Recently Intensified Chemotherapy for High-grade Osteosarcoma May Affect Fertility in Long-term Male Survivors

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1 Recently Intensified Chemotherapy for High-grade Osteosarcoma May Affect Fertility in Long-term Male Survivors TSUKASA YONEMOTO, TAKESHI ISHII, YOSHIO TAKEUCHI, YOKO HAGIWARA, SHINTARO IWATA and SHIN-ICHIRO TATEZAKI Division of Orthopaedic Surgery, Chiba Cancer Center, Nitona-cho, Chuo-ku, Chiba, , Japan Abstract. Aim: To investigate the marital status and fertility in long-term survivors of high-grade osteosarcoma. Patients and Methods: We surveyed the marital rate (number of married persons/total number of persons) in 46 long-term survivors of osteosarcoma who were treated in our hospital between 1976 and In addition, we examined the fertility rate (number of persons having offspring/number of married persons) in 29 married patients. The participants were divided into 2 groups: one group (MC) in which moderate-dose chemotherapy was performed between 1976 and 1986; and another group (IC) in which intensive-dose chemotherapy was performed between 1987 and In each group, the fertility rate was investigated. As controls, we surveyed the marital and fertility rates in 52 siblings of the patients. Results: In the patients, the marital rate was 63.0% (29/46). There was no significant difference in the marital rate between the patients and their siblings. In the patients, the overall fertility rate was 58.6% (17/29). The fertility rate of male patients in the IC group (16.7%, 1/6) was significantly lower than that of their male siblings (76.5%, 13/17) (p=0.018). Conclusion: These results suggest that recently intensified chemotherapy for osteosarcoma affects fertility in long-term male survivors. The prognosis of high-grade osteosarcoma has improved markedly and the number of long-term survivors has increased in recent years thanks to multidisciplinary therapy centering around chemotherapy (1). With an increase in the number of long-term survivors of osteosarcoma, treatment-related late side-effects such as secondary malignant neoplasm and infertility have come to pose a new problem (2-4). Correspondence to: Tsukasa Yonemoto, MD, Division of Orthopaedic Surgery, Chiba Cancer Center, 666-2, Nitona-cho, Chuo-ku, Chiba, , Japan. Tel: , Fax: , tyonemot@chiba-cc.jp Key Words: Osteosarcoma, marriage, fertility, surgery, chemotherapy. Previously, we surveyed the marital status and fertility in longterm survivors of osteosarcoma who were treated in our hospital. We reported that the marital rate was lower in male patients, and that chemotherapy for osteosarcoma had little influence on the fertility of patients or the health of their offspring (5). Since the previous survey, advances in treatment for osteosarcoma, including the introduction of the chemotherapeutic agent ifosfamide, have further improved the prognosis. For surgery, limb-sparing surgery has been positively selected and affected-limb function has also improved. Thus, intensified treatment for osteosarcoma may have altered the influence on the marital status and fertility in long-term survivors. In this study, we further studied the patients enrolled in the previous survey and patients treated in our hospital after it. Patients and Methods Patients. There were 142 patients who were treated for high-grade osteosarcoma at our hospital from 1976 to 2002 and who were younger than 25 years at initial presentation. Of them, 62 patients survived disease-free for more than 5 years after the end of treatment and were older than 25 years at the time of survey. We conducted a questionnaire survey regarding marriage and fertility by mail in 62 patients. Responses to the questionnaire were obtained from 46 of these, resulting in a response rate of 74.2%. These 46 patients were enrolled as the subjects of this study. Clinical characteristics of the patients are shown in Table I. As controls, we investigated their 52 siblings aged more than 25 years. They consisted of 27 males and 25 females. Their ages at the time of survey ranged from 25 to 47 years (median: 35.3 years). Prior to this study, the protocol was approved by the Institutional Research Board. Written informed consent was obtained from each patient or sibling. Therapeutic policy toward high-grade osteosarcoma. The surgical therapy given at our hospital will be described briefly. Several surgical methods such as amputation, rotationplasty, arthroplasty and arthrodesis are available. At our hospital, as many surgical options as possible were given to patients, and the selection of the surgical method was decided by the patient. Where there was no option but amputation, we carried out amputation after having given a full explanation until the patients were ready to accept it /2009 $

2 Table I. Clinical characteristics of the patients. Eligible patients Respondents (62 patients) (46 patients) Gender 30 males and 20 males and 32 females 26 females Age at initiaal presentation (years) (median, 14.7) ( median, 15.5) Age at survey (years) (median, 36) (median, 36) Site of the primary lesion Distal femur Proximal tibia Proximal humerus 8 8 Ilium 3 3 Proximal fibula 3 1 Distal radius 1 1 Proximal femur 1 - Distal tibia 1 - State of the affected limb Amputation Rotationplasty Limb-sparing Resection alone 9 8 TJA VFG 4 3 Time after the end of treatment (months) (median, 235) (median, 225) TJA: Total joint arthroplasty; VFG: vascularized fibular graft. The changes in chemotherapy for high-grade osteosarcoma at our hospital will be described briefly. Adjuvant chemotherapy including doxorubicin and high-dose methotrexate was started from Cisplatin from 1982, BCD (bleomycin, cyclophosphamide and dactinomycin) from 1987 and ifosfamide from 1991 were each added to adjuvant chemotherapy. Until 1986, moderate-dose chemotherapy had been administered. Since 1987, intensive-dose chemotherapy using the T10 and T12 protocols (6, 7) as a guide has been given. For patients who unfortunately developed pulmonary metastasis, second-line chemotherapy was administered after aggressive thoracotomy. HELP (vindesine, ifosfamide and cisplatin) regimen (8) and etoposide-cyclophosphamide regimen (9) were administered as second-line chemotherapy. Age at first marriage and offspring. We investigated the age at first marriage and at having offspring in long-term survivors of osteosarcoma. As controls, we examined the median age at first marriage in Japanese and first delivery in Japanese females as given by 2005 vital statistics of the Ministry of Health, Labour and Welfare of Japan (10). Influence of surgical procedures on marriage. To examine whether treatment for osteosarcoma influences the marital Table II. Age at first marriage and first offspring (years). Age at first marriage Age at first offspring Male patients (median, 29.8) (median, 29.5) n=11 n=4 (29.8*) Female patients (median, 25.1) (median, 26.0) (28.0*) (28.8*) n=18 n=13 Total (median, 26.7) (median, 26.8) n=29 n=17 *The median age in Japanese according to 2005 vital statistics of Japan. status, we investigated the marital rate (number of married persons/total number of persons) in 46 long-term survivors. As controls, we examined this rate in their siblings aged more than 25 years (n=52). Initially, we compared the marital rate between male (n=20) and female (n=26) patients. To examine the influence of surgical procedures on marriage, the patients were divided into 2 groups according to the state of the affected-limb at the time of survey: amputation (n=25) and limb-sparing (n=21) groups. The marital rate was investigated between the two groups. The former group included 7 patients who underwent knee rotationplasty and 11 who underwent amputation during the clinical course after limb-sparing surgery. The latter group included 10 patients who underwent artificial joint replacement after resection, 3 who underwent reconstruction with autologous bone graft after resection, and 8 who underwent resection alone. Influence of chemotherapy on fertility. We investigated the influence of chemotherapy on the fertility of patients. This was evaluated based on the presence or absence of offspring in married patients. Among long-term survivors, we examined the fertility rate (number of persons having offspring/number of married persons) in 29 married patients. As controls, we investigated this rate in their siblings aged more than 25 years (n=33). We also surveyed the interval from the end of treatment until offspring were born. Furthermore, we examined the presence or absence of complications during delivery and offspring abnormalities. We compared the fertility rate between married male (n=11) and female (n=18) patients. In addition, we divided 29 married longterm survivors into 2 groups: MC group (n=12) in which moderatedose chemotherapy was performed between 1976 and 1986; and IC group (n=17) in which intensive-dose chemotherapy was performed between 1987 and We compared the fertility rate between the two groups. Statistical analysis. Fisher s exact probability test was performed for statistical comparisons of the two groups. A p-value <0.05 was considered to be statistically significant for all tests. The data were entered into and analyzed with StatView 5.0 (Abacus Concepts, Inc. Piscataway, NJ, USA). 764

3 Yonemoto et al: Marriage and Fertility in Survivors of Osteosarcoma Table III. Summary of marital rate. Group Marital rate p-value Total Patients 63.0% (29/46) Siblings 63.5% (33/52) >0.999 Patients Males 55.0% (11/20) Females 69.2% (18/26) Amputation group 60.0% (15/25) Limb-sparing group 66.7% (14/21) Males in amputation group 45.5% (5/11) Females in amputation group 71.4% (10/14) Males in limb-sparing group 66.7% (6/9) Females in limb-sparing group 66.7% (8/12) >0.999 Siblings Males 63.0% (17/27) Females 64.0% (16/25) >0.999 Males Patients 55.0% (11/20) Siblings 63.0% (17/27) Females Patients 69.2% (18/26) Siblings 64.0% (16/25) Table IV. Summary of fertility rate. Group Fertility rate p-value Total Patients 58.6% (17/29) Siblings 81.8% (27/33) Patients Males 36.4% (4/11) Females 72.2% (13/18) MC group 66.7% (8/12) IC group 52.9% (9/17) Siblings Males 76.5% (13/17) Females 87.5% (14/16) Males Patients 36.4% (4/11) Siblings 76.5% (13/17) Females Patients 72.2% (13/18) Siblings 87.5% (14/16) Male patients in MC group 60.0% (3/5) Male siblings 76.5% (13/17) Female patients in MC group 71.4% (5/7) Female siblings 87.5% (14/16) Male patients in IC group 16.7% (1/6) Male siblings 76.5% (13/17) 0.018* Results The ages at first marriage and first offspring are shown in Table II. According to 2005 vital statistics of Japan (10), the median age at first marriage of Japanese males was 29.8 years and of females 28.0 years. The median age at first delivery in Japanese females was 28.8 years. The median age at first marriage and delivery in female patients was younger than that in Japanese females; however, statistical analysis cannot be performed. The marital rate is shown in Table III. In the patients, the marital rate was 63.0% (29/46). In their siblings, it was 63.5% (33/52). The marital rates in male patients and in the amputation group were lower, although there were no significant differences. The fertility rate is shown in Table IV. In the patients, the fertility rate was 58.6% (17/29). In their siblings, it was 81.8% (27/33). In male patients, the rate was lower. In particular, the fertility rate in male patients in the IC group was significantly lower than that in their male siblings (p=0.018). Twenty-nine offspring (14 boys, 15 girls) were born to 17 patients. There were no complications during delivery nor Female patients in IC group 72.7% (8/11) Female siblings 87.5% (14/16) MC group: moderate-dose chemotherapy group; IC group: intensivedose chemotherapy group. *Statistically significant. problems such as congenital deformity in any offspring. The interval from the end of treatment until offspring were born ranged from 27 to 229 months (median: 110 months). Discussion As the number of participants was small in this survey, we cannot reach a valid conclusion. Furthermore, our questionnaire survey included only patients from whom informed consent was obtained; therefore, we may not have evaluated the status of all long-term survivors of osteosarcoma. We may have excluded patients who could not participate in the questionnaire survey due to problems such as post-traumatic stress disorder, and results may have been overestimated. Furthermore, long-term follow-up is necessary for evaluating marriage and fertility; the present 765

4 evaluation reflects the outcome of treatment several years before this survey, and the outcome of current treatment can be assessed several years later. Nagarajan et al. investigated the marital status among 694 survivors of bone tumors, reporting that the marital rate was lower in male survivors (11). In our previous survey (7 years before the present survey), the marital rate in male patients was significantly lower than that in male siblings. In the present survey, the marital rate in male patients was lower; however, there was no significant difference. Maternal guidance and an intensified support system to promote patients independence based on the results of the previous survey may have contributed to an increase in the marital rate in male patients. There was little difference in the marital rate according to differences in surgical methods. Several surgical methods such as amputation, rotationplasty, arthroplasty and arthrodesis are available for the treatment of osteosarcoma. We give each patient some options for the surgical method and leave the selection of the surgical method to the patient. If the patient has accepted surgery fully, differences in the surgical method should have no influence on marriage. Many studies have reported that cancer chemotherapy did not influence the fertility rate of patients (12-17). On the other hand, Bacci et al. indicated that infertility was frequent in male patients with osteosarcoma (18). Siimes et al. reported that chemotherapy with cisplatin frequently induced infertility in male patients with osteosarcoma (19). Intensified therapy for osteosarcoma may have altered the influence of chemotherapy on the fertility in long-term survivors. To investigate whether intensified chemotherapy affects the fertility in long-term survivors, we divided the patients into moderate-dose chemotherapy (MC) and intensive-dose chemotherapy (IC) groups, and compared the fertility rate. In our previous survey, there was no marked difference in the fertility rate between MC and IC groups. On the other hand, in the present survey, this rate in male patients in the IC group was significantly lower than that in male siblings (p=0.018), suggesting that recently intensified chemotherapy for osteosarcoma affects the fertility in long-term male survivors. The median period of marriage in the MC group (165.8 months, range: 72 to 232 months) was significantly longer than that in the IC group (89.7 months, range: 35 to 180 months) (Mann-Whitney s U test, p=0.0041), which may have contributed to a higher fertility rate in the former group. However, the minimal period (35 months) in the latter group was considered to have been sufficient to bear first offspring. In this survey, there were no complications during delivery nor congenital anomalies, as reported previously. The interval from the end of treatment until offspring bearing was also similar to that in the previous survey. Intensified chemotherapy for osteosarcoma does not appear to influence delivery nor offspring development. In this survey, the number of patients was small, and various anticancer agents were administered for treatment. Therefore, we could not examine the influence of each agent. Williams et al. indicated that ifosfamide affected fertility (20). Furthermore, Longhi et al. reported that ifosfamide-related infertility was frequent in male patients with osteosarcoma (21). Of our series, one male who begot an offspring in the IC group had not taken ifosfamide. Among regimens of intensified chemotherapy for osteosarcoma, ifosfamide may affect the fertility in longterm male survivors. In the future, sperm freezing and storage should be considered before the start of chemotherapy with high-dose ifosfamide in male patients with osteosarcoma. Acknowledgements This study was supported in part by the Grant-in-Aid for Cancer Research (18-14) from the Ministry of Health, Labour and Welfare of Japan. References 1 Whelan JS: Osteosarcoma. Eur J Cancer 33: , Pratt CB, Meyer WH, Luo X, Cain AM, Kaste SC, Pappo AS, Rao BN, Fleming ID and Jenkins JJ 3rd: Second malignant neoplasms occuring in survivors of osteosarcoma. Cancer 80: , Nicholson HS, Mulvihill JJ and Byrne J: Late effects of therapy in adult survivors of osteosarcoma and Ewing's sarcoma. Med Pediatr Oncol 20: 6-12, Yonemoto T, Tatezaki S, Ishii T, Hagiwara Y and Inoue M: Multiple primary cancers in patients with osteosarcoma: the influence of anticancer drugs and genetic factors. 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5 Yonemoto et al: Marriage and Fertility in Survivors of Osteosarcoma 11 Nagarajan R, Neglia JP, Clohisy DR, Yasui Y, Greenberg M, Hudson M, Zevon MA, Tersak JM, Ablin A and Robison LL: Education, employment, insurance, and marital status among 694 survivors of pediatric lower extremity bone tumors: a report from the childhood cancer survivor study. Cancer 97: , Byrne J, Mulvihill JJ, Myers MH, Connelly RR, Naughton MD, Krauss MR, Steinhorn SC, Hassinger DD, Austin DF, Bragg K, Holmes GF, Holmes FF, Latourette HB, Weyer PJ, Meigs W, Teta MJ, Cook JW and Strong LC: Effects of treatment on fertility in long-term survivors of childhood or adolescent cancer. N Engl J Med 317: , Hawkins MM: Is there evidence of a therapy-related increase in germ cell mutation among childhood cancer survivors? J Natl Cancer Inst 83: , Nicholson HS and Byrne J: Fertility and pregnancy after treatment for cancer during childhood or adolescence. Cancer 71: , Dodds L, Marrett LD, Tomkins DJ, Green B and Sherman G: Case-control study of congenital anomalies in children of cancer patients. BMJ 307(6897): , Longhi A, Porcu E, Petracchi S, Versari M, Conticini L and Bacci G: Reproductive functions in female patients treated with adjuvant and neoadjuvant chemotherapy for localized osteosarcoma of the extremity. Cancer 89: , Hosalkar HS, Henderson KM, Weiss A, Donthineni R and Lackman RD: Chemotherapy for bone sarcoma does not affect fertility rates or childbirth. Clin Orthop Relat Res 428: , Bacci G, Ferrari S, Bertoni F, Ruggieri P, Picci P, Longhi A, Casadei R, Fabbri N, Forni C, Versari M and Campanacci M: Long-term outcome for patients with nonmetastatic osteosarcoma of the extremity treated at the Istituto Ortopedico Rizzoli according to the Istituto Ortopedico Rizzoli/Osteosarcoma-2 Protocol: an updated report. J Clin Oncol 18: , Siimes MA, Elomaa I and Koskimies A: Testicular function after chemotherapy for osteosarcoma. Eur J Cancer 26: , Williams D, Crofton PM and Levitt G: Does ifosfamide affect gonadal function? Pediatr Blood Cancer 50: , Longhi A, Macchiagodena M, Vitali G and Bacci G: Fertility in male patients treated with neoadjuvant chemotherapy for osteosarcoma. J Pediatr Hematol Oncol 25: , Received June 24, 2008 Revised November 24, 2008 Accepted December 1,