Case Report Successful Pregnancy After Sacrectomy Combined With Chemotherapy and Radiation for Ewing Sarcoma: Case Report and Literature Review Jun Kakogawa MD, PhD 1,*, Takafumi Nako MD 1, Kazuhiro Kawamura MD, PhD 1, Shin Nakamura MD 1, Ayako Mochiduki MD 2, Naohiro Kanayama MD, PhD 2, Mamoru Tanaka MD, PhD 1 1 2

Department of Obstetrics and Gynecology, St. Marianna University School of Medicine, Kanagawa, Japan Department of Obstetrics and Gynecology, Hamamatsu University School of Medicine, Shizuoka, Japan

a b s t r a c t Background: Ewing sarcoma is considered to have a poor prognosis. Recent advances in multidisciplinary management have resulted in a marked improvement in long-term survival. Case: We describe a case of successful pregnancy in a patient who underwent sacrectomy combined with multi-agent chemotherapy and radiotherapy for Ewing sarcoma. The patient was diagnosed with Ewing sarcoma of the sacrum at the age of 16. The ovaries were transposed, the uterus was shielded, and a gonadotropin-releasing hormone agonist was used during treatment to protect ovarian function. The patient spontaneously conceived at the age of 27. After an uneventful pregnancy, the patient delivered a healthy neonate at term by cesarean section. Summary and Conclusions: Successful pregnancy and delivery can be achieved after multi-modality treatment with pretreatment intervention for fertility preservation. Key Words: Fertility preservation, Pregnancy, Sacrectomy, Ewing sarcoma

Introduction

Ewing sarcoma is the second most common malignant bone tumor, with an incidence of 2.9 million per year throughout the world.1 The peak incidence of Ewing sarcoma is between 10 and 20 years of age.2 Although primary malignant sacral tumors are uncommon, Ewing sarcoma can occur as sacral lesions. Ewing sarcoma of the bone is considered to have a poor prognosis, with a long-term survival of less than 15%. However, recent advances in the multidisciplinary management of sarcomas over the past 3 decades have resulted in a marked improvement in long-term survival.3 Aggressive chemotherapy and radiotherapy in children and adolescents can result in a loss of reproductive function. There are only 4 case reports of successful pregnancy and delivery after treatment for Ewing sarcoma.4e6 Furthermore, sacrectomy, which can be associated with neurologic dysfunction and pelvic instability, is often the best definitive treatment for high grade sacral sarcomas. In this report, we describe a case of successful pregnancy in a patient who underwent sacrectomy combined with multi-agent chemotherapy and radiation therapy for Ewing sarcoma. This report is believed to be the first case of a successful pregnancy after sacrectomy due to Ewing sarcoma. We also

The authors indicate no conflicts of interest. * Address correspondence to: Jun Kakogawa, MD, PhD, Department of Obstetrics and Gynecology, St. Marianna University School of Medicine, 2-16-1, Sugao, Miyamae, Kawasaki, Kanagawa 2168511, Japan; Phone: þ81-44-977-8111; fax: þ81-44977-2944 E-mail address: [email protected] (J. Kakogawa).

reviewed all cases in the English literature of delivery after treatment for Ewing sarcoma.

Case

A 16-year-old girl had arrived at the orthopedics department of Hamamatsu University School of Medicine Hospital complaining of lower back pain in her pelvis. A radiologic investigation demonstrated a bony mass arising from the sacrum. A biopsy was performed, and the patient was diagnosed with Ewing sarcoma of the sacrum. Her menarche had begun at the age of 14, and she had normal menstruation thereafter. There was no remarkable family history. A lesional resection was performed. Subsequently, 5 courses of chemotherapy with vincristine, cyclophosphamide, pirarubicin, ifosfamide and etoposide were planned to be administered. Local pelvic radiotherapy with a total dose of 55 Gy was performed during the surgery. The patient was considered to be at a high risk of developing ovarian failure as a result of the planned treatment with chemotherapy and local pelvic radiotherapy. Thus, a gonadotropinreleasing hormone (GnRH) agonist was administered during the adjuvant chemotherapy (buserelin, 1.8 mg/28 days for 6 months). Transposition of the ovaries on the peritoneum of the Douglas pouch was performed laparoscopically just before the initiation of radiotherapy. The uterus was shielded during the radiation procedure. Her menstruation resumed normally 3 months after completing her therapy. The patient was diagnosed with local recurrence at the age of 19. The patient underwent a partial sacrectomy

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followed by 2 courses of neoadjuvant chemotherapy with cisplatin and irinotecan. The sacrum was resected between S-1 and S-2, preserving only the S-1 root nerve. This partial sacrectomy resulted in a complete loss of bladder and bowel control, although motor function was preserved. The patient was required to manage self-catheterization. Subsequently, 2 courses of chemotherapy with ifosfamide and etoposide were administered. Treatment with a GnRH agonist continued until the completion of chemotherapy (buserelin, 1.8 mg/28 days for 6 months). Local control of Ewing sarcoma was achieved by surgery and chemotherapy. The patient's menstruation resumed 6 months after the completion of her second therapy, although her menstrual cycle was irregular from day 21 to day 90. The patient married at the age of 26. At that time, a radiograph of the pelvis (Fig. 1) showed no structural deformity of the pelvic ring, and an MRI revealed no local recurrence of Ewing sarcoma (Fig. 2). Ultrasonography revealed an antral follicle count of 5, serum follicle stimulating hormone level of 4.2 mIU/ml, estradiol level of € llerian hormone level of 0.82 ng/ml 144 pg/ml and anti-Mu on day 5 of her menstrual cycle. The patient received preconception counseling about future fertility based on her ovarian reserve and the possible impacts of pregnancy on her pelvic stability after sacrectomy. Three months after her marriage, the patient became unintentionally pregnant at the age of 27. The first trimester was uneventful. The patient complained of difficulty with self-catheterization after 16 weeks of gestation due to the enlargement of her uterus. The patient was referred to our hospital to receive perinatal management at 22 weeks of gestation. There were no signs of preterm labor. Sonographic cervical assessments showed a normal length for the gestational age. The patient did not complain of pain at the surgical site or of difficulty walking. Regular fetal evaluations by ultrasonography showed normal fetal development and no gross anomalies. The history of pelvic radiotherapy led us to believe that vaginal delivery might be difficult due to the risk of pelvic floor damage. Thus, the patient gave informed consent to undergo an elective cesarean section. The cesarean section was performed at 37 weeks of gestation. The procedure was conducted under general anesthesia with the patient in the

Fig. 1. A radiograph of the pelvis showed no structural deformity of the pelvic ring.Ă

Fig. 2. MRI revealed no local recurrence of Ewing's sarcoma. The sacrum was resected between S-1 and S-2 and the sacroiliac joints were connected at the S-1 level (white arrow).

supine position. A female neonate weighing 2326 g with Apgar scores of 9 and 10 at 1 and 5 min, respectively, was delivered with no gross anomalies. The puerperal course was uneventful, and the mother and neonate were discharged 8 days after delivery. One month after the delivery, the patient's functional and clinical statuses were restored to pre-pregnancy values. Summary and Conclusion

As Ewing sarcoma tends to metastasize at an early stage, its prognosis was extremely poor in the 1960s, with a 2-year survival of only 21%. Since the 1970s, the advent of combined multi-agent chemotherapy with surgery and radiotherapy has improved the prognosis of patients with Ewing sarcoma. Among young patients presenting with nonmetastatic disease who receive modern multidisciplinary treatment, long-term survival can reach 70% to 80%.3 Ovarian damage following radiation and gonadotoxic chemotherapy has long been recognized. The current American Society of Clinical Oncology guidelines7 for fertility preservation for patients with cancer recommends that health providers discuss fertility preservation with all patients of reproductive age if infertility is a potential risk of therapy. In this guideline, oocyte cryopreservation is an established method for postpubertal minor children. However, the options for prepubertal patients are limited. Ovarian tissue cryopreservation for the purpose of future transplantation may be the only method available in children, but this technique remains still experimental. In the present case, oocyte cryopreservation was not available at the previous university hospital due to ethical considerations. This procedure had not been established as a standard care at that time. In patients receiving pelvic radiation, transposing the ovaries out of the radiation field and shielding the uterus during the radiation procedure are options to protect them from exposure. Currently, there is insufficient evidence regarding the effectiveness of GnRH

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Table 1 Summary of Case Reports of Delivery After Treatment of Ewing Sarcoma Authors

Sharon et al4

Chihara et al5

Region of the Tumor

Treatment for Ewing Sarcoma

Year

Age of Diagnosis of Ewing Sarcoma

2001

16

Fibula

25

Chemotherapy* Scapulae and pulmonary metastases Left pelvic bone Limb-sparing hemipelvectomy and chemotherapyy

Age of Pregnancy

Surgery, chemotherapy* and local radiotherapy

20

28, 30

2003

11

Bath et al6 2004

14

Left superior pubic ramus

Chemotherapy* and local radiotherapyz

20

Present case

16

Sacrum

Initial treatment: lesional resection, chemotherapyx and local radiotherapy Treatment for local recurrence; sacrectomy and chemotherapyk

27

2013

22

Pregnancy Course

Spontaneous pregnancy and uneventful pregnancy course Spontaneous pregnancy and uneventful pregnancy course Spontaneous pregnancy and inadequate descent of the fetal head due to pelvic distortion Spontaneous pregnancy and uneventful pregnancy course

Spontaneous pregnancy and uneventful pregnancy course

Delivery

Fetal Outcome

Data not available

Healthy baby

Data not available

Healthy babies

Cesarean section due to Term male baby, 2,345 g pelvic distortion at 37 weeks of gestation Term male baby, Cesarean section with 2,940 g consideration of the history of pelvic radiotherapy at 38 weeks of gestation Term female baby, Cesarean section with 2,326 g consideration of the history of pelvic radiotherapy at 37 weeks of gestation

* Chemotherapy with cyclophosphamide ifosfamide, etposide, vincristine, and adriamycin. y Chemotherapy with cyclophosphamide, adriamycin, methotrexate, vincristine, and actinomycin. z Cryopreservation was performed before the initiation of therapy for Ewing's sarcoma. x Chemotherapy with vincristine, cyclophosphamide, pirarbicin, ifosfamide, and etoposide. k Chemotherapy with cisplatin, irinotecan, ifosfamide, and etoposide.

analogs and other means of ovarian suppression on fertility preservation.7 However, it had been reported that cotreatment with a GnRH agonist and chemotherapy may be beneficial for the preservation of future fertility.8 Thus, the ovaries were transposed, the uterus was shielded and a GnRH agonist was used during treatment to maximize the likelihood that ovarian function would be restored in the present case. Sacrectomy is often the best definitive treatment for high grade sacral sarcomas. Gunterberg et al9 reported that the pelvic ring was weakened by approximately 30% after resection of one-third of the sacroiliac joints and associated ligamentous tissue; furthermore, the pelvic ring remained stable as long as half of the S1 vertebra was intact. To the best of our knowledge, the present case is the first report of pregnancy after sacrectomy due to Ewing sarcoma. The present case suggests that preserving just the S1 vertebra can maintain a patient's ability to have a successful pregnancy and an adequate quality of life after delivery. There are only 4 case reports of delivery after treatment for Ewing sarcoma.4e6 The previous case reports and the current case are summarized in Table 1. Two cases, including the present case, were delivered by cesarean section in consideration of the patients' histories of pelvic radiotherapy. Pelvic radiotherapy in young patients with cancer affects uterine function by restricting blood flow to the uterus. Green et al10 reported that the offspring of the patient who received pelvic radiotherapy were more likely to weigh less than 2,500 g at birth. In the present case, the uterine function related with previous pelvic radiotherapy may have been associated with the low birth weight of the

neonate. Although there were no established guidelines regarding future fertility, in the present case, we considered it important to perform pre-conception counseling based on the patient's clinical and functional statuses. In conclusion, successful pregnancy and delivery can be achieved after sacrectomy combined with chemotherapy and radiotherapy for Ewing sarcoma, indicating the importance of pretreatment planning and intervention for fertility preservation.

References 1. Esiashvili N, Goodman M, Marcus RB Jr: Changes in incidence and survival of Ewing sarcoma patients over the past 3 decades: Surveillance Epidemiology and End Results data. J Pediatr Hematol Oncol 2008; 30:425 2. Grier HE: The Ewing family of tumors. Ewing's sarcoma and primitive neuroectodermal tumors. Pediatr Clin North Am 1997; 44:991 € rgens H: Approaching Ewing sarcoma. Future Oncol 2010; 6:1155 3. Dirksen U, Ju 4. Sharon N, Neumann Y, Kenet G, et al: Successful pregnancy after high-dose cyclophosphamide and ifosfamide treatment in two postpubertal women. Pediatr Hematol Oncol 2001; 18:247 5. Chihara IG, Osada H, Iitsuka Y, et al: Pregnancy after limb-sparing hemipelvectomy for Ewing's sarcoma. A case report and review of the literature. Gynecol Obstet Invest 2003; 56:218 6. Bath LE, Tydeman G, Critchley HO, et al: Spontaneous conception in a young woman who had ovarian cortical tissue cryopreserved before chemotherapy and radiotherapy for a Ewing's sarcoma of the pelvis: case report. Humanit Rep 2004; 19:2569 7. Loren AW, Mangu PB, Beck LN, et al: American Society of Clinical Oncology: Fertility preservation for patients with cancer: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol 2013; 31:2500 8. Blumenfeld Z: Gynaecologic concerns for young women exposed to gonadotoxic chemotherapy. Curr Opin Obstet Gynecol 2003; 15:359 9. Gunterberg B, Romanus B, Stener B: Pelvic strength after major amputation of the sacrum. An experimental study. Acta Orthop Scand 1976; 47:635 10. Green DM, Sklar CA, Boice JD Jr, et al: Ovarian failure and reproductive outcomes after childhood cancer treatment: results from the Childhood Cancer Survivor Study. J Clin Oncol 2009; 27:2374

Successful Pregnancy After Sacrectomy Combined With Chemotherapy and Radiation for Ewing Sarcoma: Case Report and Literature Review.

Ewing sarcoma is considered to have a poor prognosis. Recent advances in multidisciplinary management have resulted in a marked improvement in long-te...
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