Surviving cancer or future motherhood? Both are possible: an Ewing sarcoma case in an 8-year-old girl

Abstract

Ewing’s sarcoma is an aggressive tumour, common in paediatric age, in which treatment often implies a decrease in reproductive potential. We describe a case of a woman who had a lumbar Ewing’s Sarcoma in 1991, at the age of 8. She was submitted to extended tumourectomy, chemotherapy and local radiotherapy without preservation techniques. In adult life, and after two in vitro fertilization (IVF) reproductive cycles without success, she spontaneously conceived at the age of 32. After an uneventful pregnancy, she delivered a healthy child by caesarean section. This is a rare successful case of a spontaneous and uneventful pregnancy without previous preservation techniques. In the last 30 years, there has been significant development in this area, and currently, there are solutions for these patients, including in prepubertal age.

Background

Ewing sarcoma represents the second most common primary bone tumour in childhood and adolescence, with a peak incidence between the ages of 10–20.¹ These tumours mainly affect children, adolescents and young adults with approximately 1.5 global cases per million.² It affects most frequently the pelvis, long bones and the thoracic wall; and symptoms such as pain and edema tend to be the first sign of the disease.³

These are aggressive tumours and multiagent chemotherapy protocols have become an important component of treatment along with surgery and radiotherapy.⁴ Advances in multidisciplinary management over the past 30 years have resulted in a marked improvement of long-term survival, with an increase in the survival rate of 5 years at around 70%, despite future sequelae including impairment of the gonadal function, causing an impact in the quality of life of girls and women.^{1 5 6} Therefore, today, the focus on these patients covers treatment-related complications in long-term survivors, such as sterility, infertility or subfertility. In fact, in addition to reproductive potential loss, these women often show poor reproductive outcomes such as a spontaneous miscarriage, preterm labour, placental abnormalities and a low birth weight.⁷

Risk factors which are more strongly related to infertility are pelvic radiation, alkylating agents and treatment after puberty.⁸ In fact, Ewing′s sarcoma approach consists, besides surgery, in pelvic irradiation and a multiagent chemotherapy protocol including alkylating agents, which in itself represents a high-risk tumour for subfertility after proper treatment in childhood and adolescence.⁹ In 2015, Mörse et al reported a study in which children and adolescents with Ewing Sarcoma presented an undetectable or very low Anti-Müllerian hormone (AMH) throughout and 3 months after treatment, noting that young women with this tumour are at high risk of severe ovarian dysfunction during treatment and first years afterward.⁸

The degree of damage of the chemotherapy treatment is dependent on the type of agent used, the dose given, the age of the patient and her baseline ovarian reserve. Alkylating agents, such as cyclophosphamide, have an extremely damaging effect and are responsible for the highest age-adjusted odds ratio of ovarian failure rates, representing the greatest threat.

Radiotherapy affects both the ovary and the uterus, and the degree of impairment depends on the radiation dose, the extension of the radiation treatment, fractionation schedule and the age at the time of treatment.⁹ Ovarian follicles are sensitive to DNA damage from ionising radiation and can result in follicular atrophy and decreased ovarian reserve, with a median lethal dose for radiation therapy lower than 2 Gy.¹⁰ Exposure to pelvic radiation also results in uterine vascular and muscular damage, impaired uterine distensibility and decreased endometrial thickness, especially pronounced if administered before puberty.^{10 11} Pelvic, abdominal and total body irradiation are the most gonadotoxic with effective total sterilisation doses 20.3 Gy at birth, 18.4 Gy at the age of 10 and 16.5 Gy at the age of 20.⁷

Case presentation

In March 1992, a healthy prepubertal 8-year-old girl recurred to a paediatric hospital with lower-limb pain for 3 months, recently aggravated and associated with lack of strength and walking difficulty. Diminishing muscular strength and sensitivity of the lower limbs, with abolished patellar reflexes, was verified.

A CT and a magnetic resonance were performed, which revealed a tumour lesion of L1–L4 occupying the spinal canal with destructive inflammation of L3 vertebral body. Neurosurgery proceeded on L2, L3 and L4 incision and verified a massive lesion, which was partially removed with complete release of L3 and L4 nerve roots. The patient underwent arthrodesis with Harrington bars (L5–S1 to D11–D12) and biopsies of the peripheral and corporeal soft tissues of L3, with a histological diagnosis of Ewing’s sarcoma. In April, a third surgery was performed for the removal of the macroscopically accessible residual tumour, followed by four chemotherapy cycles according to protocol (vincristine, doxorubicin, cyclophosphamide and actinomycin D). After a period of clinical improvement, there was a recurrence of motor complaints. The CT-scan was inconclusive due to the presence of Harrington bars, so an electromyogram was performed with evidence of root lesion at L4–L5–S1 level, and a bone scintigraphy showing a residual tumour at L3. The patient went through conventional fractured radiotherapy (performed on an external telecobaltotherapy radiotherapy equipment—Theratron 780) with a total dose of 40 Gy involving the D12–L5 vertebral segment with dose increase up to 45 Gy on L3 (14 cm height × 5 cm width × 3.5 cm depth, with the reproductive organs receiving only scattered radiation) with a good tumour response. At that time, no fertility preservation techniques were performed.

Outcome and follow-up

She continued follow-up with her family physician, with menarche by the age of 15 and normal pubertal development. She was referred to childhood and adolescence gynaecology consultation at the age of 17, where a normal physical examination was confirmed, consistent with a normal pubertal development. By the age of 26, and after a 2-year period of unprotected sexual intercourse without pregnancy, she was referenced to an assisted reproduction unit. The evaluation of the infertile couple was carried out with normal results, including ultrasound of the uterus and ovaries, normal analytical values on the third day of the cycle (follicle-stimulating hormone - FSH - 6.5 mIU/mL, luteinizing hormone - LH - 3.6 mIU /mL, Estradiol 65.5 pg/mL) and adequate values of Prolactin (19.2 ng/mL) and AMH (2.37 ng/mL). Two IVF cycles were performed: a short protocol with daily 200 IU of recombinant FSH (rFSH) associated with 150 IU of human menopausal gonadotropin (hMG), and a similar second cycle with increasing rFSH dose to 250 IU; without pregnancy. In 2014, at the age of 30, about to start a third planned cycle, she spontaneously conceived. After an uneventful pregnancy she delivered at 38 weeks and 6 days by elective caesarean section, considering the history of pelvic radiotherapy and potential pelvic floor damage after vaginal delivery. A healthy boy weighing 3165 g with Apgar scores of 9 and 10 at 1 and 5 min, respectively, was delivered, without neonatal complications. The puerperal course was uneventful, and mother and child were discharged 4 days after delivery. At postpartum medical appointment, the patient′s functional and clinical status were restored. Currently, she is clinically stable, with no history of recurrence, maintaining regular menstrual cycles and a satisfactory sex life.

Discussion

All children diagnosed with cancer, and their parents, should be informed of the potential treatment toxicity and available fertility preservation techniques. Studies reveal that fertility commitment is a significant survival concern, and there is a need for a multidisciplinary collaboration between oncologists and reproductive specialists.¹² In 2006, the American Society of Clinical Oncology first published recommendations on fertility preservation as part of education and informed consent before cancer therapy.¹

Gonadal failure in these girls is caused by the accelerated and premature depletion of germ cells as a result of gonadotoxic treatment, and the extent of damage is related to the patient′s age, increased doses of radiation and dose and type of chemotherapeutic agents.⁹ There are a number of techniques available for fertility preservation, however, in such a young patient, we have to restrict the options to the prepubertal state: ovarian transposition, modified radiotherapy techniques and ovarian tissue cryopreservation (OTC).⁷

Ovarian transposition or ovariopexy can be proposed in order to displace the ovaries from the radiation field when it affects the pelvis, and so protect them from radiation exposure and preserve ovarian function. Surgical ovarian transposition in females has been shown to reduce the risk of ovarian failure by about 50%.¹¹ Success rates are affected by patient age, radiation field dose, type of pelvic or abdominal irradiation, vascular compromise and whether concomitant chemotherapy is combined.⁹ Since this procedure does not prevent ovarian damage by cytotoxic agents, it is not feasible in patients submitted to both chemo and radiotherapy.⁷

Over time, radiotherapy has also improved its planning and techniques, in order to reduce the risk of late effects. There are some available options, such as hyperfractionated treatment schedules, intensity-modulated radiation therapy, proton radiotherapy and tailored field size, which allows a reduction of normal irradiated tissue, and allows safe delivery of higher doses to target-tissue while reducing the incidence of related irradiation complications.¹⁰

OTC consists in cryopreserve small fragments of dissected ovarian cortical tissue (rich in primordial follicles) before starting gonadotoxic treatments and may be the most feasible option to preserve the reproductive potential of prepubertal girls with cancer. Current evidence shows that in these girls the extraction of half or one ovary is recommended.⁷ When the girl is cured from cancer, tissue may be transplanted after the age of puberty: into the pelvis (orthoptic transplant) or into extra pelvic sites (heterotopic transplant). This technique allows fertility preservation in prepubertal and postpubertal children.

OTC represents an important possibility, since there is a substantial number of described cases with restoration of ovarian function, experiencing follicular development and ovulation after ovarian cortex reimplantation.⁹ Currently, in literature, transplantation of cryopreserved ovarian tissue has resulted in the births of at least 130 children, but data on transplantation of ovarian tissue removed before puberty are rare.⁶ The first publication showing the functionality of OTC before puberty was published in 2012. Poirot et al reported a case of a girl, who at the age of 10 had OTC performed and at the age of 13 had her puberty induced by transplanting ovarian tissue.¹³

Younger patients’ cryostored ovarian pieces usually contains a higher follicle density, theoretically improving the chances for conceiving per transplanted frozen-thawed ovarian piece compared with older women at the time of OTC.¹⁴ Demeestere et al reported the first birth obtained after transplantation of OTC before menarche at the age of 13. At 23 years old, the patient had a premature ovarian failure and advanced on ovarian tissue transplantation. At 25 years old, she got pregnant spontaneously, giving birth to a healthy boy.¹⁵ Those results are encouraging, but it is still necessary to wait a few more years for more results.⁶

However, autotransplantation of ovarian tissue carries a theoretical risk of reintroducing malignant cells, particularly in leukaemia survivors. In order to overcome this problem, oocyte cryopreservation obtained from ovarian stimulation¹⁶ and from surgically extracted ovarian tissue¹⁷ were described (including in prepubertal girls). In October 2020, a protocol that combines cryopreservation of ovarian tissue with the isolation and cryopreservation of mature and/or immature oocytes was proposed, clarifying all steps required to maximise the fertility preservation potential in both prepubertal girls and women.¹⁸ Although feasible, few reports have been published with promising results of this strategy in prepubertal girls with cancer,⁷ and there has not yet been any description of live birth from pre-pubertal children submitted to this technique.⁹

‘Fertoprotective adjuvant therapy’ consists in the administration of adjuvant therapy during or prior to chemotherapy (but not radiotherapy), such as gonadotrophin-releasing hormone (GnRH) agonists, to prevent loss of ovarian reserve. Even though some clinicians offer this therapy, especially in postpubertal girls, there is insufficient evidence regarding the effectiveness of GnRH in fertility preservation, and so the mechanism of GnRH analogues protection remains debatable.¹⁹ More data establishing the safety and efficacy of GnRH agonist cotreatment are needed.^{1 12}

Improvement in cancer management and increasing survival rates has created a need for oncofertility: the emphasis has moved from providing life to providing quality of life. This case report happened in the early nineties, when fertility preservation techniques were still under development in the medical field. Nowadays, all patients should be counselled and informed about currently available fertility preservation options by a multidisciplinary team, including fertility specialists.^{6 12} In fact, all healthcare providers should be prepared to discuss the negative impact of cancer therapy on reproductive health patients and parents in the same way any other risks are discussed.¹¹

Learning points.

• Ewing sarcoma is common in paediatric age, and its approach frequently consists in surgery combined with radiotherapy and multichemotherapy protocols including alkylating agents.

• Two risk factors, which are more strongly related to infertility, are pelvic radiation and alkylating agents, making Ewing sarcoma a high-risk tumour for subfertility after proper treatment.

• All patients should be informed about available fertility preservation options by a multidisciplinary team.

• In prepubertal state, there are less available fertility preservation techniques, such as ovarian transposition, modified radiotherapy techniques and transplantation of cryopreserved ovarian tissue.