Groups 1999 protocol, with modifications (19). The six cycles of preoperative chemotherapy comprised vincristine (VCR; 1.4 mg/m2/day; day 1), IFM (3.0 g/m2/day; days 1‑3), DOX (20 mg/m2/day; days 1‑3) and etoposide (ETP; 150 mg/m2/day; days 1‑3). Postoperatively, the patients received one cycle of VCR (1.5 mg/m 2; day 1), cyclophosphamide (1.5 g/m 2; day 1) and actinomycin‑D

Classification by marriage. The proportion of married subjects was defined as number of married/total number of subjects and was investigated to clarify whether treatment exerted an effect on achieving marriage. To assess the true effect of treatment, the ‘true marriage proportion’ was calculated from the difference in the proportion of patients already married at presentation and at the final follow‑up. The associations between the proportion of married patients and gender (male vs. female), age [

Fertility following treatment of high-grade malignant bone and soft tissue tumors in young adults.

This study was conducted to investigate marriage and fertility in long-term survivors with high-grade bone and soft tissue tumors following chemothera...
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