Review
Ovarian transposition in prepubescent and adolescent girls with cancer Sabine Irtan, Daniel Orbach, Sylvie Helfre, Sabine Sarnacki
Ovarian transposition was the first procedure proposed to preserve fertility in girls with cancer and is indicated for patients with tumours requiring pelvic radiation at doses of 42·0–58·4 Gy, much higher doses than those that can induce loss of ovarian function (4–20 Gy). Ovarian transposition is usually done after neoadjuvant chemotherapy and is completed by minimally invasive surgery or open surgery in case of concomitant resection of the abdominal tumour. According to the type of tumour, the ovaries are moved and placed in the paracolic gutters when the radiation field reaches the midline (for medulloblastoma or urogenital rhabdomyosarcoma), contralaterally to the tumour (for pelvic sarcomas), or in line with the iliac crests (for Hodgkin’s lymphoma). However, in 10–14% of cases the procedure can fail to protect the ovaries. Although few long-term results in adults are available, normal hormonal function and pregnancies have been reported in a few long-term follow-up studies. In view of the continued development of fertility preservation techniques, ovarian transposition should be discussed at a multidisciplinary meeting at the time of cancer diagnosis.
Introduction
Radiotherapy and ovarian function
Childhood cancers represent 1% of all cancers, corresponding to an incidence of 122 cases per million children in the USA,1 and 1800 new patients each year (700 of whom are aged 15–19 years) in France.2 Such tumours are specific to childhood and in most cases have an embryonic origin. A better understanding of the biology of these tumours and improvement of the aggressive treatment adapted to paediatric populations have greatly enhanced the life expectancy of this population. From 1980 to 2005, mortality from childhood cancer has decreased from 6·7 to 2·9 cases per 100 000 children.3,4 As a result, almost 80% of children and adolescents with a diagnosis of cancer now become long-term survivors. Reduction of morbidity related to long-term treatment is therefore a major criteria guiding the design of paediatric oncology protocols.5,6 After treatment, the potential adverse outcomes for women include impaired puberty and fertility or premature ovarian failure due to gonadal removal, genital tract injury, or damage to germ cells.7,8 At the time of diagnosis, most children with cancer are prepubescent (younger than 11 years of age); the median age at diagnosis is about 4·5 years. However, the median age can vary widely according to the type of tumour—eg, the median age is 16·3 months for vaginal germ cell tumours,9 4·3 years for pelvic rhabdomyosarcoma,10 and 16 years for Ewing’s sarcoma of the pelvic bone.11 In recent years, progress in assisted reproductive technologies has opened up new possibilities for the prevention and treatment of infertility. Ovarian transposition was the first procedure proposed for children with cancer to preserve ovarian function from damage caused by abdominal and pelvic radiotherapy. However, few studies12–17 have investigated the long-term efficacy of this technique in the preservation of the function of the ovaries. In this Review, we describe the optimum indications and techniques for ovarian transposition and define the place of this technique among other fertility preservation strategies in women with childhood cancer.
The ovaries are very radiosensitive organs. In animal experiments, irradiation causes direct DNA lesions in the ovaries and induces apoptosis in the growing follicle and dormant primordial follicle populations. Ionising radiation acts on these dividing and non-dividing cell populations.18 The extent of damage depends on the dose of radiotherapy that reaches the ovaries, the age of the girl at the time of treatment, and the associated drugs used for chemotherapy. A single dose of radiation of 2 Gy is able to destroy more than 50% of the ovarian follicular reserve, whereas a single dose of up to 10 Gy, delivered before puberty during total body irradiation, causes complete cessation of ovarian function in 55–80% of patients.19–21 Doses of 10–20 Gy in children and 4–6 Gy in adults are associated with permanent ovarian failure.22 However, fractionated radiotherapy at the same dose can preserve ovarian function.23 Lower and increasingly fractionated doses raise the possibility of repair of the damaged follicular population.24 For example, in a 10-year-old girl, fractionated radiotherapy to the ovarian field at a dose of 3 Gy induces early ovarian dysfunction at around the age of 36·7 years; a 6 Gy dose is associated with onset at 26·5 years; 9 Gy at 19·7 years, and 12 Gy at 15·3 years.25 Table 1 shows
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Lancet Oncol 2013; 14: e601–08 Paediatric Surgery Department, Necker EnfantsMalades Hospital, Paris Descartes University, Paris, France (Prof S Irtan MD, Prof S Sarnacki MD); and Adolescent and Paediatric Department (D Orbach MD), and Radiotherapy Department (S Helfre MD), Institut Curie, Paris, France Correspondence to: Prof Sabine Sarnacki, Chirurgie Pédiatrique et INSERM U-781, Hôpital et Faculté Necker Enfants-Malades, 149 rue de Sèvres, 75743 Paris Cedex 15, France [email protected]
Dose (Gy) Birth
20·3
10 years
18·4
20 years
16·5
30 years
14·3
35 years
13·0*
40 years
11·6*
Data from Wallace and colleagues.25 *Estimated from data from Wallace and colleagues.25
Table 1: Threshold doses of radiation that induced ovarian dysfunction according to age after fractionated radiotherapy
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threshold doses by age. Levine and coworkers6 investigated fertility problems in adolescents and young women after treatment of tumours by use of pelvic external beam radiotherapy and total body irradiation. Aside from cranial irradiation, which can cause hypogonadism via gonadotropin-releasing hormone deficiency at doses of 35–40 Gy, the risk of development of amenorrhoea after treatment was estimated to be as high as 80% after whole abdominal or pelvic irradiation at doses greater than 15 Gy in prepubescent girls, and after total body irradiation doses of 10 Gy in postpubertal girls, and 6 Gy in adult women. An intermediate risk (30–70%) was identified after whole abdominal or pelvic radiation at doses of 10–15 Gy in prepubescent girls and at doses of 5–10 Gy in postpubertal girls or after spinal irradiation of greater than 25 Gy. After pelvic irradiation, the obstetrical risk depends on the direct damage to the uterus and vascular tissue and the hormonal deficit. Damage to the uterus, identified as fibrosis, is noted in the uterus volume, endometrial tissue, and vascular system, particularly when delivered doses reach 20 Gy. More important than the toxic effects to the ovaries are uterine lesions if the patient is young (younger than 6 years of age) at the time of radiotherapy. Lesions are regarded as definitive and irreversible, even with a high dose of hormonal treatment. Letur-Kornisch and colleagues26 showed an improvement in endometrial thickness, myometrial dimensions, and diastolic uterine artery flow after treatment with entoxifylline-tocopherol, which led to uterine restoration after postirradiation sequellae. Critchley and coworkers27 investigated ten women with premature ovarian failure after total abdominal irradiation in childhood. The effect of radiation on the uterus was unpredictable, but the highest doses were most associated with vascular and uterine damage. In the women who had been exposed to radiation, the length of the uterus was significantly reduced, and most women had no uterine blood flow detectable by Doppler ultrasound. Three of the women showed no change in endometrial thickness after hormonal therapy. Different lesions have also been identified after brachytherapy, including endometrial atrophy, uterine fibrosis, cervical stenosis, vaginal synechiae, or fistula, which could be attributable to infertility.28 Pregnancies are also at risk after pelvic irradiation when the total dose delivered to the uterus is greater than 20–35 Gy. Stillbirths, neonatal death, low birthweight babies, and spontaneous abortions are the main problems.28 The odds ratio of a baby born with a low birthweight of less than 2500 g after a radiation dose of 5 Gy to the uterus is 6·8 (95% CI 2·1–22·2). The uterine wall is at increased risk of rupture in women who previously received radiotherapy, which can lead to the need for prophylactic caesarean section. All these risks require close monitoring throughout pregnancy.29 e602
Indications for ovarian transposition in childhood cancers The main tumours that require ovarian transposition are in adults—ie, cervical and rectal cancers—and are not usually identified in children.30–32 However, preliminary ovarian transposition should be considered for all children with tumours requiring radiotherapy implicating part of the pelvis. Rhabdomyosarcoma of the bladder, vagina, or uterus, or soft tissue or pelvic bone sarcomas, such as Ewing’s sarcoma, are the main diagnostic indications for ovarian transposition in children.9–11 Although rhabdomyosarcoma, a mesenchymal tumour, is very chemosensitive, local control is essential to avoid local and regional recurrence and radiotherapy cannot be avoided in many cases, dependent on alveolar subtype, completeness of initial surgery, nodal involvement, and age of the patients.10,33 High-dose brachytherapy, intensitymodulated radiotherapy, and intensity-modulated proton therapy are therefore proposed as an additional therapy or instead of surgery to increase local and regional tumour control and sometimes to avoid serious surgery.34,35 The total dose of irradiation for pelvic rhabdomyosarcoma usually ranges from 36 Gy to 54 Gy. To decrease the long-term adverse effects of treatment, the Malignant Mesenchymal Tumour Committee of the International Society of Paediatric Oncology have investigated effective strategies to avoid systematic irradiation or serious surgery in patients in complete remission after conservative surgery and chemotherapy.36,37 Irradiation is regularly administered for localised Ewing’s sarcoma when the initial tumour volume is greater than 200 mL (mainly pelvic primary tumours) after incomplete resection or poor response to neoadjuvant chemotherapy with more than 10% of residual viable cells on the surgical specimen.38 A total irradiation dose between 41·4 Gy and 59·4 Gy is required in these cases, and thus the ovaries need protection. Other disorders that often require ovarian transposition are metastatic medulloblastoma, in which high-dose spinal irradiation (36·0–59·4 Gy) is part of the treatment protocol,39,40 and large retroperitoneal or peritoneal seeding of nephroblastoma (Wilms’ tumour) requiring hemi-abdomen or whole abdomen irradiation at a dose of about 14·5 Gy.41 Other rare childhood tumours might also require pelvic irradiation such as rhabdomyosarcoma of the urachus, vaginal germ-cell tumours, pelvic synovial sarcoma, and inguinal nodal extension of a soft tissue sarcoma of the limbs. Clear-cell cervical carcinoma and primary or metastatic lesions of the conus medullaris also occasionally require ovarian transposition.12 However, Hodgkin’s lymphoma with abdominopelvic lymph node extension is reported in young adolescents and often requires radiotherapy. In a study42 of patients treated for Hodgkin’s lymphoma between 1980 and 1990, the investigators reported that subtotal or total abdominopelvic nodal irradiation (20 Gy dose, with an anteroposterior-posteroanterior technique) was associated www.thelancet.com/oncology Vol 14 December 2013
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with ovarian failure in 16% of patients, however ten patients had a total of 17 pregnancies. Irradiation confined to the initially involved-field in Hodgkin’s lymphoma has now mainly replaced large subtotal nodal irradiation and many of the devastating late effects have therefore been reduced.43 Moreover, the ongoing European protocol, EuroNet-PHL-C1, is trying to avoid systematic first-line radiotherapy in patients with early radiological and metabolic (PET scan) complete remission after neoadjuvant chemotherapy.44,45 Although protocols for high-risk neuroblastoma (metastatic or MYC-N amplified) include local radiotherapy, ovarian transposition is only occasionally indicated because the tumour rarely involves the pelvis and because treatment consists of high-dose chemotherapy, such as the melphalan plus busulfan regimen, which consistently induces complete suppression of ovarian function. Early ovarian cryopreservation is therefore systematically preferred for these children.46,47 Recent reports have shown the efficacy of use of immature cryopreserved ovarian tissue in the restoration of hormonal function in a prepubescent child48 and of fertility in experimental models.49,50 The indications for ovarian transposition now need revision and could include use of cryopreservation when the degree of gonadal protection is uncertain for an ovary. By contrast with when ovarian cryopreservation is indicated because of the expected toxicity of high-dose chemotherapy, ovarian transposition of the second ovary could be done if it was within the radiation field, even if viability of the ovary is unknown. Whatever the strategy used, the possibility of ovarian contamination by cancer cells is an issue, especially when the primary disease is likely to produce gonadal metastasis or to extend into the gonads. Some tumours are known to be at high risk of ovarian tumour spread— eg, rhabdomyosarcoma or other soft tissue sarcoma, A
Tranverse
neuroblastoma, and especially acute leukaemia51— whereas patients with Hodgkin’s lymphoma or nonHodgkin lymphoma are at low risk.52 Although the risk of relapse arising from ovaries either transposed or cryopreserved is probably low and has so far not been reported either in adults or children, prospective studies are needed to asses this risk. A recent review51 identified that 7% (31 of 422 all age patients) had histological evidence of malignant cell infiltration into cryopreserved ovarian tissue. According to the strategy of fertility preservation used, different risks of contamination with tumour cells arise. When ovarian transposition is undertaken, the risk of tumour relapse results from local spreading of tumour cells surrounding the transposed ovaries and is equivalent to a microscopic incomplete resection. This spread might have an important effect in some tumours, such as nephroblastoma. When the ovaries are cryopreserved, the risk is related to the potential reintroduction of the disease on transplantation. In the future, isolation of the germinal cells from the cryopreserved tissue and generation of oocytes by in-vitro culture might be possible to resolve this problem; this option has to be considered as the best alternative when ovarian transposition is thought to be hazardous because of potential cancer-cell contamination.
Technical aspects of pelvic radiotherapy in children In children, as in adults, a multidisciplinary approach involving oncologists, surgeons, radiologists, and radiation therapists is mandatory to define the optimum position for one or both of the ovaries to be transposed to. The first step in preparation for radiotherapy is to precisely define the new position of the ovaries (figure 1), possibly by use of imaging methods such as MRI or ultrasonography. In each case, the ovaries should be B
Anterior
Left Left
Right
C
Coronal
43·5 Gy 44·4 Gy 39·3 Gy 35·0 Gy 30·0 Gy 20·0 Gy 10·0 Gy 5·0 Gy 2·0 Gy 1·0 Gy
Sagittal
Right Posterior
Anterior
Posterior
Figure 1: Ovary protection from radiotherapy by transposition A 6-year-old girl with alveolar rhabdomyosarcoma of the left lower limb and left iliac lymph nodes was administered high-dose radiation therapy (41·4 Gy) delivered by tomotherapy to spare the delineated ovaries (white arrows). On the three views, (A) transverse, (B) coronal, and (C) sagittal, orange arrows show the initial position of the ovary in a high-dose radiation zone, whereas white arrows show the transposed, and therefore protected, ovary in a low-dose radiation zone. Colours show the radiation dose gradient.
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marked intraoperatively by metallic clips to make them visible on imaging before initiation of radiation therapy. The tumour volume is then delineated and all organs surrounding the tumour or tumour bed at risk of radiation damage, in the case of postoperative radiotherapy, are identified. The gross tumour volume (GTV) is defined by the tumour volume delineated on MRI and planning CT scans. The clinical target volume (CTV) is then constructed by expanding the GTV in all directions. In the case of initial complete surgical resection, the GTV cannot be precisely defined and the CTV is considered to be a larger volume encompassing the surgical bed with the appropriate safety margins defined by the chosen protocol. The planning target volume (PTV) is produced by expanding the CTV by 0·5–1 cm in all directions. The CTV-to-PTV expansion margins depend on immobilisation, image guidance, and reproducibility of the treatment set-up. Stable and reproducible positioning of the patient and treatment set-up are essential to ensure high-precision radiotherapy. The use of customised immobilisation devices (personalised thermoplastic masks) to provide reproducible daily set-up is strongly recommended, especially in children. Treatment is delivered with daily image-guided radiotherapy.53 The radiation technique is chosen on the basis of complexity and size of the tumour volume, the number and sites of organs at risk, and their radiosensitivity. Conventional and conformal irradiation techniques ensure adequate irradiation of tumour volumes, but also deliver large doses to the surrounding healthy tissues. However, intensity-modulated radiotherapy delivers a high dose to the tumour, while minimising the radiation dose to organs at risk adjacent to the tumour volume. Tomotherapy is one of the most specialised innovations in radiotherapy and combines, on the same machine, a linear electron accelerator that moves around and along the patient, and a CT scanner allowing very accurate guidance of irradiation. Helical tomotherapy delivers irradiation in the form of intensity-modulated photon beams and thus focuses a high dose on the tumour, while minimising the radiation dose to the surrounding healthy tissues and organs. Daily CT imaging allows accurate repositioning of the patient and adaptation of the radiotherapy plan on identification of major anatomical changes or tumour shrinkage. Interstitial brachytherapy is an effective method for delivery of adjuvant radiotherapy, within a substantially shorter treatment time than external beam radiotherapy and with potentially smaller treatment volumes.54 However, it is a complex and labour-intensive technique and its use in paediatric pelvic neoplasms is mainly confined to urogenital rhabdomyosarcoma.30,31 Morice and colleagues41 reported that brachytherapy used in small tumours either alone or in combination with external beam radiotherapy allowed a reduction in high radiation doses with good results on fertility. However, in some cases, uterovaginal brachytherapy might cause e604
other late effects (eg, endometrial atrophy, uterine sclerosis, or cervical stenosis) resulting in infertility. For more complex volumes, including the lymph nodes of Hodgkin’s lymphoma, more sophisticated therapies are needed, such as intensity-modulated radiotherapy, tomotherapy, stereotactic irradiation, or proton therapy. Intensity-modulated radiotherapy allows a reduction of the doses delivered to the healthy tissue and thus reduces the morbidity associated with external beam radiotherapy, while maintaining an effective local tumour dose and ensuring good local tumour control.55 A study56 comparing standard and advanced irradiation techniques showed that proton irradiation delivered the prescribed dose to pelvic sarcomas, while wholly sparing the ovaries (0% of the ovarian volume received a dose >2 Gy). Because of the physical characteristics of the Bragg peak (the path followed by ionising particles that reach a peak near the end of their path), protons have a stop dose, which stops the protons at the distal target margin, thereby sparing the normal structures beyond the tumour outline.
Technical aspects of ovarian transposition Irrespective of the surgical technique, ovarian transposition is designed to place the ovaries outside of the irradiation field. Detailed analysis of the initial pelvic MRI should be done to ensure that the tumour does not involve the ovarian region. The PTV should be precisely defined by the surgeon and the radiotherapist before ovarian transposition. Various sites of ovarian transposition can be considered. In the case of a midline irradiation field (urogenital tumours or medulloblastoma), both ovaries are usually placed away from the midline, laterally in the paracolic gutters, or laterally and anteriorly near the inguinal ring (bilateral ovarian transposition). In the case of a lateral tumour (rhabdomyosarcoma or Ewing’s sarcoma), the compromised ovary is placed on the opposite side of the tumour (unilateral ovarian transposition). In some cases of Hodgkin’s lymphoma, when the irradiation field implicates the bilateral iliac chains and the inguinal region, the ovaries are placed in line with the iliac crests (bilateral ovarian transposition).57 Ovarian transposition is usually done after neoadjuvant chemotherapy to attest tumour chemosensitivity and disease control. When the tumour is located in the abdomen or pelvis and when chemotherapy induces a tumour reduction allowing subsequent tumour resection ovarian transposition can be done during the same surgical procedure, usually via laparotomy. When the tumour is not situated in the pelvis—eg, high risk medulloblastoma—or when no surgery is planned—eg, Hodgkin’s lymphoma—laparoscopic ovarian transposition is the best option.58,59 So far, only one case of robotically assisted endoscopic ovarian transposition has been reported.60 Laparoscopic ovarian transposition is done under general anaesthesia. The patient is placed in the www.thelancet.com/oncology Vol 14 December 2013
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Trendelenburg position, so that the head is lower than the legs, which causes the intestine to fall into the upper part of the abdomen to free the pelvis and enable visualisation of the genital tract (figure 2). The bladder is emptied with a Foley’s catheter. An umbilical port is then inserted either via an infra-umbilical incision or directly through the umbilicus. Carbon dioxide is insufflated at a pressure of 10 or 12 mm Hg dependent on the patient’s age and weight. Two 5 mm ports are inserted under direct vision into the right and left hypogastric regions, almost at the same level as the umbilicus, dependent on the child’s age. A 0° or 30° angled camera can be used. The ovary is then seized and mobilised to identify which ligaments should be sectioned—the broad ligament, the ovarian ligaments, or the mesovarium—to separate the ovaries from the fallopian tubes.41 The blood supply to the ovaries should be carefully preserved, especially the ovarian vessels in the infundibulopelvic ligaments. On placement of the ovaries in their final position, the ovarian vessels should be examined to ensure the absence of any kinking or direct injuries.61 The ovaries are sutured to the peritoneum with resorbable or nonresorbable suture material (figure 3) and clips are placed to ensure visualisation on plain abdominal radiographs. When the ovaries are transposed close to the abdominal wall, they are held in position by a transparietal nonresorbable subcutaneous suture, which can simply be cut under local anaesthesia to return the ovaries to the normal position after completion of radiotherapy on outpatient basis without the need for readmission to the operating theatre.62 In children, this technique is particularly indicated in the case of a short course of irradiation (8 days), such as brachytherapy for urogenital rhabdomyosarcoma or giant-cell tumour.31 However, when a longer course of radiotherapy is needed (5–6 weeks), adhesions to the parietal paritoneum might prevent spontaneous return of the ovaries to the pelvis. The indication for another surgical procedure to return the gonads to their normal position remains controversial. Adnexal complications such as ovarian torsion and painful ovarian cysts have been reported in previous studies63,64 describing ovarian transposition techniques in adults, with some complication rates as high as 24%.65 Ovarian cysts after ovarian transposition have also been reported in children.12 However, these studies did not formally show the role of ovarian transposition in the pathogenesis of ovarian cysts, because patients in these studies also received several other methods of treatment. Another side-effect of ovarian transposition might be related to the increased distance between the ovary and the fallopian tube, in the case of mesovarium section, that distance could hamper progression of the oocyte to the genital tract, thereby impairing fertility. However, this procedure is rarely done in children. Furthermore, in a recent small series,62 a comparison of patients with or without ovarian repositioning did not show any benefit in terms of residual hormonal function. Other complications www.thelancet.com/oncology Vol 14 December 2013
reported in children include severe dyspareunia after retrouterine transposition, bowel obstruction, and pelvic adhesions resulting in tubal obstruction,12 these complications seem to be related to open laparotomy.
Figure 2: Normal laparoscopic view of the pelvis Green arrows show the position of the two ovaries and white arrow shows the position of the uterus before ovarian transposition.
A
B
Figure 3: Ovarian transposition (A) Left ovary (arrow) is sutured to the abdominal wall with a non-resorbable suture. (B) Position of left ovary (arrow) after transposition to the left paracolic gutters.
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Results of ovarian transposition Although ovarian transposition was the first approach developed for children to preserve gonadal function, very few studies have reported long-term results with laboratory and radiological assessment of ovarian function.12,66 However, several studies59,62,63,67–71 in adults have been reported and are summarised in table 2. In 1992, Thibaud and colleagues12 reported the first results of ovarian transposition in 18 children who underwent ovarian transposition at a mean age of 9·4 years (range 1·23–16·7). Investigators analysed gonadal function on the basis of results of folliclestimulating hormone, lutenising hormone, and oestradiol assays. On mean follow-up at 8·6 years (range 2·2 to 16·2 years), 16 patients had menstruated, two patients remained amenorrhoeic because of brachytherapyinduced lesions of the genital tract with no laboratory signs of ovarian insufficiency, and two pregnancies had occurred.12 A recent study66 with a follow-up of 14 years (range 5–23 years) reported 14 pregnancies after ovarian transposition in 11 women treated for Hodgkin’s lymphoma between 1972 and 1988, which resulted in 11 births and three miscarriages. None of these women underwent ovarian detransposition or artificial insemination. The frequency of congenital malformations, abortion, or prematurity did not differ from that of the general population. Only two studies12,66 report long-term follow-up results. However, another study40 reported the results of ovarian transposition in girls who received spinal irradiation for brain tumours, in which 15 girls who received ovarian transposition were compared with 11 girls who did not, and were matched for age at diagnosis, Patients Median age at (n) enrolment (year)
Type of cancer
Clough et al (1996)59
20
32·8
17 cervical cancer, 2 Hodgkin’s lymphoma, 1 ependymoma
Gareer et al (2011)62
12*
23·2
9 Hodgkin’s lymphoma, 3 rectal cancer
duration of follow-up, proportion of high risk tumours, and dose and duration of chemotherapy and radiation. Ovarian dysfunction, assessed by follicle-stimulating hormone assay and persistent amenorrhoea, was identified in 13% of patients in the ovarian transposition group, but 45% of patients in the non-ovarian transposition group. Although not significant (p=0·09), these results support the routine use of ovarian transposition whenever feasible.37 In another study, the surgical team undertook second-look laparoscopy to remove the non-resorbable sutures and took ovarian biopsy samples that showed normal follicle counts with more than ten germinal follicles per high-power field.39 Overall, the success rate of ovarian transposition in the paediatric population is difficult to establish because of the very small number of well-conducted studies, but seems to range between 60% and 83%.72,73 Because various laboratory markers, particularly inhibin B and anti-müllerian hormone assays,74 are now available to accurately assess ovarian function in survivors of cancer, long-term ovarian function should now be studied prospectively in all children who undergo ovarian transposition.
Conclusions Ovarian transposition is still a major approach to avoid ovarian damage when pelvic irradiation is indicated for childhood tumours. The development of laparoscopy should avoid the complications previously reported with laparotomy and shorten the time to resume treatment. However, the long-term results of ovarian transposition in childhood cancer have been inadequately studied. Follow-up (months)
Complications
Ovarian Pregnancy preservation
23·5
0
85·7%
0
Unknown
0
91·7%
3
50% 3 ovarian cysts, 1 haemorrhagic corpus luteum, 2 cancer recurrences
0
83%
3
Feeney et al (1995)63
132
33·5
132 cervical cancer
24
Morice et al (2000)67
107
33
107 cervical cancer
31
Pahisa et al (2008)68
28
35·7
28 cervical cancer
44·3
0
83·3%
0
Huang et al (2007)69
14
37·8
12 cervical cancer, 2 vaginal cancer
72
0
50%
0
Williams et al (1999)70
10
27·9
10 Hodgkin’s lymphoma
Unknown
0
50%
5
Anderson et al (1993)71
24
31
24 cervical cancer
58
0
33%
0
22 ovarian cysts, 1 metastasis, 1 bowel obstruction, 3 abdominal pain
*Six patients had ovarian repositioning.
Table 2: Studies investigating long-term outcome of ovarian transposition in adults
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Search strategy and selection criteria We searched PubMed for reports published in English between January, 1995, and March, 2013, with the search terms “oophoropexy”, “ovarian transplantation”, “fertility preservation”, “childhood, children, paediatric”, and “effect of radiotherapy on gonadal function (total body irradiation)”. We supplemented this search with review of the author’s own files. The final list of references was generated on the basis of their recent date of publication and their relevance to the broad scope of this Review.
Although ovarian function seems to be well preserved and several pregnancies have been reported, investigation of the hormonal status and fertility of these children, by use of the available radiological and laboratory instruments, is now essential. Because of the rarity of these cases, these data should be collected in the context of an international, multicentre study. Finally, in view of the broad range of fertility protection methods available and progress in medically assisted reproductive techniques, the best option for fertility preservation and follow-up should be established at a multidisciplinary meeting as soon as the treatment protocol has been defined. Contributors All authors contributed equally to the literature search, study design, data collection, and writing of this Review. Conflicts of interest We declare that we have no conflicts of interest. Acknowledgments We thank La Ligue Contre le Cancer for their financial support and Anthony Saul for editing assistance. References Li J, Thompson TD, Miller JW, Pollack LA, Stewart SL. Cancer 1 incidence among children and adolescents in the United States, 2001–2003. Pediatrics 2008; 121: 1470–77. 2 Lacour B, Guyot-Goubin A, Guissou S, Bellec S, Désandes E, Clavel J. Incidence of childhood cancer in France: National Children Cancer Registries, 2000-2004. Eur J Cancer Prev 2010; 19: 173–81. 3 Stiller CA, Desandes E, Danon SE, et al. Cancer incidence and survival in European adolescents (1978–1997). Report from the Automated Childhood Cancer Information System project. Eur J Cancer 2006; 42: 2006–18. 4 Desandes E, Lacour B, Belot A, et al. Cancer incidence and survival in adolescents and young adults in France, 2000–2008. Pediatr Hematol Oncol 2013; 30: 291–306. 5 Pui CH, Gajjar AJ, Kane JR, Qaddoumi IA, Pappo AS. Challenging issues in pediatric oncology. Nat Rev Clin Oncol 2011; 8: 540–49. 6 Levine J, Canada A, Stern CJ. Fertility preservation in adolescents and young adults with cancer. J Clin Oncol 2010; 28: 4831–41. 7 Sudour H, Chastagner P, Claude L, et al. Fertility and pregnancy outcome after abdominal irradiation that included or excluded the pelvis in childhood tumour survivors. Int J Radiat Oncol Biol Phys 2010; 76: 867–73. 8 Mörse H, Elfving M, Lindgren A, Wölner-Hanssen P, Andersen CY, Ora I. Acute onset of ovarian dysfunction in young females after start of cancer treatment. Pediat Blood Cancer 2013; 60: 676–81. 9 Magné N, Oberlin O, Martelli H, Gerbaulet A, Chassagne D, Haie-Meder C. Vulval and vaginal rhabdomyosarcoma in children: update and reappraisal of Institut Gustave Roussy brachytherapy experience. Int J Radiat Oncol Biol Phys 2008; 72: 878–83.
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Réguerre Y, Martelli H, Rey A, et al. Local therapy is critical in localized pelvic rhabdomyosarcoma: experience of the International Society of Paediatric Oncology Malignant Mesenchymal Tumour (SIOP-MMT) committee. Eur J Cancer 2012; 48: 2020–27. Potratz J, Dirksen U, Jürgens H, Craft A. Ewing sarcoma: clinical state-of-the-art. Pediatr Hematol Oncol 2012; 29: 1–11. Thibaud E, Ramirez M, Brauner R, et al. Preservation of ovarian function by ovarian transposition performed before pelvic irradiation during childhood. J Pediatr 1992; 121: 880–84. Detti L, Martin DC, Williams LJ. Applicability of adult techniques for ovarian preservation to childhood cancer patients. J Assist Reprod Genet 2012; 29: 985–95. Lawrenz B, Henes M, Neunhoeffer E, Fehm T, Lang P, Schwarze CP. Fertility preservation in girls and adolescents before chemotherapy and radiation–review of the literature. Klin Padiatr 2011; 223: 126–30. Gnaneswaran S, Deans R, Cohn RJ. Reproductive late effects in female survivors of childhood cancer. Obstet Gynecol Int 2012; 2012: 564794. Hudson MM. Reproductive outcomes for survivors of childhood cancer. Obstet Gynecol 2010; 116: 1171–83. 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: 2374–81. Meirow D, Nugent D. The effects of radiotherapy and chemotherapy on female reproduction. Hum Reprod Update 2001; 7: 535–43. Bakker B, Oostdijk W, Bresters D, Walenkamp MJ, Vossen JM, Wit JM. Disturbances of growth and endocrine function after busulphan-based conditioning for haematopoietic stem cell transplantation during infancy and childhood. Bone Marrow Transplant 2004; 33: 1049–56. Leiper AD, Stanhope R, Lau T, et al. The effect of total body irradiation and bone marrow transplantation during childhood and adolescence on growth and endocrine function. Br J Haematol 1987; 67: 419–26. Wallace WH, Thomson AB, Kelsey TW. The radiosensitivity of the human oocyte. Hum Reprod 2003; 18: 117–21. Chemaitilly W, Mertens AC, Mitby P, et al: Acute ovarian failure in the childhood cancer survivor study. J Clin Endocrinol Metab 2006; 91: 1723–28. Thibaud E, Rodriguez-Macias K, Trivin C, Espérou H, Michon J, Brauner R. Ovarian function after bone marrow transplantation during childhood. Bone Marrow Transplant 1998; 21: 287–90. Lo Presti A, Ruvolo G, Gancitano RA, Cittadini E. Ovarian function following radiation and chemotherapy for cancer. Eur J Obstet Gynecol Reprod Biol 2004; 113: S33–40. Wallace WH, Thomson AB, Saran F, Kelsey TW. Predicting age of ovarian failure after radiation to a field that includes the ovaries. Int J Radiat Oncol Biol Phys 2005; 62: 738–44. Letur-Kornisch H, Guis F, Delanian S. Uterine restoration by radiation sequelae regression with cobined pentoxifylline-tocopherol: a phase II study. Fertil Steril 2002; 77: 1219–26. Critchley HO, Wallace WH, Shalet SM, Mamtora H, Higginson J, Anderson DC. Abdominal irradiation in childhood; the potential for pregnancy. Br J Obstet Gynaecol 1992; 99: 392–94. Signorello LB, Cohen SS, Bosetti C, et al. Female survivors of childhood cancer: preterm birth and low birth weight among their children. J Natl Cancer Inst 2006, 98: 1453–61. Signorello LB, Mullvihill JJ, Green DM, et al. Stillbirth and neonatal death in relation to radiation exposure before conception: a retrospective cohort study. Lancet 2000 21: 624–30. Han SS, Kim YH, Lee SH, et al. Underuse of ovarian transposition in reproductive-aged cancer patients treated by primary or adjuvant pelvic irradiation. J Obstet Gynaecol Res 2011; 37: 825–29. Bisharah M, Tulandi T. Laparoscopic preservation of ovarian function: an underused procedure. Am J Obstet Gynecol 2003; 188: 367–70. Morice P, Thiam-Ba R, Castaigne D, Haie-Meder C. Fertility results after ovarian transposition for pelvic malignancies treated by external irradiation or brachytherapy. Hum Reprod 1998; 13: 660–63.
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Martelli H, Haie-Meder C, Branchereau S, et al. Conservative surgery plus brachytherapy treatment for boys with prostate and/or bladder neck rhabdomyosarcoma: a single team experience. J Pediatr Surg 2009; 44: 190–96. Magné N, Haie-Meder C. Brachytherapy for genital-tract rhabdomyosarcomas in girls: technical aspects, reports, and perspectives. Lancet Oncol 2007; 8: 725–29. Cotter SE, Herrup DA, Friedmann A, et al. Proton radiotherapy for paediatric bladder/prostate rhabdomyosarcoma: clinical outcomes and dosimetry compared to intensity-modulated radiation therapy. Int J Radiat Oncol Biol Phys 2011; 81: 1367–73. Oberlin O, Rey A, Sanchez de Toledo J, et al. Randomized comparison of intensified six-drug versus standard three-drug chemotherapy for high-risk non metastatic rhabdomyosarcoma and other chemotherapy-sensitive childhood soft tissue sarcomas: long-term results from the International Society of Paediatric Oncology MMT95 study. J Clin Oncol 2012; 30: 2457–65. Stevens MC, Rey A, Bouvet N, et al. Treatment of nonmetastatic rhabdomyosarcoma in childhood and adolescence: third study of the International Society of Paediatric Oncology-SIOP Malignant Mesenchymal Tumour 89. J Clin Oncol 2005; 23: 2618–28. Oberlin O, Deley MC, Bui BN, et al. Prognostic factors in localized Ewing’s tumours and peripheral neuroectodermaltumours: the third study of the French Society of Paediatric Oncology (EW88 study). Br J Cancer 2001; 85: 1646–54. Kung FT, Chen HC, Huang CC, Ho JT, Cheng BH. Preservation of ovarian germinal follicles by temporary laparoscopic ovarian transposition in teenaged girls undergoing craniospinal irradiation for radiosensitive central nervous system tumours. Taiwan J Obstet Gynecol 2008; 47: 300–04. Kuohung W, Ram K, Cheng DM, Marcus KJ, Diller LR, Laufer MR. Laparoscopic oophoropexy prior to radiation for paediatric brain tumour and subsequent ovarian function. Hum Reprod 2008; 23: 117–21. Laufer MR, Upton J, Schuster SR, Grier H, Emans SJ, Diller L. Ovarian tissue autologous transplantation to the upper extremity for girls receiving abdominal/pelvic radiation: 20-year follow-up of reproductive endocrine function. J Pediatr Adolesc Gynecol 2010; 23: 107–10. Hudson M, Greenwald C, Thompson E. Efficacy and toxicity of multiagent chemotherapy and low-dose involved-field radiotherapy in children and adolescents with Hodgkin’s disease. J Clin Oncol 1993; 11: 100–08. Donaldson SS. Finding the balance in paediatric Hodgkin’s lymphoma. J Clin Oncol 2012; 30: 3158–59. Staege MS, Körholz D. New treatment strategies for Hodgkin’s lymphoma. Leuk Res 2009; 33: 886–88. Kluge R, Körholz D. Role of FDG-PET in staging and therapy of children with Hodgkin lymphoma. Klin Padiatr 2011; 223: 315–19 (in German). Cho WK, Lee JW, Chung NG, et al. Primary ovarian dysfunction after hematopoietic stem cell transplantation during childhood: busulfan-based conditioning is a major concern. Pediatr Endocrinol Metab 2011; 24: 1031–35. Balashov DN, Papusha LI, Nazarenko TA, et al. Recovery of ovarian function and pregnancy in a patient with AML after myeloablative busulphan-based conditioning regimen. J Pediatr Hematol Oncol 2011; 33: 154–55. Poirot C, Abirached F, Prades M, Coussieu C, Bernaudin F, Piver P. Induction of puberty by autograft of cryopreserved ovarian tissue. Lancet 2012; 379: 588. Sauvat F, Capito C, Bachelot A, Poirot C, Sarnacki N, Binart N. Use of immature cryopreserved ovary could restore puberty and fertility in mice: clinical implications for pre pubertal girls. PLoS One 2008; 3: e1972. Sauvat F, Bouilly J, Capito C, et al. Ovarian function is restored after grafting of cryopreserved immature ovary in ewes. FASEB J 2013; 27: 1511–18. Rosendahl M, Greve T, Andersen CY. The safety of transplanting cryopreserved ovarian tissue in cancer patients: a review of the literature. J Assist Reprod Genet 2013; 30: 11–24.
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Kim SS, Radford J, Harris M, et al. Ovarian tissue harvested from lymphoma patients to preserve fertility may be safe for autotransplantation. Hum Reprod 2001; 16: 2056–60. Jairam V, Roberts KB, Yu JB. Historical trends in the use of radiation therapy for paediatric cancers: 1973-2008. Int J Radiat Oncol Biol Phys 2013; 85: 151–55. Pisters PW, Harrison LB, Leung DH, Woodruff JM, Casper ES, Brennan MF. Long-term results of a prospective randomized trial of adjuvant brachytherapy in soft tissue sarcoma. J Clin Oncol 1996; 14: 859–68. Hong L, Alektiar KM, Hunt M, Venkatraman E, Leibel SA. Intensity-modulated radiotherapy for soft tissue sarcoma of the thigh. Int J Radiat Oncol Biol Phys 2004; 59: 752–59. Lee CT, Bilton SD, Famiglietti RM, et al. Treatment planning with protons for paediatric retinoblastoma, medulloblastoma, and pelvic sarcoma: how do protons compare with other conformal techniques? Int J Radiat Oncol Biol Phys 2005; 63: 362–72. Scott SM, Schlaff W. Laparoscopic medial oophoropexy prior to radiation therapy in an adolescent with Hodgkin’s disease. J Pediatr Adolesc Gynecol 2005; 18: 355–57. Chuai Y, Xu X, Wang A. Preservation of fertility in females treated for cancer. Int J Biol Sci 2012; 8: 1005–12. Clough KB, Goffinet F, Labib A, et al. Laparoscopic unilateral ovarian transposition prior to irradiation: prospective study of 20 cases. Cancer 1996; 77: 2638–45. Molpus KL, Wedergren JS, Carlson MA. Robotically assisted endoscopic ovarian transposition. JSLS 2003; 7: 59–62. Hwang JH, Yoo HJ, Park SH, et al. Association between the location of transposed ovary and ovarian function in patients with uterine cervical cancer treated with (postoperative or primary) pelvic radiotherapy. Fertil Steril 2012; 97: 1387–93. Gareer W, Gad Z, Gareer H. Needle oophoropexy: a new simple technique for ovarian transposition prior to pelvic irradiation. Surg Endosc 2011; 25: 2241–46. Feeney DD, Moore DH, Look KY, Stehman FB, Sutton GP. The fate of the ovaries after radical hysterectomy and ovarian transposition. Gynecol Oncol 1995; 56: 3–7. Husseinzadeh N, van Aken ML, Aron B. Ovarian transposition in young patients with invasive cervical cancer receiving radiation therapy. Int J Gynecol Cancer 1994; 4: 61–65. Chambers SK, Chambers JT, Kier R, Peschel RE. Sequelae of lateral ovarian transposition in irradiated cervical cancer patients. Int J Radiat Oncol Biol Phys 1991; 20: 1305–08. Terenziani M, Piva L, Meazza C, Gandola L, Cefalo G, Merola M. Oophoropexy: a relevant role in preservation of ovarian function after pelvic irradiation. Fertil Steril 2009; 91: 935: e15–e16. Morice P, Juncker L, Rey A, El-Hassan J, Haie-Meder C, Castaigne D. Ovarian transposition for patients with cervical carcinoma treated by radiosurgical combination. Fertil Steril 2000; 74: 743–48. Pahisa J, Martínez-Román S, Martínez-Zamora MA, et al. Laparoscopic ovarian transposition in patients with early cervical cancer. Int J Gynecol Cancer 2008; 18: 584–59. Huang KG, Lee CL, Tsai CS, Han CM, Hwang LL. A new approach for laparoscopic ovarian transposition before pelvic irradiation. Gynecol Oncol 2007; 105: 234–37. Williams RS, Littell RD, Mendenhall NP. Laparoscopic oophoropexy and ovarian function in the treatment of Hodgkin disease. Cancer 1999; 86: 2138–42. Anderson B, La Polla J, Turner D, Chapman G, Buller R. Ovarian transposition in cervical cancer. Gynecol Oncol 1993; 49: 206–14. Teinturier C. Fertility in adult survivors of cancer in infancy: sex inequalities before therapy. Arch Pediatr 2002; 9: S242–S244. Sauvat F, Binart N, Poirot C, Sarnacki S. Preserving fertility in prepubertal children. Horm Res 2009; 71: 82–86. Jayaprakasan K, Campbell B, Hopkisson J, Johnson I, Raine-Fenning N. A prospective, comparative analysis of antiMüllerian hormone, inhibin-B, and three-dimensional ultrasound determinants of ovarian reserve in the prediction of poor response to controlled ovarian stimulation. Fertil Steril 2010; 93: 855–64.
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Ovarian transposition in prepubescent and adolescent girls with cancer Sabine Irtan, Daniel Orbach, Sylvie Helfre, Sabine Sarnacki
Ovarian transposition was the first procedure proposed to preserve fertility in girls with cancer and is indicated for patients with tumours requiring pelvic radiation at doses of 42·0–58·4 Gy, much higher doses than those that can induce loss of ovarian function (4–20 Gy). Ovarian transposition is usually done after neoadjuvant chemotherapy and is completed by minimally invasive surgery or open surgery in case of concomitant resection of the abdominal tumour. According to the type of tumour, the ovaries are moved and placed in the paracolic gutters when the radiation field reaches the midline (for medulloblastoma or urogenital rhabdomyosarcoma), contralaterally to the tumour (for pelvic sarcomas), or in line with the iliac crests (for Hodgkin’s lymphoma). However, in 10–14% of cases the procedure can fail to protect the ovaries. Although few long-term results in adults are available, normal hormonal function and pregnancies have been reported in a few long-term follow-up studies. In view of the continued development of fertility preservation techniques, ovarian transposition should be discussed at a multidisciplinary meeting at the time of cancer diagnosis.
Introduction
Radiotherapy and ovarian function
Childhood cancers represent 1% of all cancers, corresponding to an incidence of 122 cases per million children in the USA,1 and 1800 new patients each year (700 of whom are aged 15–19 years) in France.2 Such tumours are specific to childhood and in most cases have an embryonic origin. A better understanding of the biology of these tumours and improvement of the aggressive treatment adapted to paediatric populations have greatly enhanced the life expectancy of this population. From 1980 to 2005, mortality from childhood cancer has decreased from 6·7 to 2·9 cases per 100 000 children.3,4 As a result, almost 80% of children and adolescents with a diagnosis of cancer now become long-term survivors. Reduction of morbidity related to long-term treatment is therefore a major criteria guiding the design of paediatric oncology protocols.5,6 After treatment, the potential adverse outcomes for women include impaired puberty and fertility or premature ovarian failure due to gonadal removal, genital tract injury, or damage to germ cells.7,8 At the time of diagnosis, most children with cancer are prepubescent (younger than 11 years of age); the median age at diagnosis is about 4·5 years. However, the median age can vary widely according to the type of tumour—eg, the median age is 16·3 months for vaginal germ cell tumours,9 4·3 years for pelvic rhabdomyosarcoma,10 and 16 years for Ewing’s sarcoma of the pelvic bone.11 In recent years, progress in assisted reproductive technologies has opened up new possibilities for the prevention and treatment of infertility. Ovarian transposition was the first procedure proposed for children with cancer to preserve ovarian function from damage caused by abdominal and pelvic radiotherapy. However, few studies12–17 have investigated the long-term efficacy of this technique in the preservation of the function of the ovaries. In this Review, we describe the optimum indications and techniques for ovarian transposition and define the place of this technique among other fertility preservation strategies in women with childhood cancer.
The ovaries are very radiosensitive organs. In animal experiments, irradiation causes direct DNA lesions in the ovaries and induces apoptosis in the growing follicle and dormant primordial follicle populations. Ionising radiation acts on these dividing and non-dividing cell populations.18 The extent of damage depends on the dose of radiotherapy that reaches the ovaries, the age of the girl at the time of treatment, and the associated drugs used for chemotherapy. A single dose of radiation of 2 Gy is able to destroy more than 50% of the ovarian follicular reserve, whereas a single dose of up to 10 Gy, delivered before puberty during total body irradiation, causes complete cessation of ovarian function in 55–80% of patients.19–21 Doses of 10–20 Gy in children and 4–6 Gy in adults are associated with permanent ovarian failure.22 However, fractionated radiotherapy at the same dose can preserve ovarian function.23 Lower and increasingly fractionated doses raise the possibility of repair of the damaged follicular population.24 For example, in a 10-year-old girl, fractionated radiotherapy to the ovarian field at a dose of 3 Gy induces early ovarian dysfunction at around the age of 36·7 years; a 6 Gy dose is associated with onset at 26·5 years; 9 Gy at 19·7 years, and 12 Gy at 15·3 years.25 Table 1 shows
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Lancet Oncol 2013; 14: e601–08 Paediatric Surgery Department, Necker EnfantsMalades Hospital, Paris Descartes University, Paris, France (Prof S Irtan MD, Prof S Sarnacki MD); and Adolescent and Paediatric Department (D Orbach MD), and Radiotherapy Department (S Helfre MD), Institut Curie, Paris, France Correspondence to: Prof Sabine Sarnacki, Chirurgie Pédiatrique et INSERM U-781, Hôpital et Faculté Necker Enfants-Malades, 149 rue de Sèvres, 75743 Paris Cedex 15, France [email protected]
Dose (Gy) Birth
20·3
10 years
18·4
20 years
16·5
30 years
14·3
35 years
13·0*
40 years
11·6*
Data from Wallace and colleagues.25 *Estimated from data from Wallace and colleagues.25
Table 1: Threshold doses of radiation that induced ovarian dysfunction according to age after fractionated radiotherapy
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threshold doses by age. Levine and coworkers6 investigated fertility problems in adolescents and young women after treatment of tumours by use of pelvic external beam radiotherapy and total body irradiation. Aside from cranial irradiation, which can cause hypogonadism via gonadotropin-releasing hormone deficiency at doses of 35–40 Gy, the risk of development of amenorrhoea after treatment was estimated to be as high as 80% after whole abdominal or pelvic irradiation at doses greater than 15 Gy in prepubescent girls, and after total body irradiation doses of 10 Gy in postpubertal girls, and 6 Gy in adult women. An intermediate risk (30–70%) was identified after whole abdominal or pelvic radiation at doses of 10–15 Gy in prepubescent girls and at doses of 5–10 Gy in postpubertal girls or after spinal irradiation of greater than 25 Gy. After pelvic irradiation, the obstetrical risk depends on the direct damage to the uterus and vascular tissue and the hormonal deficit. Damage to the uterus, identified as fibrosis, is noted in the uterus volume, endometrial tissue, and vascular system, particularly when delivered doses reach 20 Gy. More important than the toxic effects to the ovaries are uterine lesions if the patient is young (younger than 6 years of age) at the time of radiotherapy. Lesions are regarded as definitive and irreversible, even with a high dose of hormonal treatment. Letur-Kornisch and colleagues26 showed an improvement in endometrial thickness, myometrial dimensions, and diastolic uterine artery flow after treatment with entoxifylline-tocopherol, which led to uterine restoration after postirradiation sequellae. Critchley and coworkers27 investigated ten women with premature ovarian failure after total abdominal irradiation in childhood. The effect of radiation on the uterus was unpredictable, but the highest doses were most associated with vascular and uterine damage. In the women who had been exposed to radiation, the length of the uterus was significantly reduced, and most women had no uterine blood flow detectable by Doppler ultrasound. Three of the women showed no change in endometrial thickness after hormonal therapy. Different lesions have also been identified after brachytherapy, including endometrial atrophy, uterine fibrosis, cervical stenosis, vaginal synechiae, or fistula, which could be attributable to infertility.28 Pregnancies are also at risk after pelvic irradiation when the total dose delivered to the uterus is greater than 20–35 Gy. Stillbirths, neonatal death, low birthweight babies, and spontaneous abortions are the main problems.28 The odds ratio of a baby born with a low birthweight of less than 2500 g after a radiation dose of 5 Gy to the uterus is 6·8 (95% CI 2·1–22·2). The uterine wall is at increased risk of rupture in women who previously received radiotherapy, which can lead to the need for prophylactic caesarean section. All these risks require close monitoring throughout pregnancy.29 e602
Indications for ovarian transposition in childhood cancers The main tumours that require ovarian transposition are in adults—ie, cervical and rectal cancers—and are not usually identified in children.30–32 However, preliminary ovarian transposition should be considered for all children with tumours requiring radiotherapy implicating part of the pelvis. Rhabdomyosarcoma of the bladder, vagina, or uterus, or soft tissue or pelvic bone sarcomas, such as Ewing’s sarcoma, are the main diagnostic indications for ovarian transposition in children.9–11 Although rhabdomyosarcoma, a mesenchymal tumour, is very chemosensitive, local control is essential to avoid local and regional recurrence and radiotherapy cannot be avoided in many cases, dependent on alveolar subtype, completeness of initial surgery, nodal involvement, and age of the patients.10,33 High-dose brachytherapy, intensitymodulated radiotherapy, and intensity-modulated proton therapy are therefore proposed as an additional therapy or instead of surgery to increase local and regional tumour control and sometimes to avoid serious surgery.34,35 The total dose of irradiation for pelvic rhabdomyosarcoma usually ranges from 36 Gy to 54 Gy. To decrease the long-term adverse effects of treatment, the Malignant Mesenchymal Tumour Committee of the International Society of Paediatric Oncology have investigated effective strategies to avoid systematic irradiation or serious surgery in patients in complete remission after conservative surgery and chemotherapy.36,37 Irradiation is regularly administered for localised Ewing’s sarcoma when the initial tumour volume is greater than 200 mL (mainly pelvic primary tumours) after incomplete resection or poor response to neoadjuvant chemotherapy with more than 10% of residual viable cells on the surgical specimen.38 A total irradiation dose between 41·4 Gy and 59·4 Gy is required in these cases, and thus the ovaries need protection. Other disorders that often require ovarian transposition are metastatic medulloblastoma, in which high-dose spinal irradiation (36·0–59·4 Gy) is part of the treatment protocol,39,40 and large retroperitoneal or peritoneal seeding of nephroblastoma (Wilms’ tumour) requiring hemi-abdomen or whole abdomen irradiation at a dose of about 14·5 Gy.41 Other rare childhood tumours might also require pelvic irradiation such as rhabdomyosarcoma of the urachus, vaginal germ-cell tumours, pelvic synovial sarcoma, and inguinal nodal extension of a soft tissue sarcoma of the limbs. Clear-cell cervical carcinoma and primary or metastatic lesions of the conus medullaris also occasionally require ovarian transposition.12 However, Hodgkin’s lymphoma with abdominopelvic lymph node extension is reported in young adolescents and often requires radiotherapy. In a study42 of patients treated for Hodgkin’s lymphoma between 1980 and 1990, the investigators reported that subtotal or total abdominopelvic nodal irradiation (20 Gy dose, with an anteroposterior-posteroanterior technique) was associated www.thelancet.com/oncology Vol 14 December 2013
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with ovarian failure in 16% of patients, however ten patients had a total of 17 pregnancies. Irradiation confined to the initially involved-field in Hodgkin’s lymphoma has now mainly replaced large subtotal nodal irradiation and many of the devastating late effects have therefore been reduced.43 Moreover, the ongoing European protocol, EuroNet-PHL-C1, is trying to avoid systematic first-line radiotherapy in patients with early radiological and metabolic (PET scan) complete remission after neoadjuvant chemotherapy.44,45 Although protocols for high-risk neuroblastoma (metastatic or MYC-N amplified) include local radiotherapy, ovarian transposition is only occasionally indicated because the tumour rarely involves the pelvis and because treatment consists of high-dose chemotherapy, such as the melphalan plus busulfan regimen, which consistently induces complete suppression of ovarian function. Early ovarian cryopreservation is therefore systematically preferred for these children.46,47 Recent reports have shown the efficacy of use of immature cryopreserved ovarian tissue in the restoration of hormonal function in a prepubescent child48 and of fertility in experimental models.49,50 The indications for ovarian transposition now need revision and could include use of cryopreservation when the degree of gonadal protection is uncertain for an ovary. By contrast with when ovarian cryopreservation is indicated because of the expected toxicity of high-dose chemotherapy, ovarian transposition of the second ovary could be done if it was within the radiation field, even if viability of the ovary is unknown. Whatever the strategy used, the possibility of ovarian contamination by cancer cells is an issue, especially when the primary disease is likely to produce gonadal metastasis or to extend into the gonads. Some tumours are known to be at high risk of ovarian tumour spread— eg, rhabdomyosarcoma or other soft tissue sarcoma, A
Tranverse
neuroblastoma, and especially acute leukaemia51— whereas patients with Hodgkin’s lymphoma or nonHodgkin lymphoma are at low risk.52 Although the risk of relapse arising from ovaries either transposed or cryopreserved is probably low and has so far not been reported either in adults or children, prospective studies are needed to asses this risk. A recent review51 identified that 7% (31 of 422 all age patients) had histological evidence of malignant cell infiltration into cryopreserved ovarian tissue. According to the strategy of fertility preservation used, different risks of contamination with tumour cells arise. When ovarian transposition is undertaken, the risk of tumour relapse results from local spreading of tumour cells surrounding the transposed ovaries and is equivalent to a microscopic incomplete resection. This spread might have an important effect in some tumours, such as nephroblastoma. When the ovaries are cryopreserved, the risk is related to the potential reintroduction of the disease on transplantation. In the future, isolation of the germinal cells from the cryopreserved tissue and generation of oocytes by in-vitro culture might be possible to resolve this problem; this option has to be considered as the best alternative when ovarian transposition is thought to be hazardous because of potential cancer-cell contamination.
Technical aspects of pelvic radiotherapy in children In children, as in adults, a multidisciplinary approach involving oncologists, surgeons, radiologists, and radiation therapists is mandatory to define the optimum position for one or both of the ovaries to be transposed to. The first step in preparation for radiotherapy is to precisely define the new position of the ovaries (figure 1), possibly by use of imaging methods such as MRI or ultrasonography. In each case, the ovaries should be B
Anterior
Left Left
Right
C
Coronal
43·5 Gy 44·4 Gy 39·3 Gy 35·0 Gy 30·0 Gy 20·0 Gy 10·0 Gy 5·0 Gy 2·0 Gy 1·0 Gy
Sagittal
Right Posterior
Anterior
Posterior
Figure 1: Ovary protection from radiotherapy by transposition A 6-year-old girl with alveolar rhabdomyosarcoma of the left lower limb and left iliac lymph nodes was administered high-dose radiation therapy (41·4 Gy) delivered by tomotherapy to spare the delineated ovaries (white arrows). On the three views, (A) transverse, (B) coronal, and (C) sagittal, orange arrows show the initial position of the ovary in a high-dose radiation zone, whereas white arrows show the transposed, and therefore protected, ovary in a low-dose radiation zone. Colours show the radiation dose gradient.
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marked intraoperatively by metallic clips to make them visible on imaging before initiation of radiation therapy. The tumour volume is then delineated and all organs surrounding the tumour or tumour bed at risk of radiation damage, in the case of postoperative radiotherapy, are identified. The gross tumour volume (GTV) is defined by the tumour volume delineated on MRI and planning CT scans. The clinical target volume (CTV) is then constructed by expanding the GTV in all directions. In the case of initial complete surgical resection, the GTV cannot be precisely defined and the CTV is considered to be a larger volume encompassing the surgical bed with the appropriate safety margins defined by the chosen protocol. The planning target volume (PTV) is produced by expanding the CTV by 0·5–1 cm in all directions. The CTV-to-PTV expansion margins depend on immobilisation, image guidance, and reproducibility of the treatment set-up. Stable and reproducible positioning of the patient and treatment set-up are essential to ensure high-precision radiotherapy. The use of customised immobilisation devices (personalised thermoplastic masks) to provide reproducible daily set-up is strongly recommended, especially in children. Treatment is delivered with daily image-guided radiotherapy.53 The radiation technique is chosen on the basis of complexity and size of the tumour volume, the number and sites of organs at risk, and their radiosensitivity. Conventional and conformal irradiation techniques ensure adequate irradiation of tumour volumes, but also deliver large doses to the surrounding healthy tissues. However, intensity-modulated radiotherapy delivers a high dose to the tumour, while minimising the radiation dose to organs at risk adjacent to the tumour volume. Tomotherapy is one of the most specialised innovations in radiotherapy and combines, on the same machine, a linear electron accelerator that moves around and along the patient, and a CT scanner allowing very accurate guidance of irradiation. Helical tomotherapy delivers irradiation in the form of intensity-modulated photon beams and thus focuses a high dose on the tumour, while minimising the radiation dose to the surrounding healthy tissues and organs. Daily CT imaging allows accurate repositioning of the patient and adaptation of the radiotherapy plan on identification of major anatomical changes or tumour shrinkage. Interstitial brachytherapy is an effective method for delivery of adjuvant radiotherapy, within a substantially shorter treatment time than external beam radiotherapy and with potentially smaller treatment volumes.54 However, it is a complex and labour-intensive technique and its use in paediatric pelvic neoplasms is mainly confined to urogenital rhabdomyosarcoma.30,31 Morice and colleagues41 reported that brachytherapy used in small tumours either alone or in combination with external beam radiotherapy allowed a reduction in high radiation doses with good results on fertility. However, in some cases, uterovaginal brachytherapy might cause e604
other late effects (eg, endometrial atrophy, uterine sclerosis, or cervical stenosis) resulting in infertility. For more complex volumes, including the lymph nodes of Hodgkin’s lymphoma, more sophisticated therapies are needed, such as intensity-modulated radiotherapy, tomotherapy, stereotactic irradiation, or proton therapy. Intensity-modulated radiotherapy allows a reduction of the doses delivered to the healthy tissue and thus reduces the morbidity associated with external beam radiotherapy, while maintaining an effective local tumour dose and ensuring good local tumour control.55 A study56 comparing standard and advanced irradiation techniques showed that proton irradiation delivered the prescribed dose to pelvic sarcomas, while wholly sparing the ovaries (0% of the ovarian volume received a dose >2 Gy). Because of the physical characteristics of the Bragg peak (the path followed by ionising particles that reach a peak near the end of their path), protons have a stop dose, which stops the protons at the distal target margin, thereby sparing the normal structures beyond the tumour outline.
Technical aspects of ovarian transposition Irrespective of the surgical technique, ovarian transposition is designed to place the ovaries outside of the irradiation field. Detailed analysis of the initial pelvic MRI should be done to ensure that the tumour does not involve the ovarian region. The PTV should be precisely defined by the surgeon and the radiotherapist before ovarian transposition. Various sites of ovarian transposition can be considered. In the case of a midline irradiation field (urogenital tumours or medulloblastoma), both ovaries are usually placed away from the midline, laterally in the paracolic gutters, or laterally and anteriorly near the inguinal ring (bilateral ovarian transposition). In the case of a lateral tumour (rhabdomyosarcoma or Ewing’s sarcoma), the compromised ovary is placed on the opposite side of the tumour (unilateral ovarian transposition). In some cases of Hodgkin’s lymphoma, when the irradiation field implicates the bilateral iliac chains and the inguinal region, the ovaries are placed in line with the iliac crests (bilateral ovarian transposition).57 Ovarian transposition is usually done after neoadjuvant chemotherapy to attest tumour chemosensitivity and disease control. When the tumour is located in the abdomen or pelvis and when chemotherapy induces a tumour reduction allowing subsequent tumour resection ovarian transposition can be done during the same surgical procedure, usually via laparotomy. When the tumour is not situated in the pelvis—eg, high risk medulloblastoma—or when no surgery is planned—eg, Hodgkin’s lymphoma—laparoscopic ovarian transposition is the best option.58,59 So far, only one case of robotically assisted endoscopic ovarian transposition has been reported.60 Laparoscopic ovarian transposition is done under general anaesthesia. The patient is placed in the www.thelancet.com/oncology Vol 14 December 2013
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Trendelenburg position, so that the head is lower than the legs, which causes the intestine to fall into the upper part of the abdomen to free the pelvis and enable visualisation of the genital tract (figure 2). The bladder is emptied with a Foley’s catheter. An umbilical port is then inserted either via an infra-umbilical incision or directly through the umbilicus. Carbon dioxide is insufflated at a pressure of 10 or 12 mm Hg dependent on the patient’s age and weight. Two 5 mm ports are inserted under direct vision into the right and left hypogastric regions, almost at the same level as the umbilicus, dependent on the child’s age. A 0° or 30° angled camera can be used. The ovary is then seized and mobilised to identify which ligaments should be sectioned—the broad ligament, the ovarian ligaments, or the mesovarium—to separate the ovaries from the fallopian tubes.41 The blood supply to the ovaries should be carefully preserved, especially the ovarian vessels in the infundibulopelvic ligaments. On placement of the ovaries in their final position, the ovarian vessels should be examined to ensure the absence of any kinking or direct injuries.61 The ovaries are sutured to the peritoneum with resorbable or nonresorbable suture material (figure 3) and clips are placed to ensure visualisation on plain abdominal radiographs. When the ovaries are transposed close to the abdominal wall, they are held in position by a transparietal nonresorbable subcutaneous suture, which can simply be cut under local anaesthesia to return the ovaries to the normal position after completion of radiotherapy on outpatient basis without the need for readmission to the operating theatre.62 In children, this technique is particularly indicated in the case of a short course of irradiation (8 days), such as brachytherapy for urogenital rhabdomyosarcoma or giant-cell tumour.31 However, when a longer course of radiotherapy is needed (5–6 weeks), adhesions to the parietal paritoneum might prevent spontaneous return of the ovaries to the pelvis. The indication for another surgical procedure to return the gonads to their normal position remains controversial. Adnexal complications such as ovarian torsion and painful ovarian cysts have been reported in previous studies63,64 describing ovarian transposition techniques in adults, with some complication rates as high as 24%.65 Ovarian cysts after ovarian transposition have also been reported in children.12 However, these studies did not formally show the role of ovarian transposition in the pathogenesis of ovarian cysts, because patients in these studies also received several other methods of treatment. Another side-effect of ovarian transposition might be related to the increased distance between the ovary and the fallopian tube, in the case of mesovarium section, that distance could hamper progression of the oocyte to the genital tract, thereby impairing fertility. However, this procedure is rarely done in children. Furthermore, in a recent small series,62 a comparison of patients with or without ovarian repositioning did not show any benefit in terms of residual hormonal function. Other complications www.thelancet.com/oncology Vol 14 December 2013
reported in children include severe dyspareunia after retrouterine transposition, bowel obstruction, and pelvic adhesions resulting in tubal obstruction,12 these complications seem to be related to open laparotomy.
Figure 2: Normal laparoscopic view of the pelvis Green arrows show the position of the two ovaries and white arrow shows the position of the uterus before ovarian transposition.
A
B
Figure 3: Ovarian transposition (A) Left ovary (arrow) is sutured to the abdominal wall with a non-resorbable suture. (B) Position of left ovary (arrow) after transposition to the left paracolic gutters.
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Results of ovarian transposition Although ovarian transposition was the first approach developed for children to preserve gonadal function, very few studies have reported long-term results with laboratory and radiological assessment of ovarian function.12,66 However, several studies59,62,63,67–71 in adults have been reported and are summarised in table 2. In 1992, Thibaud and colleagues12 reported the first results of ovarian transposition in 18 children who underwent ovarian transposition at a mean age of 9·4 years (range 1·23–16·7). Investigators analysed gonadal function on the basis of results of folliclestimulating hormone, lutenising hormone, and oestradiol assays. On mean follow-up at 8·6 years (range 2·2 to 16·2 years), 16 patients had menstruated, two patients remained amenorrhoeic because of brachytherapyinduced lesions of the genital tract with no laboratory signs of ovarian insufficiency, and two pregnancies had occurred.12 A recent study66 with a follow-up of 14 years (range 5–23 years) reported 14 pregnancies after ovarian transposition in 11 women treated for Hodgkin’s lymphoma between 1972 and 1988, which resulted in 11 births and three miscarriages. None of these women underwent ovarian detransposition or artificial insemination. The frequency of congenital malformations, abortion, or prematurity did not differ from that of the general population. Only two studies12,66 report long-term follow-up results. However, another study40 reported the results of ovarian transposition in girls who received spinal irradiation for brain tumours, in which 15 girls who received ovarian transposition were compared with 11 girls who did not, and were matched for age at diagnosis, Patients Median age at (n) enrolment (year)
Type of cancer
Clough et al (1996)59
20
32·8
17 cervical cancer, 2 Hodgkin’s lymphoma, 1 ependymoma
Gareer et al (2011)62
12*
23·2
9 Hodgkin’s lymphoma, 3 rectal cancer
duration of follow-up, proportion of high risk tumours, and dose and duration of chemotherapy and radiation. Ovarian dysfunction, assessed by follicle-stimulating hormone assay and persistent amenorrhoea, was identified in 13% of patients in the ovarian transposition group, but 45% of patients in the non-ovarian transposition group. Although not significant (p=0·09), these results support the routine use of ovarian transposition whenever feasible.37 In another study, the surgical team undertook second-look laparoscopy to remove the non-resorbable sutures and took ovarian biopsy samples that showed normal follicle counts with more than ten germinal follicles per high-power field.39 Overall, the success rate of ovarian transposition in the paediatric population is difficult to establish because of the very small number of well-conducted studies, but seems to range between 60% and 83%.72,73 Because various laboratory markers, particularly inhibin B and anti-müllerian hormone assays,74 are now available to accurately assess ovarian function in survivors of cancer, long-term ovarian function should now be studied prospectively in all children who undergo ovarian transposition.
Conclusions Ovarian transposition is still a major approach to avoid ovarian damage when pelvic irradiation is indicated for childhood tumours. The development of laparoscopy should avoid the complications previously reported with laparotomy and shorten the time to resume treatment. However, the long-term results of ovarian transposition in childhood cancer have been inadequately studied. Follow-up (months)
Complications
Ovarian Pregnancy preservation
23·5
0
85·7%
0
Unknown
0
91·7%
3
50% 3 ovarian cysts, 1 haemorrhagic corpus luteum, 2 cancer recurrences
0
83%
3
Feeney et al (1995)63
132
33·5
132 cervical cancer
24
Morice et al (2000)67
107
33
107 cervical cancer
31
Pahisa et al (2008)68
28
35·7
28 cervical cancer
44·3
0
83·3%
0
Huang et al (2007)69
14
37·8
12 cervical cancer, 2 vaginal cancer
72
0
50%
0
Williams et al (1999)70
10
27·9
10 Hodgkin’s lymphoma
Unknown
0
50%
5
Anderson et al (1993)71
24
31
24 cervical cancer
58
0
33%
0
22 ovarian cysts, 1 metastasis, 1 bowel obstruction, 3 abdominal pain
*Six patients had ovarian repositioning.
Table 2: Studies investigating long-term outcome of ovarian transposition in adults
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Search strategy and selection criteria We searched PubMed for reports published in English between January, 1995, and March, 2013, with the search terms “oophoropexy”, “ovarian transplantation”, “fertility preservation”, “childhood, children, paediatric”, and “effect of radiotherapy on gonadal function (total body irradiation)”. We supplemented this search with review of the author’s own files. The final list of references was generated on the basis of their recent date of publication and their relevance to the broad scope of this Review.
Although ovarian function seems to be well preserved and several pregnancies have been reported, investigation of the hormonal status and fertility of these children, by use of the available radiological and laboratory instruments, is now essential. Because of the rarity of these cases, these data should be collected in the context of an international, multicentre study. Finally, in view of the broad range of fertility protection methods available and progress in medically assisted reproductive techniques, the best option for fertility preservation and follow-up should be established at a multidisciplinary meeting as soon as the treatment protocol has been defined. Contributors All authors contributed equally to the literature search, study design, data collection, and writing of this Review. Conflicts of interest We declare that we have no conflicts of interest. Acknowledgments We thank La Ligue Contre le Cancer for their financial support and Anthony Saul for editing assistance. References Li J, Thompson TD, Miller JW, Pollack LA, Stewart SL. Cancer 1 incidence among children and adolescents in the United States, 2001–2003. Pediatrics 2008; 121: 1470–77. 2 Lacour B, Guyot-Goubin A, Guissou S, Bellec S, Désandes E, Clavel J. Incidence of childhood cancer in France: National Children Cancer Registries, 2000-2004. Eur J Cancer Prev 2010; 19: 173–81. 3 Stiller CA, Desandes E, Danon SE, et al. Cancer incidence and survival in European adolescents (1978–1997). Report from the Automated Childhood Cancer Information System project. Eur J Cancer 2006; 42: 2006–18. 4 Desandes E, Lacour B, Belot A, et al. Cancer incidence and survival in adolescents and young adults in France, 2000–2008. Pediatr Hematol Oncol 2013; 30: 291–306. 5 Pui CH, Gajjar AJ, Kane JR, Qaddoumi IA, Pappo AS. Challenging issues in pediatric oncology. Nat Rev Clin Oncol 2011; 8: 540–49. 6 Levine J, Canada A, Stern CJ. Fertility preservation in adolescents and young adults with cancer. J Clin Oncol 2010; 28: 4831–41. 7 Sudour H, Chastagner P, Claude L, et al. Fertility and pregnancy outcome after abdominal irradiation that included or excluded the pelvis in childhood tumour survivors. Int J Radiat Oncol Biol Phys 2010; 76: 867–73. 8 Mörse H, Elfving M, Lindgren A, Wölner-Hanssen P, Andersen CY, Ora I. Acute onset of ovarian dysfunction in young females after start of cancer treatment. Pediat Blood Cancer 2013; 60: 676–81. 9 Magné N, Oberlin O, Martelli H, Gerbaulet A, Chassagne D, Haie-Meder C. Vulval and vaginal rhabdomyosarcoma in children: update and reappraisal of Institut Gustave Roussy brachytherapy experience. Int J Radiat Oncol Biol Phys 2008; 72: 878–83.
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