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Cancer, pregnancy and fertility: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

      introduction

      Over the past four decades, there has been a rising trend of delaying childbearing [
      • Matthews T.J.
      • Hamilton B.E.
      Delayed childbearing: more women are having their first child later in life.
      ]. Given that cancer incidence increases with age, more women are either diagnosed with cancer during the course of gestation or inquire into the feasibility and safety of pregnancy following cancer diagnosis. Here, we provide the ESMO Clinical Practice Guidelines for managing patients diagnosed with cancer during pregnancy. Also, we provide guidance on fertility considerations for women desiring pregnancy following cancer diagnosis. Given the relative rarity of the topic, we lack data from large randomised trials. Hence, the recommendations provided here are mainly based on well-conducted prospective and retrospective cohort studies along with systematic reviews and meta-analyses.

      cancer during pregnancy: incidence

      The diagnosis of cancer during pregnancy is uncommon. It is estimated that 1 in every 1000 pregnant women is diagnosed with cancer. Breast, melanoma and cervical cancers are those most commonly diagnosed during pregnancy, followed by haematological malignancies [
      • Pentheroudakis G.
      • Pavlidis N.
      Cancer and pregnancy: poena magna, not anymore.
      ,
      • Stensheim H.
      • Møller B.
      • van Dijk T.
      • Fosså S.D.
      Cause-specific survival for women diagnosed with cancer during pregnancy or lactation: a registry-based cohort study.
      ,
      • Mieog J.S.
      • van der Hage J.A.
      • van de Velde C.J.
      Neoadjuvant chemotherapy for operable breast cancer.
      ].

      diagnosis and biological features

      Obstetricians and general practitioners should be well informed of the possibility that a breast lump, an atypical vaginal discharge, a changing mole or an enlarging lymph node may be associated with a cancer diagnosis [V, A]. When indicated, pathological examination of suspected lesions should follow standard procedures as in the non-pregnant setting, including immunohistochemical or molecular analysis [
      • Amant F.
      • Deckers S.
      • Van Calsteren K.
      • et al.
      Breast cancer in pregnancy: Recommendations of an international consensus meeting.
      ] [V, B]. No clear evidence exists regarding the presence of different pathological features in patients diagnosed with cancer during pregnancy. Pathological features and prognosis of patients diagnosed during pregnancy are usually comparable with age- and stage-matched non-pregnant patients [
      • Stensheim H.
      • Møller B.
      • van Dijk T.
      • Fosså S.D.
      Cause-specific survival for women diagnosed with cancer during pregnancy or lactation: a registry-based cohort study.
      ] [IV, B]. The discussion remains open for breast cancer during pregnancy; while few studies have pointed to poor prognosis of patients diagnosed during pregnancy, others did not reproduce the same results [
      • Azim Jr, H.A.
      • Santoro L.
      • Russell-Edu W.
      • et al.
      Prognosis of pregnancy-associated breast cancer: a meta-analysis of 30 studies.
      ].
      Once the diagnosis of cancer during pregnancy is confirmed, we recommend referring the patient to an institution with expertise in dealing with such cases and possibly involving her partner and family in the decision-making process. Patients should be managed within a multidisciplinary team which includes an obstetrician and a neonatologist in addition to the oncology team in order to adequately evaluate potential maternal benefits and possible fetal risks [V, A].

      staging and risk assessment

      Imaging procedures should aim to limit the exposure to ionizing radiation, whenever possible. Ultrasound is the preferred imaging modality for breast, abdomen and pelvis. Chest X-ray and mammography with abdominal shielding can be safely carried out during pregnancy [IV, B]. Magnetic resonance imaging (MRI) without gadolinium can be used if any of the previously mentioned modalities were inconclusive or in cases of suspicious bone or brain metastases [IV, C]. Computed tomography (CT), bone and positron emission tomography (PET) scans should be avoided throughout the course of pregnancy [
      • Wang P.I.
      • Chong S.T.
      • Kielar A.Z.
      • et al.
      Imaging of pregnant and lactating patients: part 2, evidence-based review and recommendations.
      ].
      Considerable variations are observed in evaluating serum tumour markers during pregnancy, particularly for CA125 and CA15.3 [
      • Han S.N.
      • Lotgerink A.
      • Gziri M.M.
      • et al.
      Physiologic variations of serum tumor markers in gynecological malignancies during pregnancy: a systematic review.
      ], hence they should not be considered in the management of pregnant cancer patients [IV, C].

      obstetric care and fetal follow-up

      Systemic treatment with chemotherapy during the first trimester is associated with a high risk of miscarriage and in some cases congenital malformations, this being the period of organogenesis. The situation is less problematic when treatments are initiated in the second trimester. However, an increased number of obstetric and fetal complications are still observed even when chemotherapy is used in the second or third trimesters (Table 1) [
      • Van Calsteren K.
      • Heyns L.
      • De Smet F.
      • et al.
      Cancer during pregnancy: an analysis of 215 patients emphasizing the obstetrical and the neonatal outcomes.
      ,
      • Cardonick E.
      • Dougherty R.
      • Grana G.
      • et al.
      Breast cancer during pregnancy: maternal and fetal outcomes.
      ,
      • Loibl S.
      • Han S.N.
      • von Minckwitz G.
      • et al.
      Treatment of breast cancer during pregnancy: an observational study.
      ]. This includes a relatively higher risk of intrauterine growth restriction, premature rupture of membranes and premature labour. Thus, while current recommendations advocate standard chemotherapy regimens in pregnant cancer patients after the first trimester, this might not be feasible in all cases and hence tailored approaches may sometimes be needed.
      Table 1Obstetric complications, fetal weight and complications at birth secondary to exposure to chemotherapy during the second and third trimesters in three large cohort studies
      Cancer typeObstetric complicationsFetal weight below 10th percentileFetal complications at birth
      Chemo
      All treatments were given during the second or third trimesters; 85%–90% of chemotherapy was anthracycline-based
      No chemoChemoNo chemoChemoNo chemo
      Van Calsteren et al. [
      • Van Calsteren K.
      • Heyns L.
      • De Smet F.
      • et al.
      Cancer during pregnancy: an analysis of 215 patients emphasizing the obstetrical and the neonatal outcomes.
      ]
      All17/62 (27%)11/118 (9%)14/62 (22%)12/113 (11%)7/62 (11%)6/113 (5%)
      Cardonick et al. [
      • Cardonick E.
      • Dougherty R.
      • Grana G.
      • et al.
      Breast cancer during pregnancy: maternal and fetal outcomes.
      ]
      Breast Cancer22/104 (22%)NR8/104 (7.5%)0/12 (0%)12/104 (11%)2/12 (16%)
      Loibl et al. [
      • Loibl S.
      • Han S.N.
      • von Minckwitz G.
      • et al.
      Treatment of breast cancer during pregnancy: an observational study.
      ]
      Breast Cancer31/179 (17%)15/149 (9%)15/175 (9%)5/139 (4%)31/203 (15%)7/170 (4%)
      a All treatments were given during the second or third trimesters; 85%–90% of chemotherapy was anthracycline-based
      Available clinical data suggest that fetuses exposed to chemotherapy starting in the second trimester do not experience significant long-term complications [
      • Amant F.
      • Van Calsteren K.
      • Halaska M.J.
      • et al.
      Long-term cognitive and cardiac outcomes after prenatal exposure to chemotherapy in children aged 18 months or older: an observational study.
      ,
      • Litton J.K.
      • Hodge S.
      • Mattair D.
      • et al.
      Outcomes of children exposed to chemotherapy in utero for breast cancer.
      ]. Nevertheless, these pregnancies should be regarded as high risk, and it is therefore reasonable to consider regular fetal monitoring during gestation [V, C]. We recommend targetting full-term delivery (i.e. ≥37 weeks) whenever possible [III, A], since subtle but significant cognitive impairment has been described in preterm babies who have been exposed to chemotherapy in-utero [
      • Amant F.
      • Van Calsteren K.
      • Halaska M.J.
      • et al.
      Long-term cognitive and cardiac outcomes after prenatal exposure to chemotherapy in children aged 18 months or older: an observational study.
      ]. Early or very early delivery (i.e. between 34–37 weeks and <34 weeks, respectively) should be discouraged, unless maternal and/or fetal health are endangered by the postponement of delivery until term.
      Placental metastases remain a rare event. However, whenever possible, we recommend subjecting the placenta to histological examination, particularly in patients diagnosed with melanoma, which remains the most common tumour associated with placental metastasis [
      • Perret-Court A.
      • Fernandez C.
      • Monestier S.
      • et al.
      [Placental metastasis of melanoma: a new case and literature review].
      ].

      local treatments

       general concepts

       surgery

      Surgery can be safely carried out at any time during the course of the pregnancy. However, a slightly higher risk of miscarriage has been reported during the first trimester [IV, B]. Major abdominal and pelvic surgery might be associated with increased morbidity, and pregnancy complications during the whole pregnancy and their indications should follow a thorough discussion with the patient and the multidisciplinary team. Nevertheless, surgery should never be postponed if deemed to be crucial in the management plan [IV, B], with careful monitoring of maternal and fetal conditions, particularly after the 25th week of gestation.

       radiotherapy

      Several fetal adverse effects, including the risk of childhood cancer, intrauterine growth restriction, mental retardation or even fetal death have been described after gestational radiotherapy. The critical factors are fetal dosage, radiation field extension and gestational age [
      • Gentilini O.
      • Cremonesi M.
      • Trifirò G.
      • et al.
      Safety of sentinel node biopsy in pregnant patients with breast cancer.
      ]. An increased risk of fetal malformation and mental retardation occurs with radiation doses >100–200 mGy [
      • Kal H.B.
      • Struikmans H.
      Radiotherapy during pregnancy: fact and fiction.
      ]. This dose is generally not reached with curative radiotherapy during pregnancy, provided that tumours are located sufficiently far from the uterus with adequate shielding. Nevertheless, even lower dosages might be causal in the development of childhood cancer or sterility. Hence, it is preferable to postpone radiation therapy to the postpartum period irrespective of the treated site, unless there is an urgent clinical need and provided that the site is located sufficiently far from the uterus [IV, C].

       breast cancer

      The decision to proceed to mastectomy or breast conservative surgery should follow the standard practice as in the non-pregnant setting [IV, B]. Either can be safely carried out at any time during the course of gestation [
      • Amant F.
      • Deckers S.
      • Van Calsteren K.
      • et al.
      Breast cancer in pregnancy: Recommendations of an international consensus meeting.
      ].
      Relatively limited data are available on sentinel lymph node biopsy (SLNB) in breast cancer patients diagnosed during pregnancy. Several simulation studies pointed out to the safety of lymphoscintigraphy using Technetium-99 [
      • Gentilini O.
      • Cremonesi M.
      • Trifirò G.
      • et al.
      Safety of sentinel node biopsy in pregnant patients with breast cancer.
      ,
      • Spanheimer P.M.
      • Graham M.M.
      • Sugg S.L.
      • et al.
      Measurement of uterine radiation exposure from lymphoscintigraphy indicates safety of sentinel lymph node biopsy during pregnancy.
      ]. Only one clinical series involving 12 pregnant breast cancer patients has been reported to date [
      • Gentilini O.
      • Cremonesi M.
      • Toesca A.
      • et al.
      Sentinel lymph node biopsy in pregnant patients with breast cancer.
      ]. No fetal defects secondary to SLNB were observed and no evidence of axillary relapse was encountered at a median follow-up of 32 months. It is clear that more data on SLNB are needed in the pregnancy setting; however, we would not discourage SLNB in pregnant breast cancer patients in centres in which SLNB is routine practice in the non-pregnant setting [IV, C]. We discourage the use of vital blue dye in pregnant patients [V, D], which is associated with a 2% risk of allergic reactions which could be life-threatening [
      • Cimmino V.M.
      • Brown A.C.
      • Szocik J.F.
      • et al.
      Allergic reactions to isosulfan blue during sentinel node biopsy—a common event.
      ].
      The fetal exposure secondary to adjuvant breast irradiation is expected to be low and below the threshold for deterministic effects, if radiation is during the first or second trimesters. However, adjuvant radiotherapy is never an urgent procedure and hence it is advisable to postpone it until delivery [V, D]. Careful planning of the local management strategy should be made in breast cancer patients diagnosed during the first trimester. When breast-conserving surgery is planned, it should be acknowledged that postponement of radiotherapy until delivery could result in delay of radiotherapy for >6 months, which could increase the risk of local recurrence [
      • Chen Z.
      • King W.
      • Pearcey R.
      • et al.
      The relationship between waiting time for radiotherapy and clinical outcomes: a systematic review of the literature.
      ]. Hence, thorough discussion should take place between the patient and the multidisciplinary team to discuss the risks and benefits of the different surgical modalities and the timing of radiotherapy in such cases.

       cervical cancer

      Radical hysterectomy and/or pelvic radiotherapy with or without cisplatin are the main modalities used in managing cervical cancer. Radical surgery and pelvic radiation would result in pregnancy termination and fetal death. Therefore, patients who wish to preserve their pregnancy should be informed that management would require modification of standard local treatment. Whether this could potentially have detrimental effects on patient outcome remains unknown.
      Treatment depends on stage and gestational age. In early-stage cervical cancer, definitive treatment can be postponed until after delivery, with close monitoring during pregnancy [V, B].
      For more advanced cases (stage IB1, IB2, IIA), in patients who wish to preserve the pregnancy, thorough radiological and surgical staging is used to discriminate between immediate treatment and watchful waiting [V, C].
      Pelvic MRI during pregnancy has shown a good positive predictive value for nodal metastases [
      • Balleyguier C.
      • Fournet C.
      • Ben Hassen W.
      • et al.
      Management of cervical cancer detected during pregnancy: role of magnetic resonance imaging.
      ], but the gold standard remains lymphadenectomy. This procedure can be safely carried out laparoscopically during pregnancy, even if the risk of bleeding or complications may be higher, compared with non-pregnant cases [
      • Shepherd J.H.
      Cervical cancer.
      ].
      If the patient needs treatment for a locally advanced or high-risk tumour, platinum-based chemotherapy with or without paclitaxel can be proposed [
      • Morice P.
      • Uzan C.
      • Gouy S.
      • et al.
      Gynaecological cancers in pregnancy.
      ,
      • Fruscio R.
      • Villa A.
      • Chiari S.
      • et al.
      Delivery delay with neoadjuvant chemotherapy for cervical cancer patients during pregnancy: a series of nine cases and literature review.
      ], with a local response rate similar to non-pregnant cases.
      Radical surgery can be offered concomitantly to Caesarean section in qualified centres [V, B].
      Table 2 summarises the ESMO Clinical Practice Guidelines for managing cervical cancer during pregnancy [V, C]. Active treatment with modified strategies has been advocated also by other groups [
      • Morice P.
      • Uzan C.
      • Gouy S.
      • et al.
      Gynaecological cancers in pregnancy.
      ,
      • Amant F.
      • Van Calsteren K.
      • Halaska M.J.
      • et al.
      Gynecologic cancers in pregnancy: guidelines of an international consensus meeting.
      ].
      Table 2ESMO Clinical Practice Guidelines in patients diagnosed with cervical cancer during pregnancy
      Time of diagnosisRecommendations
      First trimesterDiscuss pregnancy termination and standard treatment as outside pregnancy.

      If the patient wishes to preserve the pregnancy, discuss close monitoring up to second trimester (see below).
      Second trimesterStage IB1Lymphadenectomy
      • i)
        Node-negative: watchful waiting or chemotherapy
        Cisplatin (75 mg/m2 q 3 weeks) or carboplatin-based regimens ± paclitaxel regimens q 3 weeks or weekly.
        during pregnancy, followed by hysterectomy or large cone after delivery.
      • ii)
        Node-positive: chemotherapy
        Cisplatin (75 mg/m2 q 3 weeks) or carboplatin-based regimens ± paclitaxel regimens q 3 weeks or weekly.
        during pregnancy followed by radical hysterectomy at delivery or chemo-radiotherapy following delivery.
      Discuss pregnancy termination and standard treatment as outside pregnancy.
      Stage IB2-IVAChemotherapy
      Cisplatin (75 mg/m2 q 3 weeks) or carboplatin-based regimens ± paclitaxel regimens q 3 weeks or weekly.
      during pregnancy. Manage the case by surgery and/or chemoradiotherapy according to the stage and level of nodal involvement after delivery.

      Discuss pregnancy termination and standard treatment as outside pregnancy.
      Distant metastasisChemotherapy during pregnancy.

      Discuss pregnancy termination and standard treatment as outside pregnancy.
      Third trimesterDelay treatment until delivery and consider early induction of labour.
      a Cisplatin (75 mg/m2 q 3 weeks) or carboplatin-based regimens ± paclitaxel regimens q 3 weeks or weekly.

      systemic treatments

       general concepts on the use of chemotherapy during pregnancy

      Chemotherapy should not be administered during the first trimester of gestation [IV, D] since it is associated with a high risk of fetal congenital malformations reaching as high as 20% [
      • Azim Jr, H.A.
      • Peccatori F.A.
      • Pavlidis N.
      Treatment of the pregnant mother with cancer: a systematic review on the use of cytotoxic, endocrine, targeted agents and immunotherapy during pregnancy. Part I: solid tumors.
      ]. In patients requiring chemotherapy initiation during the first trimester, pregnancy termination would be considered [IV, B]. Administration of chemotherapy during the second and third trimesters has not been associated with significant fetal defects in the short or long term. However, it is important to note that not all chemotherapeutic agents should be regarded as ‘equally safe’ even when administered after the first trimester [
      • Azim Jr, H.A.
      • Peccatori F.A.
      • Pavlidis N.
      Treatment of the pregnant mother with cancer: a systematic review on the use of cytotoxic, endocrine, targeted agents and immunotherapy during pregnancy. Part I: solid tumors.
      ,
      • Azim Jr, H.A.
      • Pavlidis N.
      • Peccatori F.A.
      Treatment of the pregnant mother with cancer: a systematic review on the use of cytotoxic, endocrine, targeted agents and immunotherapy during pregnancy. Part II: hematological tumors.
      ]. This will be further discussed in subsequent sections.
      Dose calculation should follow the standard procedures outside the pregnancy setting [IV, B], acknowledging that the pharmacokinetics of some cytotoxic drugs might be altered during pregnancy [
      • Van Calsteren K.
      • Verbesselt R.
      • Ottevanger N.
      • et al.
      Pharmacokinetics of chemotherapeutic agents in pregnancy: a preclinical and clinical study.
      ].
      A 3-week period should be allowed between the last chemotherapy dose and the expected date of delivery to avoid delivery during the nadir period [IV, B]. However, spontaneous delivery could occur any time after week 34 of gestation and hence chemotherapy should not be administered beyond week 33 of gestation. This risk is relatively lower when weekly schedules are used, particularly with doxorubicin, epirubicin and paclitaxel. Their weekly application has been shown to be associated with lower risk of haematological toxic effects and shorter nadir periods [
      • Ellis G.K.
      • Barlow W.E.
      • Gralow J.R.
      • et al.
      Phase III comparison of standard doxorubicin and cyclophosphamide versus weekly doxorubicin and daily oral cyclophosphamide plus granulocyte colony-stimulating factor as neoadjuvant therapy for inflammatory and locally advanced breast cancer: SWOG 0012.
      ,
      • Sparano J.A.
      • Wang M.
      • Martino S.
      • et al.
      Weekly paclitaxel in the adjuvant treatment of breast cancer.
      ], warranting the consideration of this approach in pregnant cancer patients [IV, C].

       breast cancer

      The indications for systemic therapy should follow those for the non-pregnant setting, taking into consideration the gestational age at diagnosis and the expected date of delivery. Table 3 summarises the ESMO Clinical Practice Guidelines for the management of breast cancer during pregnancy according to the gestational age and breast cancer subtype [IV, B].
      Table 3ESMO Clinical Practice Guidelines for systemic management of patients diagnosed with breast cancer during pregnancy according to gestational age at diagnosis and breast cancer subtype
      Breast cancer subtypeRecommendations
      Endocrine-sensitiveHormonal agents (LHRH, tamoxifen) are contraindicated during pregnancy.

      Early (i.e. adjuvant, neoadjuvant)
      • i)
        If node-positive, and/or signs of aggressive disease (i.e. luminal-B), wait until second trimester and start anthracycline-based chemotherapy. Patients diagnosed in the third trimester could be counselled on a case-by-case basis and in some of them treatment could be deferred until delivery.
      • ii)
        If node-negative, low proliferative disease (i.e. luminal-A), observe until delivery, then start hormonal therapy.
      Metastatic
      • i)
        Wait until the second trimester and start an anthracycline-based regimen.
      HER2-positiveHER2-targeted agents are contraindicated during pregnancy.

      Early (i.e. adjuvant, neoadjuvant)
      • i)
        Wait until second trimester and start anthracycline-based chemotherapy until delivery. Taxanes could be added in sequence during pregnancy if needed,
      • ii)
        Trastuzumab to be added following delivery.
      • iii)
        Patients diagnosed in the third trimester could start chemotherapy until W34 and aim to deliver at term.
      Metastatic
      • i)
        If chemotherapy and/or trastuzumab need to be urgently started during the first trimester, discuss pregnancy termination. Otherwise, follow the procedure as in the early setting.
      Triple negativeEarly (i.e. adjuvant, neoadjuvant)
      • i)
        Wait until the second trimester and start an anthracycline-based chemotherapy until delivery. Taxanes could be added in sequence during pregnancy if needed.
      • ii)
        Patients diagnosed in the third trimester could start chemotherapy until W34 and aim to deliver at term.
      Metastatic
      • i)
        If chemotherapy needs to be urgently started during the first trimester, discuss pregnancy termination. Otherwise, follow the procedure as in the early setting.
      Anthracycline-based regimens are the most studied during pregnancy and remain the first choice [
      • Cardonick E.
      • Dougherty R.
      • Grana G.
      • et al.
      Breast cancer during pregnancy: maternal and fetal outcomes.
      ,
      • Loibl S.
      • Han S.N.
      • von Minckwitz G.
      • et al.
      Treatment of breast cancer during pregnancy: an observational study.
      ,
      • Hahn K.M.
      • Johnson P.H.
      • Gordon N.
      • et al.
      Treatment of pregnant breast cancer patients and outcomes of children exposed to chemotherapy in utero.
      ,
      • Peccatori F.A.
      • Azim Jr, H.A.
      • Scarfone G.
      • et al.
      Weekly epirubicin in the treatment of gestational breast cancer (GBC).
      ] [III, A]. There is no particular preference given for one regimen over another (e.g. AC, FAC, FEC, EC), hence the choice should be made based on the local practice in the non-pregnant setting. To date, none of the studies has shown an increased risk of fetal cardiotoxicity secondary to in-utero exposure to an anthracycline-based regimen [
      • Cardonick E.
      • Dougherty R.
      • Grana G.
      • et al.
      Breast cancer during pregnancy: maternal and fetal outcomes.
      ,
      • Loibl S.
      • Han S.N.
      • von Minckwitz G.
      • et al.
      Treatment of breast cancer during pregnancy: an observational study.
      ,
      • Hahn K.M.
      • Johnson P.H.
      • Gordon N.
      • et al.
      Treatment of pregnant breast cancer patients and outcomes of children exposed to chemotherapy in utero.
      ,
      • Peccatori F.A.
      • Azim Jr, H.A.
      • Scarfone G.
      • et al.
      Weekly epirubicin in the treatment of gestational breast cancer (GBC).
      ].
      Data from animal models have shown that transplacental transfer of both paclitaxel and docetaxel is minimal, probably as a result of high expression of p-glycoprotein in the placenta [
      • Van Calsteren K.
      • Verbesselt R.
      • Van Bree R.
      • et al.
      Substantial variation in transplacental transfer of chemotherapeutic agents in a mouse model.
      ]. A recent systemic overview of 50 breast cancer patients treated with taxanes has shown adequate pregnancy outcomes [
      • Zagouri F.
      • Sergentanis T.N.
      • Chrysikos D.
      • et al.
      Taxanes for breast cancer during pregnancy: a systematic review.
      ]. The same data were shown in 15 and 12 patients reported within European- and American-based registries, respectively [
      • Loibl S.
      • Han S.N.
      • von Minckwitz G.
      • et al.
      Treatment of breast cancer during pregnancy: an observational study.
      ,
      • Cardonick E.
      • Bhat A.
      • Gilmandyar D.
      • Somer R.
      Maternal and fetal outcomes of taxane chemotherapy in breast and ovarian cancer during pregnancy: case series and review of the literature.
      ]. Hence, we endorse the use of taxanes during pregnancy in cases where they are clinically indicated or the use of anthracyclines is contraindicated [IV, C]. Outside the pregnancy setting, weekly paclitaxel (80 mg/m2) or 3-weekly docetaxel (100 mg/m2) are the most effective schedules. During pregnancy, the former would allow close pregnancy monitoring since it is a weekly schedule; it is also associated with a better overall toxicity profile [
      • Sparano J.A.
      • Wang M.
      • Martino S.
      • et al.
      Weekly paclitaxel in the adjuvant treatment of breast cancer.
      ], with no need for high dose steroid premedication or prophylactic use of granulocyte colony stimulating factor (GCSF). Very limited data are available on the safety of the docetaxel schedule, and thus its use should be restricted to situations in which it is clinically urgent [V, C]. Weekly paclitaxel would therefore be the preferred option if taxanes were to be considered in pregnant breast cancer patients [V, C].
      The use of tamoxifen during pregnancy is contraindicated at any time during the course of pregnancy as it has been shown to be associated with fetal malformation [
      • Braems G.
      • Denys H.
      • De Wever O.
      • et al.
      Use of tamoxifen before and during pregnancy.
      ] [V, E].
      Trastuzumab is a monoclonal antibody that crosses the placenta at increased levels starting in the second trimester [
      • Pentsuk N.
      • van der Laan J.W.
      An interspecies comparison of placental antibody transfer: new insights into developmental toxicity testing of monoclonal antibodies.
      ]. Consistent observations have been made of an apparent high risk of oligo-anhydramnios secondary to exposure to trastuzumab during the second and third trimesters [
      • Azim Jr, H.A.
      • Azim H.
      • Peccatori F.A.
      Treatment of cancer during pregnancy with monoclonal antibodies: a real challenge.
      ,
      • Zagouri F.
      • Sergentanis T.N.
      • Chrysikos D.
      • et al.
      Trastuzumab administration during pregnancy: a systematic review and meta-analysis.
      ]. Hence, in patients with HER2-positive disease, trastuzumab or any other HER2-targeted agent should be postponed until after delivery [IV, D].

       lymphoma

      Low-grade non-Hodgkin's lymphoma (NHL) is a disease of the elderly and is rarely diagnosed in young women and during pregnancy. In case a diagnosis is made, these patients are often asymptomatic and do not require immediate therapy. Hence, they should be kept under close observation until delivery [V, B].
      Immediate therapy should be initiated in patients with aggressive NHL. If diagnosis is made early during the first trimester, pregnancy termination should be considered since initiation of chemotherapy is associated with a high risk of fetal malformations [IV, B]. CHOP is the standard chemotherapy regimen used in managing NHL [V, B], and it remains the first choice in patients diagnosed during pregnancy. Several reports have shown favourable pregnancy outcomes when administration is started in the second trimester [
      • Brenner B.
      • Avivi I.
      • Lishner M.
      Haematological cancers in pregnancy.
      ].
      Administration of rituximab during pregnancy in patients with B-cell lymphoma has been shown to increase the risk of B-cell depletion in the new-born [
      • Azim Jr, H.A.
      • Azim H.
      • Peccatori F.A.
      Treatment of cancer during pregnancy with monoclonal antibodies: a real challenge.
      ]. Patients starting rituximab during pregnancy should be informed that this approach may influence fetal immunity for some time even if spontaneous recovery of the neonatal B cell count has been observed in all reported cases. Thus, we do not discourage the administration of rituximab during pregnancy in patients in which postponement of rituximab would significantly compromise maternal prognosis [V, C].
      Patients diagnosed with Hodgkin's lymphoma who need prompt treatment with chemotherapy may receive ABVD starting from the second trimester of gestation [V, B], without significant fetal impairment described [
      • Azim Jr, H.A.
      • Pavlidis N.
      • Peccatori F.A.
      Treatment of the pregnant mother with cancer: a systematic review on the use of cytotoxic, endocrine, targeted agents and immunotherapy during pregnancy. Part II: hematological tumors.
      ].

       leukaemia

      Table 4 summarises the ESMO Clinical Practice Guidelines for managing leukaemia during pregnancy [IV, B].
      Table 4ESMO Clinical Practice Guidelines for systemic management of patients diagnosed with leukaemia during pregnancy according to gestational age at diagnosis
      First trimesterSecond trimesterThird trimester
      Acute leukaemia (myeloid or lymphocytic leukaemia)Discuss pregnancy terminationInduction therapy with doxorubicin and cytarabineInduction of labour and initiation of therapy after delivery
      Acute promyelocytic leukaemiaDiscuss pregnancy terminationDoxorubicin and All Trans-Retinoic Acid (ATRA)Induction of labour and initiation of therapy after delivery
      Chronic myeloid leukaemiaInterferon-alphaInterferon-alpha or imatinibInterferon-alpha or imatinib
      Daunorubicin or idarubicin are classically used in combination with cytarabine in managing patients with acute myeloid leukaemia. However, their administration in pregnancy has been associated with considerable fetal morbidity and mortality, possibly due to their high placental crossing [V, D] [
      • Azim Jr, H.A.
      • Pavlidis N.
      • Peccatori F.A.
      Treatment of the pregnant mother with cancer: a systematic review on the use of cytotoxic, endocrine, targeted agents and immunotherapy during pregnancy. Part II: hematological tumors.
      ]. Therefore, we propose instead the use of cytarabine in combination with doxorubicin. The latter has been used in managing acute leukaemia in the past with acceptable results.
      More than 200 pregnant women with chronic myeloid leukaemia (CML) have been reported in the literature. Interferon-alpha can be used safely even during the first trimester [
      • Peccatori F.A.
      • Azim Jr, H.A.
      • Scarfone G.
      • et al.
      Weekly epirubicin in the treatment of gestational breast cancer (GBC).
      ]. No data are available on the use of targeted agents except for imatinib, which seems to be safe only when administered during the second and third trimesters [
      • Azim Jr, H.A.
      • Pavlidis N.
      • Peccatori F.A.
      Treatment of the pregnant mother with cancer: a systematic review on the use of cytotoxic, endocrine, targeted agents and immunotherapy during pregnancy. Part II: hematological tumors.
      ,
      • Pye S.M.
      • Cortes J.
      • Ault P.
      • et al.
      The effects of imatinib on pregnancy outcome.
      ].

       other tumours

      Melanoma is one of the common tumours diagnosed during pregnancy. Surgical management should follow standard procedures outside pregnancy [
      • Hoekstra H.J.
      Melanoma during pregnancy: therapeutic management and outcome. Recent results in cancer research. Fortschritte der Krebsforschung.
      ]. While a recent study pointed to the potential safety of SLNB using vital blue dye [
      • Andtbacka R.H.
      • Donaldson M.R.
      • Bowles T.L.
      • et al.
      Sentinel lymph node biopsy for melanoma in pregnant women.
      ], we would rather restrict the SLNB procedure using Technetium-99 until more data are available. In patients with metastatic melanoma, we lack any safety data on the use of ipilimumab or vemurafenib during gestation and hence they should not be used during pregnancy [V, D]. If clinically appropriate, an alternative could be interferon-alpha, which could be safely administered during pregnancy.
      Treatment recommendations for other solid tumours commonly presenting with advanced and/or metastatic disease requiring systemic treatment are summarised in Table 5 [V, C]. These include soft tissue sarcoma, ovarian and lung cancers. These recommendations are based on small case series and case reports.
      Table 5ESMO Clinical Practice Guidelines for systemic management of patients diagnosed with soft tissue sarcoma, ovarian and lung cancer during pregnancy according to gestational age at diagnosis
      First trimesterSecond trimesterThird trimester
      Soft tissue sarcomaObserve until second trimester. If urgent treatment is required, discuss pregnancy termination.Single agent doxorubicin (60–75 mg/m2)
      Epithelial ovarian cancerObserve until second trimester. If urgent treatment is required, discuss pregnancy termination.Carboplatin (AUC5 or 6) + weekly paclitaxel (80 mg/m2)
      Germ cell ovarian tumoursObserve until second trimester. If urgent treatment is required, discuss pregnancy termination.Cisplatin (75 mg/m2) and weekly paclitaxel (80 mg/m2)
      Non-small-cell lung cancerObserve until second trimester. If urgent treatment is required, discuss pregnancy termination.Carboplatin (AUC5 or 6) + weekly paclitaxel (60–80 mg/m2)Carboplatin + weekly paclitaxel. If diagnosed later in the third trimester, consider pre-term delivery and initiation of therapy afterwards
      In patients with soft tissue sarcoma, we recommend single-agent doxorubicin in patients with metastatic disease. This is based on the overall safety of using doxorubicin during pregnancy in other cancer types. A case series of nine patients using the combination of doxorubicin and ifosfamide during pregnancy has been reported [
      • Mir O.
      • Berrada N.
      • Domont J.
      • et al.
      Doxorubicin and ifosfamide for high-grade sarcoma during pregnancy.
      ]. However, the limited safety information on ifosfamide during pregnancy, its toxicity profile, and the lack of survival advantage of the combination over single-agent doxorubicin [
      • Judson I.
      • Verweij J.
      • Gelderblom H.
      • et al.
      Results of a randomised phase III trial (EORTC 62012) of single agent doxorubicin versus doxorubicin plus ifosfamide as first line chemotherapy for patients with advanced or metastatic soft tissue sarcoma. A survival study by the EORTC soft tissue and bone sarcoma group.
      ] would favour single agent regimens in these patients [V, C]. Switching to a combination therapy could be done after delivery, if necessary.
      Germ cell ovarian tumours are classically treated with an etoposide-platinum based combination (BEP or EP). While some reports have been published on the potential safety of this regimen [
      • Ghaemmaghami F.
      • Abbasi F.
      • Abadi A.G.
      A favorable maternal and neonatal outcome following chemotherapy with etoposide, bleomycin, and cisplatin for management of grade 3 immature teratoma of the ovary.
      ], it remains relatively toxic, particularly etoposide, which has been shown to be associated with relatively high risk of fetal growth restriction and new-born complications including myelosuppression [
      • Ghaemmaghami F.
      • Abbasi F.
      • Abadi A.G.
      A favorable maternal and neonatal outcome following chemotherapy with etoposide, bleomycin, and cisplatin for management of grade 3 immature teratoma of the ovary.
      ,
      • Cardonick E.
      • Usmani A.
      • Ghaffar S.
      Perinatal outcomes of a pregnancy complicated by cancer, including neonatal follow-up after in utero exposure to chemotherapy: results of an international registry.
      ,
      • Han J.Y.
      • Nava-Ocampo A.A.
      • Kim T.J.
      • et al.
      Pregnancy outcome after prenatal exposure to bleomycin, etoposide and cisplatin for malignant ovarian germ cell tumors: report of 2 cases.
      ,
      • Peterson C.
      • Lester Jr, D.R.
      • Sanger W.
      Burkitt's lymphoma in early pregnancy.
      ]. The latter has been reported in at least 6 infants of around 40 reported pregnancies in the literature. Hence, an alternative regimen that can be considered during pregnancy is the combination of cisplatin with paclitaxel [IV, C]. Paclitaxel has been shown to be effective as single agent in relapsed germ cell tumours [
      • Bokemeyer C.
      • Beyer J.
      • Metzner B.
      • et al.
      Phase II study of paclitaxel in patients with relapsed or cisplatin-refractory testicular cancer.
      ] and is currently incorporated in combination with other agents including cisplatin in the management of relapsed germ cell tumours outside the pregnancy setting [
      • Kondagunta G.V.
      • Bacik J.
      • Donadio A.
      • et al.
      Combination of paclitaxel, ifosfamide, and cisplatin is an effective second-line therapy for patients with relapsed testicular germ cell tumors.
      ].
      Around 50 patients with lung cancer during pregnancy have been reported in the literature [
      • Azim Jr, H.A.
      • Peccatori F.A.
      • Pavlidis N.
      Lung cancer in the pregnant woman: to treat or not to treat, that is the question.
      ]. However, incidence is believed to be on the rise given the rising trend of cigarette smoking in the young population. Anti-metabolites (e.g. gemcitabine and pemetrexed) should be avoided during pregnancy. The preferred combination is carboplatin and weekly paclitaxel [V, C], which has been reported both in ovarian and lung cancer during pregnancy with acceptable toxicity. Very limited data are available on the use of epidermal growth factor receptor inhibitors and hence we discourage their use during pregnancy.

      managing pregnancies diagnosed while undergoing anti-cancer therapy

      All pre-menopausal patients undergoing any form of systemic anti-cancer therapy (i.e. chemotherapy, hormonal therapy, immunotherapy or targeted therapy) should be advised to use active contraception [IV, A]. The same applies for male cancer patients as some of these agents could be partially excreted in semen and influence sperm DNA integrity. It is generally advised to continue using active contraception up to 3–6 months following the last administered dose.
      If pregnancy occurs while on tamoxifen, the patients should be informed of the possible increased risk of fetal malformations secondary to the first trimester exposure [
      • Braems G.
      • Denys H.
      • De Wever O.
      • et al.
      Use of tamoxifen before and during pregnancy.
      ] and hence pregnancy termination could be considered [V, D]. The same applies to patients accidentally becoming pregnant while on chemotherapy [V, D].
      The situation is somewhat different with monoclonal antibodies, which do not cross the placenta early in gestation [
      • Pentsuk N.
      • van der Laan J.W.
      An interspecies comparison of placental antibody transfer: new insights into developmental toxicity testing of monoclonal antibodies.
      ]. Data from the HERA trial on patients who became accidentally pregnant while receiving trastuzumab (n = 16) as well as sporadic case reports (n = 5) did not show fetal malformations secondary to brief first trimester exposure [
      • Azim Jr, H.A.
      • Metzger-Filho O.
      • de Azambuja E.
      • et al.
      Pregnancy occurring during or following adjuvant trastuzumab in patients enrolled in the HERA trial (BIG 01–01).
      ]. Hence, we would not encourage pregnancy termination in patients willing to preserve their pregnancy [IV, C], provided that trastuzumab is stopped and the patient is informed that this recommendation is based on data from a limited number of patients. The same applies for patients becoming pregnant while receiving rituximab.
      Tyrosine kinase inhibitors cross the placenta during the first trimester and hence high fetal exposure could be of concern. Data on imatinib in patients with CML suggest a high risk of fetal malformation and miscarriage following first trimester exposure [
      • Azim Jr, H.A.
      • Pavlidis N.
      • Peccatori F.A.
      Treatment of the pregnant mother with cancer: a systematic review on the use of cytotoxic, endocrine, targeted agents and immunotherapy during pregnancy. Part II: hematological tumors.
      ].

      pregnancy in cancer survivors

      In general, cancer survivors have reduced rates of subsequent pregnancy compared with the general population, although the rates are higher in males compared with female cancer survivors [
      • Stensheim H.
      • Cvancarova M.
      • Møller B.
      • Fosså S.D.
      Pregnancy after adolescent and adult cancer: a population-based matched cohort study.
      ]. On average, pregnancy rates are 40% lower among female cancer survivors compared with the general population adjusting for women's age, education level and previous parity. This observation is highly dependent on the cancer type, in which women diagnosed with melanoma or thyroid cancer have pregnancy rates highly comparable with the general population (Figure 1). On the contrary, women diagnosed with breast cancer have the lowest chance of subsequent pregnancy, which is nearly 70% lower compared to the general population. This is believed to be secondary to frequent treatment with gonadotoxic chemotherapy, prolonged treatment periods with tamoxifen in patients with endocrine-sensitive disease and also a general misconception that pregnancy could stimulate cancer recurrence being a hormonally driven disease.
      Figure 1
      Figure 1Female cancer survivors have 40% less chance of becoming pregnant compared with the general population. Chances of subsequent pregnancy depend on the type of cancer. Analysis adjusted for age, previous parity and level of education. Data adopted from a population-based study from Norway, which included 16 105 female cancer survivors and 85 500 controls [
      • Stensheim H.
      • Cvancarova M.
      • Møller B.
      • Fosså S.D.
      Pregnancy after adolescent and adult cancer: a population-based matched cohort study.
      ].
      Apart from breast cancer, no reservations were made regarding the safety of pregnancy following cancer. Neonatal outcomes in men or women with prior history of cancer were highly comparable with those of the general population [
      • Langagergaard V.
      • Gislum M.
      • Skriver M.V.
      • et al.
      Birth outcome in women with breast cancer.
      ,
      • De Sanctis V.
      • Filippone F.R.
      • Alfo M.
      • et al.
      Impact of different treatment approaches on pregnancy outcomes in 99 women treated for Hodgkin lymphoma.
      ]. However, concerns were raised in women with history of breast cancer. Despite several studies and a meta-analysis having shown that pregnancy after breast cancer is safe [
      • Ives A.
      • Saunders C.
      • Bulsara M.
      • Semmens J.
      Pregnancy after breast cancer: population based study.
      ,
      • Kroman N.
      • Jensen M.B.
      • Wohlfahrt J.
      • Ejlertsen B.
      Pregnancy after treatment of breast cancer—a population-based study on behalf of Danish Breast Cancer Cooperative Group.
      ,
      • Azim Jr, H.A.
      • Santoro L.
      • Pavlidis N.
      • et al.
      Safety of pregnancy following breast cancer diagnosis: a meta-analysis of 14 studies.
      ], if not associated with better outcomes, selection bias and lack of information on the outcome according to the ER status resulted in a lack of confidence in the reliability of these data. A recent large-matched multicentre retrospective study including more than 1000 patients confirmed that pregnancy after ER-positive breast cancer is not detrimental, at least during the first 5 years following pregnancy [
      • Azim Jr, H.A.
      • Kroman N.
      • Paesmans M.
      • et al.
      Prognostic impact of pregnancy after breast cancer according to estrogen receptor status: a multicenter retrospective study.
      ]. Hence, we do not discourage pregnancy following breast cancer diagnosis irrespective of the ER status [III, A]. Importantly, once pregnancy has occurred, induction of abortion has no impact on maternal prognosis and hence is strongly discouraged for such purposes [IV, A].
      There is no particular time-point when it is considered optimal to allow patients to become pregnant following cancer diagnosis. The timing should consider the time of completion of therapy, risk of relapse, and the age and ovarian function of the patient. Hence, in breast cancer patients, it is reasonable to postpone pregnancy for 2 years following diagnosis [IV, C] to allow resumption of adequate ovarian function, and to overcome the time frame associated with a relatively high risk of recurrence. In patients considered for 5 years of adjuvant tamoxifen, we lack data to support the safety of early interruption of tamoxifen. Hence, in patients in whom the completion of the full course of tamoxifen would hinder their chances of future pregnancy, it should be made clear that early interruption could have potential detrimental effects on their breast cancer outcome. In women willing to consider this risk, interruption after 2 to 3 years of tamoxifen could be considered to allow pregnancy [V, C]. We strongly encourage the resumption of tamoxifen following delivery in these patients.

      fertility preservation methods in cancer patients

      For males who are scheduled for treatments that may affect their chance of future fertility, sperm banking should be planned before treatment initiation. Semen cryopreservation with one to three samples collection is recommended [III, A]. With the advent of intra-cytoplasmic sperm injection, collection of one sample could suffice in case more samples cannot be obtained. Sperm banking can be proposed independently of patients' age, according to their wishes of future paternity. There is no role for gonadal protection by any form of hormonal or pharmacological means.
      Young women desiring future fertility should be counselled on available fertility preserving options before starting anticancer treatments. Counselling should be implemented soon after diagnosis, to allow prompt referral to fertility specialists [IV, B]. Age is the most important determinant of chemotherapy or radiotherapy-induced ovarian dysfunction [
      • Abusief M.E.
      • Missmer S.A.
      • Ginsburg E.S.
      • et al.
      The effects of paclitaxel, dose density, and trastuzumab on treatment-related amenorrhea in premenopausal women with breast cancer.
      ]. The younger the patient's age, the lower her risk of ovarian dysfunction [
      • Partridge A.
      • Gelber S.
      • Gelber R.D.
      • et al.
      Age of menopause among women who remain premenopausal following treatment for early breast cancer: long-term results from International Breast Cancer Study Group Trials V and VI.
      ]. The other factors that influence ovarian toxicity are the use of alkylating agents and the total dose of chemotherapy delivered [
      • Abusief M.E.
      • Missmer S.A.
      • Ginsburg E.S.
      • et al.
      The effects of paclitaxel, dose density, and trastuzumab on treatment-related amenorrhea in premenopausal women with breast cancer.
      ]. If pelvic radiotherapy is used, fields and dosage are strictly related to subsequent ovarian dysfunction as well. In most studies, persistence of regular menstruation after treatment has been used to assess the residual ovarian function. Yet women who resume menses after treatment have compromised ovarian reserve [
      • Partridge A.H.
      • Ruddy K.J.
      • Gelber S.
      • et al.
      Ovarian reserve in women who remain premenopausal after chemotherapy for early stage breast cancer.
      ] and hence, may have reduced fertility. Thus, better markers of ovarian function are needed for counselling patients before and after treatment. Probably, the best available markers of ovarian reserve are anti-Müllerian hormone and antral follicle count carried out in the first part of the menstrual cycle [
      • Peccatori F.A.
      • Pup L.D.
      • Salvagno F.
      • et al.
      Fertility Preservation Methods in Breast Cancer.
      ].
      The concomitant use of gonadotropin-releasing hormone (GnRH) agonists during the course of chemotherapy as a mean of preserving fertility has been addressed in several phase III trials with conflicting results [
      • Badawy A.
      • Elnashar A.
      • El-Ashry M.
      • Shahat M.
      Gonadotropin-releasing hormone agonists for prevention of chemotherapy-induced ovarian damage: prospective randomised study.
      ,
      • Gerber B.
      • von Minckwitz G.
      • Stehle H.
      • et al.
      Effect of luteinizing hormone-releasing hormone agonist on ovarian function after modern adjuvant breast cancer chemotherapy: the GBG 37 ZORO study.
      ,
      • Munster P.N.
      • Moore A.P.
      • Ismail-Khan R.
      • et al.
      Randomized trial using gonadotropin-releasing hormone agonist triptorelin for the preservation of ovarian function during (neo)adjuvant chemotherapy for breast cancer.
      ,
      • Del Mastro L.
      • Boni L.
      • Michelotti A.
      • et al.
      Effect of the gonadotropin-releasing hormone analogue triptorelin on the occurrence of chemotherapy-induced early menopause in premenopausal women with breast cancer: a randomised trial.
      ,
      • Demeestere I.
      • Brice P.
      • Peccatori F.A.
      • et al.
      Gonadotropin-releasing hormone agonist for the prevention of chemotherapy-induced ovarian failure in patients with lymphoma: 1-year follow-up of a prospective randomised trial.
      ]. Some studies have shown higher rates of menses recovery in the GnRH arms, but others failed to reproduce the same results. These studies did not have the same patient population, and their primary end points were defined differently across the different studies. In addition, most of these studies reported on menstrual rather than on ovarian function, with no increase in pregnancy rates. Hence, the use of GnRH analogues concomitantly with chemotherapy should not be regarded as a reliable means of preserving fertility. Data on long-term ovarian function and pregnancy rates in these cohorts are warranted.
      Embryo or oocyte cryopreservation is the main method to preserve female fertility [II, B]. Ovarian stimulation should be carried out before commencing chemotherapy [IV, A]. This may result in relative delay in oncological treatment and in increased serum estradiol levels, which could be of concern in hormone-driven tumours like breast cancer.
      The use of gonadotropins and letrozole or tamoxifen has been shown to be associated with adequate yield of oocytes with a lower increase in serum estradiol levels compared with standard stimulation regimens [
      • Oktay K.
      • Buyuk E.
      • Libertella N.
      • et al.
      Fertility preservation in breast cancer patients: a prospective controlled comparison of ovarian stimulation with tamoxifen and letrozole for embryo cryopreservation.
      ,
      • Oktay K.
      • Hourvitz A.
      • Sahin G.
      • et al.
      Letrozole reduces estrogen and gonadotropin exposure in women with breast cancer undergoing ovarian stimulation before chemotherapy.
      ] and is generally recommended for cancer patients [III, B]. In endocrine-sensitive breast cancer, this regimen has been used and was not associated with a higher risk of recurrence, at least during the first 2 years [
      • Azim A.A.
      • Costantini-Ferrando M.
      • Oktay K.
      Safety of fertility preservation by ovarian stimulation with letrozole and gonadotropins in patients with breast cancer: a prospective controlled study.
      ]. Long-term follow-up is needed to confirm its safety. Until then, consideration of such an approach in patients with endocrine-receptor-positive breast cancer should be made during a personal discussion with the patient and requires intensive interdisciplinary discussion, including oncologists, radiotherapists and reproductive medicine specialists [III, B].
      Chemotherapy- and radiotherapy-induced sterility can be prevented also by freezing ovarian tissue before treatment. The tissue is harvested with laparoscopy, and re-implanted—after thawing—in the pelvis, when needed. The procedure implies two surgical interventions and around 28 pregnancies have been reported so far [
      • Donnez J.
      • Silber S.
      • Andersen C.Y.
      • et al.
      Children born after autotransplantation of cryopreserved ovarian tissue. a review of 13 live births.
      ]. It is still considered experimental, but remains a unique option for young girls with cancer.

      note

      A summary of recommendations is given in Table 6. Levels of evidence and grades of recommendation have been applied using the system shown in Table 7. Statements without grading were considered justified standard clinical practice by the experts and the ESMO faculty.
      Table 6Summary of recommendations
      Cancer during pregnancy
      Diagnosis and biological features
      • i)
        When indicated, pathological examination of suspected lesions should follow standard procedures as in the non-pregnant setting, including immunohistochemical or molecular analysis.
      • ii)
        Once diagnosis is confirmed, the patient should be referred to an institution with expertise in dealing with such cases.
      • iii)
        Patients should be managed within a multidisciplinary team which includes an obstetrician and a neonatologist in addition to the oncology team.
      Staging and risk assessment
      • i)
        Imaging procedures should aim to limit the exposure to ionizing radiation.
      • ii)
        Ultrasound is the preferred imaging modality for breast, abdomen and pelvis.
      • iii)
        Chest X-ray and mammography with abdominal shielding can be safely carried out during pregnancy.
      • iv)
        MRI without gadolinium can be used if any of the above modalities was inconclusive or in cases of suspicious bone or brain metastases.
      • v)
        CT, bone and PET scans should be avoided throughout the course of pregnancy.
      Obstetric care and fetal follow-up
      • i)
        Chemotherapy is generally safe beyond the first trimester of gestation. However, increased rates of premature delivery, growth retardation and stillbirth have been reported.
      • ii)
        Standard chemotherapy regimens in pregnant cancer patients after the first trimester might not be feasible in all cases and hence tailored approaches may be needed.
      • iii)
        Pregnancies where the fetus has been exposed to chemotherapy starting in the second trimester should be regarded as high-risk and regular fetal monitoring during gestation should be considered.
      • iv)
        Full-term delivery (i.e. ≥37 weeks) should be targeted whenever possible.
      • v)
        Early or very early delivery should be discouraged, unless maternal and/or fetal health are endangered by the postponement of delivery until term.
      • vi)
        The placenta should be subjected to histological examination whenever possible, and particularly in patients diagnosed with melanoma or leukaemias.
      Local treatments:

       General concepts—surgery
      • i)
        Surgery can be carried out with relative safety at any time during the course of the pregnancy.
      • ii)
        Major abdominal and pelvic surgery should only be indicated following a thorough discussion with the patient and the multidisciplinary team.
      • iii)
        Surgery should never be postponed if deemed crucial in the management plan and careful monitoring of the maternal and fetal conditions particularly after the 25th week of gestation is recommended.
       General concepts—radiotherapy
      • i)
        It is preferable to postpone radiation therapy to the postpartum period irrespective of the treated site, unless there is an urgent clinical need and provided that the site is located sufficiently far from the uterus.
       Breast cancer
      • i)
        The decision to proceed to mastectomy or breast conservative surgery should follow the standard practice as in the non-pregnant setting.
      • ii)
        SLNB in pregnant breast cancer patients in centres in which SLNB is routine practice in the non-pregnant setting is not discouraged.
      • iii)
        The use of vital blue dye is discouraged in pregnant patients.
      • iv)
        Adjuvant radiotherapy is never an urgent procedure and hence it is advisable to postpone it until after delivery.
      • v)
        Careful planning of the local management strategy should be made in breast cancer patients diagnosed during the first trimester.
      • vi)
        If breast-conserving surgery is planned, radiotherapy may be delayed for more than 6 months increasing the risk of local recurrence—thorough discussion with the patient and the multidisciplinary team to review the risks and benefits of the different surgical modalities and the timing of radiotherapy is advised.
       Cervical cancer
      • i)
        Radical surgery and pelvic radiation would result in pregnancy termination and fetal death—patients who wish to preserve their pregnancy should be informed that management would require modification of standard local treatment.
      • ii)
        In early-stage cervical cancer, definitive treatment can be postponed until after delivery, with close monitoring during pregnancy.
      • iii)
        For more advanced cases (stage IB1, IB2 and IIA), in patients who wish to preserve the pregnancy, thorough radiological and surgical staging is used to discriminate between the need for immediate treatment and watchful waiting.
        For assessment of nodal metastases, the gold standard is lymphadenectomy, which can be safely carried out laparoscopically during pregnancy.
      • iv)
        If the patient needs treatment for a locally advanced or high-risk tumour, platinum-based chemotherapy with or without paclitaxel can be proposed.
      • v)
        Radical surgery can be offered concomitantly to Caesarean section in qualified centres.
      Systemic treatments:
      • i)
        Chemotherapy should not be administered during the first trimester of gestation. In patients requiring chemotherapy initiation during the first trimester, pregnancy termination would be considered.
      • ii)
        Dose calculation should follow the standard procedures outside the pregnancy setting, acknowledging that the pharmacokinetics of some cytotoxic drugs might be altered during pregnancy.
      • iii)
        A 3-week period should be allowed between the last chemotherapy dose and the expected date of delivery.
      • iv)
        Weekly schedules of chemotherapy allow close pregnancy monitoring and are associated with shorter nadir periods warranting consideration of this approach in pregnant cancer patients.
      Managing pregnancies diagnosed while undergoing anticancer therapy
      • i)
        All pre-menopausal patients undergoing any form of systemic anti-cancer therapy (i.e. chemotherapy, hormonal therapy, immunotherapy or targeted therapy) should be advised to use active contraception. This applies also to male patients. It is advised to continue active contraception up to 3–6 months following the last dose of anticancer therapy.
      • ii)
        If pregnancy occurs during tamoxifen treatment, the patient should be informed of the possible increased risk of fetal malformations secondary to first trimester exposure and pregnancy termination could be considered. The same applies to patients accidentally becoming pregnant while on chemotherapy.
      • iii)
        In patients receiving trastuzumab or rituximab treatment, pregnancy could be allowed to continue, provided that treatment is stopped and the patient is informed that this recommendation is based on data from a limited number of patients.
      Pregnancy in cancer survivors
      • i)
        Timing of pregnancy following cancer diagnosis should take into consideration the time of completion of therapy, risk of relapse, age and ovarian function of the patient.
      • ii)
        After this period, pregnancy is not discouraged, even in women with history of an endocrine-sensitive breast cancer. Once pregnancy has occurred, induction of abortion has no impact on maternal prognosis and is strongly discouraged for such purposes.
      • iii)
        In patients considered for 5 years of adjuvant tamoxifen in whom the completion of the course would hinder their chances of future pregnancy, it should be made clear that it is unknown whether early interruption could have detrimental effects on their breast cancer outcome. We strongly encourage the resumption of tamoxifen following delivery in these patients.
      Fertility preservation methods in cancer patients

       Males:
      • i)
        For males scheduled to receive treatment which could affect their future fertility, sperm banking should be planned before treatment initiation. Semen cryopreservation with one to three samples collection is recommended.
      • ii)
        There is no role for gonadal protection by any form of hormonal or pharmacological means.
       Females:
      • i)
        Young women desiring future fertility should be counselled on available fertility preserving options before starting anti-cancer treatment. Counselling should be implemented soon after diagnosis to allow prompt referral to fertility specialists.
      • ii)
        The use of GnRH analogues concomitantly with chemotherapy should not be regarded as a reliable means of preserving fertility.
      • iii)
        Embryo or oocyte cryopreservation is the main method to preserve female fertility.
      • iv)
        Ovarian stimulation should be carried out before commencing chemotherapy.
      • v)
        The use of gonadotropins and letrozole or tamoxifen for ovarian stimulation is suggested for cancer patients. Consideration of such an approach in patients with ER-positive breast cancer should be made during a discussion with the patient and requires intensive interdisciplinary discussion including oncologists, radiotherapists and reproductive medicine specialists.
      • vi)
        Chemotherapy and radiotherapy-induced sterility can be prevented also by freezing ovarian tissue before treatment. This is still experimental.
      Table 7Levels of evidence and grades of recommendation (adapted from the Infectious Diseases Society of America-United States Public Health Service Grading System
      Dykewicz CA. Summary of the guidelines for preventing opportunistic infections among hematopoietic stem cell transplant recipients. Clin Infect Dis 2001; 33: 139–144. By permission of the Infectious Diseases Society of America.
      )
      Levels of evidence
      IEvidence from at least one large randomised, controlled trial of good methodological quality (low potential for bias) or meta-analyses of well-conducted randomised trials without heterogeneity
      IISmall randomised trials or large randomised trials with a suspicion of bias (lower methodological quality) or meta-analyses of such trials or of trials with demonstrated heterogeneity
      IIIProspective cohort studies
      IVRetrospective cohort studies or case–control studies
      VStudies without control group, case reports, experts opinions
      Grades of recommendation
      AStrong evidence for efficacy with a substantial clinical benefit, strongly recommended
      BStrong or moderate evidence for efficacy but with a limited clinical benefit, generally recommended
      CInsufficient evidence for efficacy or benefit does not outweigh the risk or the disadvantages (adverse events, costs, …), optional
      DModerate evidence against efficacy or for adverse outcome, generally not recommended
      EStrong evidence against efficacy or for adverse outcome, never recommended
      a Dykewicz CA. Summary of the guidelines for preventing opportunistic infections among hematopoietic stem cell transplant recipients. Clin Infect Dis 2001; 33: 139–144. By permission of the Infectious Diseases Society of America.

      conflict of interest

      The authors have declared no potential conflicts of interest.

      references

        • Matthews T.J.
        • Hamilton B.E.
        Delayed childbearing: more women are having their first child later in life.
        NCHS Data Brief. 2009; : 1-8
        • Pentheroudakis G.
        • Pavlidis N.
        Cancer and pregnancy: poena magna, not anymore.
        Eur J Cancer. 2006; 42: 126-140
        • Stensheim H.
        • Møller B.
        • van Dijk T.
        • Fosså S.D.
        Cause-specific survival for women diagnosed with cancer during pregnancy or lactation: a registry-based cohort study.
        J Clin Oncol. 2009; 27: 45-51
        • Mieog J.S.
        • van der Hage J.A.
        • van de Velde C.J.
        Neoadjuvant chemotherapy for operable breast cancer.
        Br J Surg. 2007; 94: 1189-1200
        • Amant F.
        • Deckers S.
        • Van Calsteren K.
        • et al.
        Breast cancer in pregnancy: Recommendations of an international consensus meeting.
        Eur J Cancer. 2010; 46: 3158-3168
        • Azim Jr, H.A.
        • Santoro L.
        • Russell-Edu W.
        • et al.
        Prognosis of pregnancy-associated breast cancer: a meta-analysis of 30 studies.
        Cancer Treat Rev. 2012; 38: 834-842
        • Wang P.I.
        • Chong S.T.
        • Kielar A.Z.
        • et al.
        Imaging of pregnant and lactating patients: part 2, evidence-based review and recommendations.
        AJR Am J Roentgenol. 2012; 198: 785-792
        • Han S.N.
        • Lotgerink A.
        • Gziri M.M.
        • et al.
        Physiologic variations of serum tumor markers in gynecological malignancies during pregnancy: a systematic review.
        BMC Med. 2012; 10: 86
        • Van Calsteren K.
        • Heyns L.
        • De Smet F.
        • et al.
        Cancer during pregnancy: an analysis of 215 patients emphasizing the obstetrical and the neonatal outcomes.
        J Clin Oncol. 2010; 28: 683-689
        • Cardonick E.
        • Dougherty R.
        • Grana G.
        • et al.
        Breast cancer during pregnancy: maternal and fetal outcomes.
        Cancer J. 2010; 16: 76-82
        • Loibl S.
        • Han S.N.
        • von Minckwitz G.
        • et al.
        Treatment of breast cancer during pregnancy: an observational study.
        Lancet Oncol. 2012; 13: 887-896
        • Amant F.
        • Van Calsteren K.
        • Halaska M.J.
        • et al.
        Long-term cognitive and cardiac outcomes after prenatal exposure to chemotherapy in children aged 18 months or older: an observational study.
        Lancet Oncol. 2012; 13: 256-264
        • Litton J.K.
        • Hodge S.
        • Mattair D.
        • et al.
        Outcomes of children exposed to chemotherapy in utero for breast cancer.
        J Clin Oncol. 2011; (29 Abstr # 1099)
        • Perret-Court A.
        • Fernandez C.
        • Monestier S.
        • et al.
        [Placental metastasis of melanoma: a new case and literature review].
        Ann Pathol. 2010; 30: 143-146
        • Gentilini O.
        • Cremonesi M.
        • Trifirò G.
        • et al.
        Safety of sentinel node biopsy in pregnant patients with breast cancer.
        Ann Oncol. 2004; 15: 1348-1351
        • Kal H.B.
        • Struikmans H.
        Radiotherapy during pregnancy: fact and fiction.
        Lancet Oncol. 2005; 6: 328-333
        • Spanheimer P.M.
        • Graham M.M.
        • Sugg S.L.
        • et al.
        Measurement of uterine radiation exposure from lymphoscintigraphy indicates safety of sentinel lymph node biopsy during pregnancy.
        Ann Surg Oncol. 2009; 16: 1143-1147
        • Gentilini O.
        • Cremonesi M.
        • Toesca A.
        • et al.
        Sentinel lymph node biopsy in pregnant patients with breast cancer.
        Eur J Nucl Med Mol Imaging. 2010; 37: 78-83
        • Cimmino V.M.
        • Brown A.C.
        • Szocik J.F.
        • et al.
        Allergic reactions to isosulfan blue during sentinel node biopsy—a common event.
        Surgery. 2001; 130: 439-442
        • Chen Z.
        • King W.
        • Pearcey R.
        • et al.
        The relationship between waiting time for radiotherapy and clinical outcomes: a systematic review of the literature.
        Radiother Oncol. 2008; 87: 3-16
        • Balleyguier C.
        • Fournet C.
        • Ben Hassen W.
        • et al.
        Management of cervical cancer detected during pregnancy: role of magnetic resonance imaging.
        Clin Imaging. 2013; 37: 70-76
        • Shepherd J.H.
        Cervical cancer.
        Best Pract Res Clin Obstet Gynaecol. 2012; 26: 293-309
        • Morice P.
        • Uzan C.
        • Gouy S.
        • et al.
        Gynaecological cancers in pregnancy.
        Lancet. 2012; 379: 558-569
        • Fruscio R.
        • Villa A.
        • Chiari S.
        • et al.
        Delivery delay with neoadjuvant chemotherapy for cervical cancer patients during pregnancy: a series of nine cases and literature review.
        Gynecol Oncol. 2012; 126: 192-197
        • Amant F.
        • Van Calsteren K.
        • Halaska M.J.
        • et al.
        Gynecologic cancers in pregnancy: guidelines of an international consensus meeting.
        Int J Gynecol Cancer. 2009; 19: S1-S12
        • Azim Jr, H.A.
        • Peccatori F.A.
        • Pavlidis N.
        Treatment of the pregnant mother with cancer: a systematic review on the use of cytotoxic, endocrine, targeted agents and immunotherapy during pregnancy. Part I: solid tumors.
        Cancer Treat Rev. 2010; 36: 101-109
        • Azim Jr, H.A.
        • Pavlidis N.
        • Peccatori F.A.
        Treatment of the pregnant mother with cancer: a systematic review on the use of cytotoxic, endocrine, targeted agents and immunotherapy during pregnancy. Part II: hematological tumors.
        Cancer Treat Rev. 2010; 36: 110-121
        • Van Calsteren K.
        • Verbesselt R.
        • Ottevanger N.
        • et al.
        Pharmacokinetics of chemotherapeutic agents in pregnancy: a preclinical and clinical study.
        Acta Obstet Gynecol Scand. 2010; 89: 1338-1345
        • Ellis G.K.
        • Barlow W.E.
        • Gralow J.R.
        • et al.
        Phase III comparison of standard doxorubicin and cyclophosphamide versus weekly doxorubicin and daily oral cyclophosphamide plus granulocyte colony-stimulating factor as neoadjuvant therapy for inflammatory and locally advanced breast cancer: SWOG 0012.
        J Clin Oncol. 2011; 29: 1014-1021
        • Sparano J.A.
        • Wang M.
        • Martino S.
        • et al.
        Weekly paclitaxel in the adjuvant treatment of breast cancer.
        N Engl J Med. 2008; 358: 1663-1671
        • Hahn K.M.
        • Johnson P.H.
        • Gordon N.
        • et al.
        Treatment of pregnant breast cancer patients and outcomes of children exposed to chemotherapy in utero.
        Cancer. 2006; 107: 1219-1226
        • Peccatori F.A.
        • Azim Jr, H.A.
        • Scarfone G.
        • et al.
        Weekly epirubicin in the treatment of gestational breast cancer (GBC).
        Breast Cancer Res Treat. 2009; 115: 591-594
        • Van Calsteren K.
        • Verbesselt R.
        • Van Bree R.
        • et al.
        Substantial variation in transplacental transfer of chemotherapeutic agents in a mouse model.
        Reprod Sci. 2011; 18: 57-63
        • Zagouri F.
        • Sergentanis T.N.
        • Chrysikos D.
        • et al.
        Taxanes for breast cancer during pregnancy: a systematic review.
        Clin Breast Cancer. 2013; 13: 16-23
        • Cardonick E.
        • Bhat A.
        • Gilmandyar D.
        • Somer R.
        Maternal and fetal outcomes of taxane chemotherapy in breast and ovarian cancer during pregnancy: case series and review of the literature.
        Ann Oncol. 2012; 23: 3016-3023
        • Braems G.
        • Denys H.
        • De Wever O.
        • et al.
        Use of tamoxifen before and during pregnancy.
        Oncologist. 2011; 16: 1547-1551
        • Pentsuk N.
        • van der Laan J.W.
        An interspecies comparison of placental antibody transfer: new insights into developmental toxicity testing of monoclonal antibodies.
        Birth Defects Res Part B Dev Reprod Toxicol. 2009; 86: 328-344
        • Azim Jr, H.A.
        • Azim H.
        • Peccatori F.A.
        Treatment of cancer during pregnancy with monoclonal antibodies: a real challenge.
        Expert Rev Clin Immunol. 2010; 6: 821-826
        • Zagouri F.
        • Sergentanis T.N.
        • Chrysikos D.
        • et al.
        Trastuzumab administration during pregnancy: a systematic review and meta-analysis.
        Breast Cancer Res Treat. 2013; 137: 349-357
        • Brenner B.
        • Avivi I.
        • Lishner M.
        Haematological cancers in pregnancy.
        Lancet. 2012; 379: 580-587
        • Pye S.M.
        • Cortes J.
        • Ault P.
        • et al.
        The effects of imatinib on pregnancy outcome.
        Blood. 2008; 111: 5505-5508
        • Hoekstra H.J.
        Melanoma during pregnancy: therapeutic management and outcome. Recent results in cancer research. Fortschritte der Krebsforschung.
        Progres dans les recherches sur le cancer. 2008; 178: 175-181
        • Andtbacka R.H.
        • Donaldson M.R.
        • Bowles T.L.
        • et al.
        Sentinel lymph node biopsy for melanoma in pregnant women.
        Ann Surg Oncol. 2013; 20: 689-696
        • Mir O.
        • Berrada N.
        • Domont J.
        • et al.
        Doxorubicin and ifosfamide for high-grade sarcoma during pregnancy.
        Cancer Chemother Pharmacol. 2012; 69: 357-367
        • Judson I.
        • Verweij J.
        • Gelderblom H.
        • et al.
        Results of a randomised phase III trial (EORTC 62012) of single agent doxorubicin versus doxorubicin plus ifosfamide as first line chemotherapy for patients with advanced or metastatic soft tissue sarcoma. A survival study by the EORTC soft tissue and bone sarcoma group.
        Ann Oncol. 2012; 23: LBA7
        • Ghaemmaghami F.
        • Abbasi F.
        • Abadi A.G.
        A favorable maternal and neonatal outcome following chemotherapy with etoposide, bleomycin, and cisplatin for management of grade 3 immature teratoma of the ovary.
        J Gynecol Oncol. 2009; 20: 257-259
        • Cardonick E.
        • Usmani A.
        • Ghaffar S.
        Perinatal outcomes of a pregnancy complicated by cancer, including neonatal follow-up after in utero exposure to chemotherapy: results of an international registry.
        Am J Clin Oncol. 2010; 33: 221-228
        • Han J.Y.
        • Nava-Ocampo A.A.
        • Kim T.J.
        • et al.
        Pregnancy outcome after prenatal exposure to bleomycin, etoposide and cisplatin for malignant ovarian germ cell tumors: report of 2 cases.
        Reprod Toxicol. 2005; 19: 557-561
        • Peterson C.
        • Lester Jr, D.R.
        • Sanger W.
        Burkitt's lymphoma in early pregnancy.
        J Clin Oncol. 2010; 28: e136-138
        • Bokemeyer C.
        • Beyer J.
        • Metzner B.
        • et al.
        Phase II study of paclitaxel in patients with relapsed or cisplatin-refractory testicular cancer.
        Ann Oncol. 1996; 7: 31-34
        • Kondagunta G.V.
        • Bacik J.
        • Donadio A.
        • et al.
        Combination of paclitaxel, ifosfamide, and cisplatin is an effective second-line therapy for patients with relapsed testicular germ cell tumors.
        J Clin Oncol. 2005; 23: 6549-6555
        • Azim Jr, H.A.
        • Peccatori F.A.
        • Pavlidis N.
        Lung cancer in the pregnant woman: to treat or not to treat, that is the question.
        Lung Cancer. 2010; 67: 251-256
        • Azim Jr, H.A.
        • Metzger-Filho O.
        • de Azambuja E.
        • et al.
        Pregnancy occurring during or following adjuvant trastuzumab in patients enrolled in the HERA trial (BIG 01–01).
        Breast Cancer Res Treat. 2012; 133: 387-391
        • Stensheim H.
        • Cvancarova M.
        • Møller B.
        • Fosså S.D.
        Pregnancy after adolescent and adult cancer: a population-based matched cohort study.
        Int J Cancer. 2011; 129: 1225-1236
        • Langagergaard V.
        • Gislum M.
        • Skriver M.V.
        • et al.
        Birth outcome in women with breast cancer.
        Br J Cancer. 2006; 94: 142-146
        • De Sanctis V.
        • Filippone F.R.
        • Alfo M.
        • et al.
        Impact of different treatment approaches on pregnancy outcomes in 99 women treated for Hodgkin lymphoma.
        Int J Radiat Oncol Biol Phys. 2012; 84: 755-761
        • Ives A.
        • Saunders C.
        • Bulsara M.
        • Semmens J.
        Pregnancy after breast cancer: population based study.
        BMJ. 2007; 334: 194
        • Kroman N.
        • Jensen M.B.
        • Wohlfahrt J.
        • Ejlertsen B.
        Pregnancy after treatment of breast cancer—a population-based study on behalf of Danish Breast Cancer Cooperative Group.
        Acta Oncol. 2008; 47: 545-549
        • Azim Jr, H.A.
        • Santoro L.
        • Pavlidis N.
        • et al.
        Safety of pregnancy following breast cancer diagnosis: a meta-analysis of 14 studies.
        Eur J Cancer. 2011; 47: 74-83
        • Azim Jr, H.A.
        • Kroman N.
        • Paesmans M.
        • et al.
        Prognostic impact of pregnancy after breast cancer according to estrogen receptor status: a multicenter retrospective study.
        J Clin Oncol. 2013; 31: 73-79
        • Abusief M.E.
        • Missmer S.A.
        • Ginsburg E.S.
        • et al.
        The effects of paclitaxel, dose density, and trastuzumab on treatment-related amenorrhea in premenopausal women with breast cancer.
        Cancer. 2010; 116: 791-798
        • Partridge A.
        • Gelber S.
        • Gelber R.D.
        • et al.
        Age of menopause among women who remain premenopausal following treatment for early breast cancer: long-term results from International Breast Cancer Study Group Trials V and VI.
        Eur J Cancer. 2007; 43: 1646-1653
        • Partridge A.H.
        • Ruddy K.J.
        • Gelber S.
        • et al.
        Ovarian reserve in women who remain premenopausal after chemotherapy for early stage breast cancer.
        Fertil Steril. 2010; 94: 638-644
        • Peccatori F.A.
        • Pup L.D.
        • Salvagno F.
        • et al.
        Fertility Preservation Methods in Breast Cancer.
        Breast care. 2012; 7: 197-202
        • Badawy A.
        • Elnashar A.
        • El-Ashry M.
        • Shahat M.
        Gonadotropin-releasing hormone agonists for prevention of chemotherapy-induced ovarian damage: prospective randomised study.
        Fertil Steril. 2009; 91: 694-697
        • Gerber B.
        • von Minckwitz G.
        • Stehle H.
        • et al.
        Effect of luteinizing hormone-releasing hormone agonist on ovarian function after modern adjuvant breast cancer chemotherapy: the GBG 37 ZORO study.
        J Clin Oncol. 2011; 29: 2334-2341
        • Munster P.N.
        • Moore A.P.
        • Ismail-Khan R.
        • et al.
        Randomized trial using gonadotropin-releasing hormone agonist triptorelin for the preservation of ovarian function during (neo)adjuvant chemotherapy for breast cancer.
        J Clin Oncol. 2012; 30: 533-538
        • Del Mastro L.
        • Boni L.
        • Michelotti A.
        • et al.
        Effect of the gonadotropin-releasing hormone analogue triptorelin on the occurrence of chemotherapy-induced early menopause in premenopausal women with breast cancer: a randomised trial.
        JAMA. 2011; 306: 269-276
        • Demeestere I.
        • Brice P.
        • Peccatori F.A.
        • et al.
        Gonadotropin-releasing hormone agonist for the prevention of chemotherapy-induced ovarian failure in patients with lymphoma: 1-year follow-up of a prospective randomised trial.
        J Clin Oncol. 2013; 31: 903-909
        • Oktay K.
        • Buyuk E.
        • Libertella N.
        • et al.
        Fertility preservation in breast cancer patients: a prospective controlled comparison of ovarian stimulation with tamoxifen and letrozole for embryo cryopreservation.
        J Clin Oncol. 2005; 23: 4347-4353
        • Oktay K.
        • Hourvitz A.
        • Sahin G.
        • et al.
        Letrozole reduces estrogen and gonadotropin exposure in women with breast cancer undergoing ovarian stimulation before chemotherapy.
        J Clin Endocrinol Metab. 2006; 91: 3885-3890
        • Azim A.A.
        • Costantini-Ferrando M.
        • Oktay K.
        Safety of fertility preservation by ovarian stimulation with letrozole and gonadotropins in patients with breast cancer: a prospective controlled study.
        J Clin Oncol. 2008; 26: 2630-2635
        • Donnez J.
        • Silber S.
        • Andersen C.Y.
        • et al.
        Children born after autotransplantation of cryopreserved ovarian tissue. a review of 13 live births.
        Ann Med. 2011; 43: 437-450