Surviving childhood and reproductive-age malignancy: effects on fertility and future parenthood

Review

Surviving childhood and reproductive-age malignancy: effects on fertility and future parenthood Jaime M Knopman, Esperenza B Papadopoulos, James A Grifo, M Elizabeth Fino, Nicole Noyes

Annually, more than 50 000 cancer diagnoses are made in the USA in patients under the age of 35 years. Despite this staggering statistic, medical advancements have substantially improved survival rates. Thus, for both male and female patients with cancer, quality-of-life issues, such as fertility preservation and parenthood, have become an essential component of treatment. Unfortunately, many of the treatments to eradicate malignant processes can also compromise reproductive function. In these cases, fertility preservation should be discussed and initiated with early treatment planning, to allow the best chance for future parenthood, when appropriate. The effects of cancer and cancer treatments on fertility and future parenthood, including health risks for patients, their gametes, and offspring are discussed.

Lancet Oncol 2010; 11: 490–98 Published Online February 15, 2010 DOI:10.1016/S14702045(09)70317-1 New York University Fertility Center, Department of Obstetrics and Gynecology, New York University School of Medicine, New York, NY, USA (J M Knopman MD, Prof J A Grifo MD, M E Fino MD, Prof N Noyes MD); and Bone Marrow Transplant Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA (E B Papadopoulos MD)

Introduction Early detection programmes combined with effective treatment regimens have allowed men and women with cancer to live substantially longer, making fertility preservation an essential component of therapy. Maintaining fertility and future parenthood are quality-oflife issues now desired by many survivors of cancer; in fact, one of the strongest predictors of emotional satisfaction in survivors is feeling healthy enough to be a good parent.1 However, patients are often fearful that their history of cancer and previous treatment will not only increase their risk of cancer recurrence, but also have an adverse obstetric or postnatal effect on their child (figure 1). Surveys suggest that only 50% of patients are counselled regarding the option of fertility preservation and the potential risks associated with pregnancy and parenthood after cancer,1 and even fewer are referred to a reproductive endocrinologist. This review discusses survival statistics and the medical and psychological effects of cancer on fertility treatment and future parenthood, including health risks for afflicted patients, their gametes, and offspring. It is estimated that 1 372 910 people were diagnosed with cancer in the USA in 2005, with 4% (55 000) younger than 35 years.2 Overall, more than 75% of cancer patients

Courtesy of Ilan Timor

Correspondence to: Dr Nicole Noyes, NYU Fertility Centre, 660 First Avenue, Fifth Floor, New York, NY 10015, USA [email protected]

Figure 1: Three-dimensional ultrasonography of a second trimester fetus Patients with a history of cancer and previous treatment worry about an adverse obstetric or postnatal effect on their child.

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under the age of 45 years now survive at least 5 years from the time of their diagnosis,3 with childhood cancers seeing striking improvements in survival; now, roughly one in every 1000 adults is a survivor of childhood cancer.4 The most common cancer diagnoses in younger patients include melanoma, non-Hodgkin and Hodgkin’s lymphoma, leukaemia, breast, cervical, and testicular cancer. Women of reproductive age are most often afflicted with breast or gynaecological malignancies, with up to 15% of breast and 43% of cervical cancer diagnoses in patients younger than 45 years.5 Reproductive-age males are most often diagnosed with testicular cancer and Hodgkin’s lymphoma, with around 90% of all testicular tumours arising from age 20–54 years. Lastly, haematological malignancies, such as leukaemias and lymphomas, are most often seen in children and young adults. Corresponding with increased survival of cancer is a high incidence of ovarian and testicular failure.6 Therefore, the American Society of Clinical Oncology guidelines now recommend that all patients receive some form of fertility preservation counselling.6

Effects of cancer and treatment on fertility Women Although female reproduction requires a functioning hypothalamic-pituitary-gonadal (H-P-G) axis, ovaries, and uterus, reproductive potential in women is mainly limited by available oocytes. The process of oogenesis begins before birth with a peak in oocyte number (6–7 million) at 20 weeks’ gestation, followed by progressive atresia and a quantitative oocyte drop to 1–2 million at birth and 300 000 at puberty.7 Oocytes remain arrested as primordial follicles until puberty, a stage postulated to be less sensitive to gonadotoxins.7 Once puberty is initiated, a monthly cohort of follicles is recruited, but only one will become dominant; the others undergo atresia. Accelerated atresia coincides with a decrease in the quantity and quality of oocytes, raising the risk of infertility, aneuploidy, and spontaneous miscarriage. A rise in serum follicle-stimulating hormone (FSH) is often an indicator of accelerated atresia and impending ovarian failure; before age 40 years, persistent FSH concentrations above 30 IU/L in the setting of www.thelancet.com/oncology Vol 11 May 2010

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amenorrhoea, regardless of inciting events, suggests a diagnosis of premature ovarian failure.8 Importantly, the maintenance of fertility is not equivalent to the maintenance of menses. Mitotic and meiotic events which occur during female gametogenesis have a pivotal role in the damage that ensues after cancer treatments. Cancer processes do not seem to have a direct effect on oocytes, although removal of reproductive organs and cytotoxic treatment can result in ovarian damage or failure. The damage after chemotherapy is mainly to maturing follicles, and the extent of damage depends on three factors; medication received, drug dosage, and patient age (panel 1). The exact dose of chemotherapy associated with gonadal failure is not always predictable, but depends on the agent given and age at time of administration.9 Decreased ovarian reserve and higher baseline follicular FSH levels, even in young patients with cancer, are indicative of accelerated oocyte atresia and decreased oocyte quality. By contrast with chemotherapy, radiation therapy has been shown to have damaging effects on the ovaries and on the uterus and hypothalamic-pituitary axis (figure 2). Abdominal-pelvic and total-body irradiation cause a doserelated reduction in the ovarian follicular pool, the magnitude of which is age-dependent. A recent mathematical model showed that around 2 Gy can destroy 50% of immature oocytes, and incrementally smaller doses cause more damage with advancing age.10 Furthermore, single-dose radiotherapy seems to be more toxic than fractionated doses. Radiation has several effects on the uterus. First, uterine vasculature is altered, potentially impairing cytotrophoblast invasion and resulting in decreased fetal-placental blood flow and fetal growth restriction.11 Second, uterine elasticity and volume can be decreased from radiation-induced myometrial changes, which can lead to preterm labour and delivery. Third, radiotherapy can injure the endometrium, preventing normal decidualisation and causing disorders of placental attachment, such as placenta accrete.11,12 Lastly, cranial radiation can lead to disruption of the H-P-G axis, resulting in dysregulation of the hormonal pathways responsible for menstruation and fertility. Associated side-effects are endocrinopathies (such as hypogonadism and hyperprolactinaemia), which result in amenorrhoea and infertility, and luteal phase defects, which are associated with pregnancy loss.13

Men Cancer as a disease process can have deleterious effects on male fertility. Several studies have shown that testicular cancer and Hodgkin’s lymphoma have a direct immunological or cytotoxic effect on germinal epithelium within the testes, through disruption of the H-P-G axis, even before the start of treatment.14,15 Anatomical changes and systemic processes, such as fever, can also lead to fertility impairment, and such events are associated with abnormalities in spermatogenesis in patients with www.thelancet.com/oncology Vol 11 May 2010

testicular cancer.14 Although the mechanism for this is unclear, some have suggested a paracrine effect from the tumour as well as a pre-existing germ-cell defect leading not only to defective spermatogenesis but also to cancer. Pretreatment impairment of spermatogenesis in patients with Hodgkin’s lymphoma has been suggested to occur as a result of immunological processes.16 By contrast with germ-cell development in women, where the gamete is not present until week 20 of gestation, germinal stem cells exist in the testes at birth, but do not develop into haploid gametes until puberty.3 Once initiated, germ cells in the mature testes constantly renew and differentiate into sperm, a process that takes about 67 days. This constant renewal assures that there are germ cells at different developmental stages in the mature testes at all times after puberty. By contrast, in the prepubertal testes, turnover is limited to early germ cells, making them highly sensitive to cytotoxic therapy.3 In addition to the seminiferous epithelium, which produces germ cells with support from Sertoli cells, the testes contain testosterone-producing Leydig cells. However, the seminiferous epithelium is more sensitive to the effects of both chemotherapy and radiotherapy than the Leydig cells. Therefore, azoospermia is often seen after cancer treatment, whereas clinical hypogonadism (with decreased testosterone) is less common.17 As with female patients, the effect of chemotherapy on male fertility depends on the agent used, dosage administered, and the age of the patient; however, prepubertal testes, with constant early germ cell turnover, are more sensitive to gonadotoxic agents than mature testes (panel 2).7 One study reported that almost one-third of male childhood cancer survivors become azoospermic and one-fifth oligozoospermic after chemotherapy; fortunately, the sperm produced after recovery appeared to contain the same amount of healthy DNA as control individuals, and is safe for use to achieve pregnancy.18 Radiation, similar to chemotherapy, interferes with rapidly dividing cells, thereby making the germ cells of spermatogenesis a target. Again, the effects of radiation are dictated by dosage, patient age and radiation field (figure 3).15 Spermatogenesis is highly susceptible to Panel 1: Factors affecting the incidence of ovarian failure after chemotherapy Age Increased incidence of ovarian failure in older patients (decreased primordial follicle reserve) Dose Increased incidence of ovarian failure with higher doses of gonadotoxic drugs Drug • High risk: cyclophosphamide, ifosfamide, chlomethine, busulfan, melphalan, procarbazine, chlorambucil • Moderate risk: cisplatin, carboplatin, doxorubicin • Low risk: methotrexate, vincristine, fluorouracil, bleomycin, dactinomycin, vinblastine

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radiation; doses exceeding 1·2 Gy are harmful and 4 Gy permanently damaging.7 Around 4–6 months after radiation, sperm counts will nadir. Pretreatment levels are not regained for 10–24 months; however, male patients receiving high doses require even longer recovery periods. 80% of those who receive total-body irradiation for stem-cell transplantation experience permanent gonadal failure.19 For patients in whom spermatogenesis returns, numerical, structural, and chromosomal abnormalities in the sperm seem to be increased. These abnormalities are known to resolve over time, and should be considered relative to the timing of future pregnancies.20 During treatment and recovery, attempts at pregnancy should be avoided. Leydig cells are more resistant to radiation damage and can preserve function at radiation doses of up to 20 Gy before puberty and up to 30 Gy after puberty.20 Thus, whereas spermatogenesis is severely impaired following such treatments, puberty and testosterone levels are unaffected.

Reproductive success after cancer and treatments In patients who have cancer treatment without a prior fertility preservation procedure, reproduction seems to be substantially reduced.21–25 The Childhood Cancer Survivor Study provided information on the reproductive outcome of survivors of paediatric cancer in the USA, who were diagnosed and treated from 1970–86.21,22 These data showed that female survivors and the partners of male survivors were substantially less likely to have livebirths compared with their siblings. Magelseen and colleagues23 showed an increase in the use of in-vitro fertilisation (IVF) in both male and female cancer patients, and a significant decrease in first-time parenthood probability in female patients compared with the general population. A Finnish study24 compared 25 784 childhood, adolescent, and young adulthood survivors of cancer with their 44 811 siblings and found that the relative probability of having a first child was reduced to 0·46 for women and 0·57 for men. Lastly, Cvancarova and co-workers25 compared the 10-year postdiagnosis reproduction rate of patients treated at a Norwegian institution to that of the general population, and found the rate in cancer survivors reduced by about 50% in females and 30% in males. The researchers also noted an association between sex, prediagnosis parenthood, cancer treatment period (before vs after 1988), and type of malignancy relative to post-diagnosis reproductive outcome; in general, higher reproduction was noted among female and male cancer patients who were childless at diagnosis, regardless of the timeperiod studied. This might reflect a patient’s satisfaction with having one biological child. Substantial improvement in post-diagnosis reproduction rates were seen after 1988, specifically in localised cervical and testicular cancers. Marginal improvement was observed in patients with localised ovarian cancer. With regard to post treatment, after 1988, male patients likely benefited from the 492

• Hypogonadism

Hypothalamus

GnRH

• Endocrinopathies (hypogonadism, hyperprolactinaemia) • Luteal phase defects

Pituitary FSH/LH • Ovarian damage and failure

Ovary

Uterus

• Alteration in uterine vasculature • Decreased uterine elasticity and volume • Endometrial damage

Oestrogen

Progesterone

Figure 2: Radiation effects on female fertility and reproductive outcome GnRH=gonadotropin-releasing hormone. FSH=follicle-stimulating hormone. LH=luteinising hormone.

increased availability of semen and testicular tissue cryopreservation, along with IVF and intracytoplasmic sperm injection (ICSI), the latter improving fertilisation for patients with suboptimum sperm. Fertility preservation in female patients probably contributed less to improved reproduction, since the availability of these options only recently improved after greater reporting of live births.26–28 Reproduction rates after specific cancer types have been reported. Haematological malignancies, particularly Hodgkin’s lymphoma, have received a great deal of attention because of their high curability and prevalence in the paediatric population. There has been an improvement in reproduction rates after treatment for Hodgkin’s lymphoma, as a result of changes in drug regimens and pelvic shielding for abdominal or pelvic irradiation; modern treatment attempts to limit the use of the gonadotoxic regimen, mechlorethamine, vincristine, procarbazine, and prednisone (MOPP), in favour of the less gonadotoxic, yet equally effective regimen of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD).29 Although marked improvement in reproductive potential after treatment with ABVD in male patients has been well documented, studies of www.thelancet.com/oncology Vol 11 May 2010

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female patients are somewhat limited because most have used premature amenorrhea rather than pregnancy as an endpoint.30,31 However, two recent independent studies reported a greater than 70% pregnancy rate in survivors of Hodgkin’s lymphoma treated with ABVD,30,32 a statistic which is reassuring when compared with the 76% amenorrhea rate reported in patients who had received more traditional treatment regimens.33 Although these data are reassuring, small sample sizes and young age at which patients attempted conception limit the generalisability of the results.32 The most common regimens for non-Hodgkin lymphoma include the highly gonadotoxic cyclophosphamide; therefore, the incidence of gonadal failure is high.34 Some studies have shown that the administration of gonadotropin-releasing hormone agonists, antagonists, or oral contraceptives before and during chemotherapy may inhibit ovarian function and therefore provide gonadal protection in female cancer patients, however currently available data is inconclusive.35 Bone-marrow transplant, a mainstay treatment for many haematological malignancies, usually requires pretreatment with highdose chemotherapy and with radiation doses associated with a high incidence of permanent gonadal failure.36 By contrast with treatment for lymphomas, leukaemia treatments mainly include antimetabolites and anthracyclines rather than alkylating agents, resulting in a reduced, although still substantial, incidence of gonadal failure.3,37 Despite these somewhat reassuring data, prophylactic cranial irradiation (PCI) remains an adjuvant treatment that, in some instances, is administered to children with acute lymphoblastic leukaemia (ALL); this treatment is associated with post-treatment compromise of H-P-G function. Bath and colleagues38 assessed adult H-P-G function after chemotherapy and PCI for childhood ALL and found that, although all 12 patients achieved puberty, they had significantly decreased urinary excretion of luteinising hormone, attenuated luteinising-hormone surges, and shorter luteal phases. Although pregnancy outcome was not studied, based on the association between shorter luteal phases and increased incidence of miscarriage, these findings suggest that PCI can contribute to infertility. Furthermore, first-birth rates in female survivors of childhood ALL receiving PCI were noted to be lower than in survivors who did not receive irradiation.39 The effects of breast-cancer treatment on ovarian function are difficult to generalise, because the incidence of gonadal failure is intricately linked to patient age, treatment regimen, cycle number, and medication dosage. The typical therapeutic regimen for early-stage disease includes cyclophosphamide, which is associated with a decreased incidence of post-treatment pregnancy when given to women of reproductive age. In fact, in a population-based study of 10 295 women aged 45 years or younger, 371 women (3·6%) had a total of 465 pregnancies.40 The pregnancy rates were somewhat more promising when stratified by patient age (3% for www.thelancet.com/oncology Vol 11 May 2010

Panel 2: Factors affecting the incidence of testicular failure after chemotherapy Age Increased incidence of testicular failure in younger patients (prepubertal testes with constant turnover of early germ cells are more sensitive than mature testes) Dose Increased incidence of testicular failure with higher doses of gonadotoxic drugs Cumulative dose for effect (prolonged azoospermia):2 cyclophosphamide 19 g/m², ifosfamide 42 g/m², busulfan 600 mg/kg, melphalan 140 mg/m², procarbazine 4 g/m², chlorambucil 1·4 g/m² Drug • High risk: cyclophosphamide, ifosfamide, chlomethine, busulfan, melphalan, procarbazine, chlorambucil • Moderate risk: cisplatin, carboplatin, doxorubicin • Low risk: methotrexate, vincristine, fluorouracil, bleomycin, dactinomycin, vinblastine

those younger than 45 years vs 8% for those younger than 35 years), although still quite low. For brain tumours (both benign and malignant), hypogonadism and endocrinopathies related to irradiation of the hypothalamus and pituitary, combined with direct gonadal damage produced by chemotherapy in the case of malignant disease, can result in reduced reproduction rates and even gonadal failure. Although studies show that the growth-hormone axis is the most radiosensitive region and is most often affected after paediatric and adult cranial irradiation, gonadal dysfunction as a result of highdose treatment (greater than 40 Gy) is common.41 In fact, the incidence of gonadotropin deficiency is 20–50% in long-term follow-up of such patients.41,42 Gonadotropin administration, with or without IVF, should restore pregnancy and livebirth success rates in those with hypopituitarism to that of the general population (depending on the amount of damage to ovarian function that results from combined chemotherapy and abdominal or pelvic irradiation). However, in Green and co-workers21,22 analysis of the Childhood Cancer Survivor Study, patients with a CNS tumour, and those with ALL treated with cranial spinal irradiation, had a substantially higher risk of miscarriage compared to patients with other tumour types, suggesting that despite the ability to achieve pregnancy, fertility remains compromised. In bone and soft-tissue sarcomas, which are uncommon but have a relatively high incidence in adolescent boys, there are only a few studies of fertility outcomes after treatment. Azoospermia and amenorrhoea have been reported,43 although a recent study reviewing fertility after treatment reported that all 15 male and female survivors who attempted conception succeeded.43,44

Health risks with fertility treatments after cancer Congenital anomalies in offspring The incidence of congenital anomalies after chemotherapy and radiation has been studied extensively. Patients with cancer often report fear of increased risk of congenital 493

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• Hypogonadism

Hypothalamus

GnRH

in an increased incidence of X-linked mutations.49 Furthermore, there does not seem to be an increase in childhood malignancies in the offspring, with the exception of cancers arising as a result of inherited syndromes (familial adenomatous polyposis, hereditary non-polyposis colon cancer, retinoblastoma, Li-Fraumeni syndrome, etc). An increase in the risk of congenital anomalies has been reported in the offspring of female survivors of cancer previously diagnosed with Wilms’ tumours and treated with flank radiation. The mechanism to explain this risk has not yet been identified, but may be the result of radiation damage to the female gamete.50

Female survivors • Endocrinopathies (hypogonadism, hyperprolactinaemia)

Pituitary

FSH/LH

Testes

• Testicular damage and azoospermia

Testosterone

Figure 3: Radiation effects on male fertility GnRH=gonadotropin-releasing hormone. FSH=follicle-stimulating hormone. LH=luteinising hormone.

anomalies in their offspring as the primary reason for abstaining from pregnancy after a cancer diagnosis.45 This concern is valid because drugs used to treat cancer are designed to interfere with DNA, cell division, and cellular metabolism, processes essential to embryogenesis and fetogenesis. Initial data from survivors of the atomic bomb in Japan did not identify an increased incidence of congenital or structural anomalies in their offspring, suggesting that although somatic cells were subject to damage from irradiation, germ cells were protected. Later, studies of the offspring of cancer survivors did not report an increased incidence of children with congenital or chromosomal anomalies.46,47 In an international study by Boice and colleagues,48 which included more than 25 000 survivors of childhood cancer who either fathered or gave birth to around 6000 children, there was no difference in the incidence of genetic or chromosomal anomalies in these children compared with their siblings controls. Additional studies have reported similar results.46,47 Some researchers have assessed the sex ratio of fetuses born to cancer survivors after treatment compared with the general population and noted no difference, ensuring that cancer treatment does not result 494

Maternal morbidity does not seem to be increased in most pregnancies of female cancer survivors; however, because treatment with some chemotherapy drugs can have lasting effects on specific organ systems, preconception counselling is often advised. Obstetrical complications that can occur seem to be specific to cancer type. For some patients with cervical cancer, the fertility-sparing procedure, radical trachelectomy, is now often done instead of radical hysterectomy. Accumulating evidence suggests that, in appropriately selected patients, diseasefree and overall survival is similar to that of radical hysterectomy.51 Despite cervical absence, post-operative pregnancy rates are about 50%, although these pregnancies are not without risk; so far, about 10% have ended in second trimester loss and another 19% were delivered prematurely in the third trimester, despite almost all being singleton deliveries.26 To reduce obstetrical risks, frequent midtrimester cervical surveillance has been advocated, and some surgeons are now leaving a small sliver of superior cervix in vivo when medically possible.26 In the 5% of endometrial carcinoma cases that occur in women of reproductive age, progestin therapy is associated with a greater than 80% rate of remission, albeit recurrences happen in up to 50% of patients.52 40% of reviewed patients achieved pregnancy, although two-thirds required assisted reproductive technologies.53 Because of the high recurrence rate, women who elect for conservative management are encouraged to undergo definitive treatment soon after delivery. Borderline, early-stage invasive epithelial and germ-cell ovarian tumours are now often managed by unilateral oophorectomy rather than bilateral gonadectomy and hysterectomy. The largest study of patients with earlystage, invasive epithelial ovarian cancers (EOC) who desired fertility preservation included 52 patients; 24 attempted conception and 17 conceived and delivered.54 Maltaris and colleagues55 reviewed obstetric outcome in 282 patients with EOC undergoing conservative surgical management, and found pregnancy rates of about 41%. Borderline, low-malignant-potential tumours treated conservatively also have excellent postoperative obstetrical outcomes, with 70% of those attempting conception being succesful, without an increase in recurrence risk.55 www.thelancet.com/oncology Vol 11 May 2010

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The most common fertility preservation option chosen by female cancer survivors includes removal and storage of gametes, embryo, or gonadal tissue. Of these options, embryo cryopreservation has been available longest and is therefore considered the gold standard. Babies born after frozen embryo transfer have shown no increased health risks.56 Alternatively, for women without a consenting male partner or who do not wish to create embryos using donated sperm, recent data supports the use of oocyte cryopreservation as a means of fertility preservation.57 Although earlier results with oocyte freezing were disappointing, improvements in freezing and thawing protocols have resulted in better outcomes in some centres. More than 900 babies have been born worldwide as a result of egg freezing, without any apparent increase in birth defects.28 Cryopreservation of ovarian tissue, whole ovaries, or both remains experimental but promising, with fewer than ten babies born from either technology using a woman’s own tissue.58–61 Although data is limited, the babies resulting from such procedures are without any notable abnormalities. As more patients successfully undergo fertility preservation treatment, newer strategies are emerging, with the best option based on patientspecific factors (age, diagnosis, treatment, prognosis, baseline health, and relationship status). The treatment should not introduce considerable additional risk, impede cancer treatment, or be carried out in cases of extremely poor prognosis.

Male survivors For male cancer patients, semen and sperm cryopreservation before cancer treatment are an effective means to store male gametes.17,62 Semen can be ejaculated or alternatively, sperm can be obtained surgically (when ejaculation is not possible) from the epididymis or testicular tissue and cryopreserved.62 Testicular tissue can also be frozen. For ejaculated semen, depending on the quantity and quality of stored samples, pregnancy can be achieved in the future with either insemination or IVF. Sperm derived from testicular biopsy or the epididymis invariably requires IVF with ICSI to achieve fertilisation and pregnancy. Pregnancy rates following these technologies using frozen-thawed male gametes can be equivalent to those using fresh semen, depending on the quality of the tissue or sperm obtained.63

Cancer recurrence in women related to post-diagnosis pregnancy Another fear associated with fertility after a cancer diagnosis is the effect that pregnancy will have on cancer recurrence. This is a particular concern for patients with breast cancer since oestrogen, a hormone markedly increased during pregnancy, is a growth factor for these tumours. Much debate has centred on whether women with breast cancer should be advised to abstain from pregnancy after diagnosis. Most studies addressing the prognostic effect of pregnancy after breast-cancer www.thelancet.com/oncology Vol 11 May 2010

treatment have included a small number of patients. However, the consensus of such studies is that women who achieve pregnancy following breast-cancer diagnoses and treatment do as well as, if not better than, women who abstain from pregnancy.40,64–66 Although raised oestrogen levels are a theoretical concern in patients with oestrogen-receptor-positive tumours, receptor status does not seem to affect recurrence rates after pregnancy.67 Assessment is limited, however, since most cancers diagnosed in women of reproductive age are oestrogenreceptor-negative. There is inherent selection bias in studies of breast-cancer recurrence after pregnancy— women who are healthier chose to get pregnant more than those who are not, and women who die will be considered lost to follow-up—as well as a limited number of study participants. However, the results are reassuring and offer hope for patients with breast cancer. A large population-based Danish study66 found that pregnancy did not confer an increased risk of recurrence, and these results were confirmed by an additional 10 years of data.40 In fact, in this study and one other,68 a slightly protective effect was noted after pregnancy. Although this conclusion must consider the healthy mother bias (women who conceived had earlier-stage disease than those who did not), the data are still promising.69 The ideal interval between diagnosis and treatment of breast cancer and pregnancy is unknown. Patients are currently advised to wait about 2 years after diagnosis before attempting conception. This recommendation is mainly derived from a large Canadian series, which found that women who became pregnant within 6 months of their treatment had a somewhat poor prognosis (5-year survival of 53·8%) compared with those who deferred pregnancy until 2 years after treatment (5-year survival of 78%).70 Furthermore, those who waited 5 or more years to become pregnant had a 100% survival rate. Adjuvant antioestrogen therapy (tamoxifen), administered for 5 years, can delay childbearing and compromise fertility as a result of advanced maternal age. Premature discontinuation of tamoxifen to achieve pregnancy is not recommended, because of the possible reduction in treatment efficacy, and women are not advised to conceive while taking tamoxifen, because of an increased incidence of congenital anomalies.71 However, there is no apparent increased risk of abnormalities in pregnancies conceived after tamoxifen therapy has been completed. Infertility after treatment is common among survivors of breast cancer, and some women diagnosed with a potentially treatable malignancy in their reproductive years will consider fertility preservation before initiation of cancer therapy. Oocyte and embryo freezing require a short cycle of ovarian hyperstimulation to achieve multifollicular development. Just as there are concerns regarding the safety of pregnancy (and increased oestrogen levels) after breast cancer, ovarian stimulation, which leads to supraphysiological oestradiol levels, can evoke similar fears. This concern led investigators to 495

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research new protocols that result in lower peak-serum oestradiol levels during ovarian stimulation.72 It is not yet clear whether these newer protocols will have any effect on cancer prognosis. Carriers of BRCA1 and BRCA2 are at increased risk for developing both breast and ovarian cancer. The American College of Obstetrics and Gynecologists recommends that a risk-reducing procedure (bilateral gonad removal) be offered to such patients by the age of 40 years, or after childbearing is finished, to reduce their risk of cancer. Although there is concern regarding the use of fertility medications in such patients, this has not been substantiated. Therefore, a diagnosis of carrying BRCA1 or BRCA2 may present another indication for fertility preservation.73 There is a paucity of long-term follow-up in patients with gynaecological malignancies regarding fertility preserving measures and cancer recurrence after successful pregnancy. In patients with ovarian cancer, most data regarding oncological outcomes after pregnancy come from patients with borderline ovarian tumours, early-stage invasive epithelial tumours, and germ-cell tumours. Although data is limited, recurrence rates do not seem to be increased in those who undergo fertility preservation procedures and subsequent pregnancy. Cancer recurrence after pregnancy in women with a history of non-gynaecological or non-oestrogen-sensitive tumours, such as brain and bone cancers, has not been well studied, but the mechanism of disease and tumourproliferation factors suggest that pregnancy should not result in an increased risk of recurrence. However, in concurrence with breast-cancer recommendations, patients are advised to wait about 2 years after treatment to conceive, because this is (in general) the most likely time for a recurrence to occur. Additionally, this provides ample time for the patient’s health status to return to baseline in preparation for pregnancy. Although recurrence after treatment for haematological malignancies, such as acute myeloid leukaemia and ALL, does not seem to be increased, patients with chronic myeloid leukaemia (CML; specifically those pretreated with total-body irradiation followed by allogenic bonemarrow transplant) may have a unique risk of relapse with subsequent pregnancy.74 Although patients with other malignant and non-malignant diseases have an increased risk of pregnancy complications after such treatment (total-body irradiation can negatively affect uterine competency), they do not seem to have an increased risk of recurrence. Data suggest that in patients with CML, the immunological surveillance required to sustain remission after bone-marrow transplant might be compromised by the immunotolerant state of pregnancy, contributing to an increased risk of relapse.74 Additionally, imatinib, a first-line treatment for CML, was found to be teratogenic in animals and is not currently recommended for use during pregnancy or breastfeeding. Patients who have shown a positive response to the drug are advised not to interrupt their therapy to conceive, because they 496

Search strategy and selection criteria References for this review were identified by searches of Medline and PubMed by use of the search terms “fertility”, “pregnancy”, “reproduction”, “cancer”, “recurrence rates”, “chemotherapy”, “radiation therapy”, “congenital anomalies”, “perinatal outcome after cancer treatment”, “obstetrical complications and cancer”, and “emotional side-effects of cancer”. Abstracts and reports from previous meetings were not included. Only papers published in English between January, 1979, and June, 2009, were included.

could risk a suboptimum treatment response or relapse.75 There is no consensus regarding the appropriate time interval required between imatinib use and pregnancy. Therefore, cryopreservation of oocytes or embryos with subsequent transfer to a gestational carrier might be the safest fertility preservation option for achieving biological parenthood in these patients.

Conclusion Despite the desire of many cancer patients to maintain fertility, several factors hinder the initiation of this discussion. In a survey given to oncologists, knowledge of resources, practice behaviours, perceptions of patient characteristics, and quality of discussion were identified as barriers to discussing fertility preservation.76 Discussions are further limited for paediatric patients, likely because of the consent process, issues surrounding the experimental nature of procedures, and gamete disposition in the event of death. However, most patients state that maintaining fertility and subsequent parenthood is of the highest importance. In fact, research has shown that experiencing cancer places an additional emphasis on family closeness and parent-child relationships. A web-based survey of patients with breast cancer reported that 57% had substantial concern regarding fertility at the time of diagnosis; 29% stated that fear of infertility affected their cancer treatment decisions and only 51% felt that their concerns were taken seriously.77 These percentages were lower in adolescents and young adults, with most reporting dissatisfaction with the information provided. Additionally, a survey of adolescent patients with cancer revealed that 81% would undergo investigative or research-based procedures in an attempt to maintain fertility.78 Oncologists must be aware of such desires and tailor treatment plans to include referral to a reproductive endocrinologist before the initiation of cancer treatment, when feasible. In summary, despite concerns regarding parenthood and pregnancy after cancer, maintaining fertility is a viable and often crucial option for many patients, and therefore must be addressed. A dedicated multidisciplinary team consisting of medical or surgical oncologists, a reproductive endocrinologist, genetics counsellor, perinatologist, and psychologist are required. This is currently achievable in centres where the disciplines, expertise, and interest exist. www.thelancet.com/oncology Vol 11 May 2010

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Contributors JMK was the primary author and organised the writing of the manuscript. NN wrote and reviewed the manuscript and recruited the efforts of a cancer specialist. EBP reviewed the manuscript and contributed content in specific areas. JAG reviewed the manuscript and contributed comments. MEF reviewed the manuscript and provided key references.

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Conflicts of interest The authors declared no conflicts of interest.

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