Advertisement

Locally advanced cervical cancer complicating pregnancy: A case of competing risks from the Catholic University of the Sacred Heart in Rome

      Abstract

      A case of stage IB2 cervical cancer at 27 weeks of pregnancy, treated with neoadjuvant chemotherapy followed by radical Cesarean hysterectomy with full pelvic and infra-mesenteric lymphadenectomy, and adjuvant chemo-radiation is described. While she remains without disease, her baby was diagnosed with acute myelogenous leukemia. We highlight the pre-operative work-up, treatment options, safety, feasibility, and outcomes for the mother and her fetus.

      Keywords

      1. Description of case

      A 35-year-old nulligravid woman was diagnosed with a poorly differentiated, invasive squamous-cell carcinoma of the cervix at 27 weeks of pregnancy. Two weeks earlier she was admitted to another emergency department for intermittent and persistent vaginal spotting. An ultrasound excluded obstetric conditions such as abruptio placentae and placenta praevia, but pelvic examination showed a large exophytic friable mass involving the cervix. A biopsy confirmed poorly differentiated squamous cell carcinoma of the cervix. A Magnetic Resonance Imaging (MRI) without contrast revealed a 4.0 × 6.2 × 7.0 cm (vol. 90 cm3) cervical mass involving the entire cervix, with stromal invasion, no parametrial and vaginal infiltration, and no lymphadenopathy (Fig. 1A ). Her tumor was classified as International Federation of Gynecology and Obstetrics (FIGO) Stage IB2 with radiographically negative nodes.
      Fig. 1
      Fig. 1MRI assessment of cervical tumor diameter. A) 4.0 × 6.2 × 7.0 cm cervical mass (arrow) at diagnosis; B) 4.0 × 2.2 × 3.4 cm cervical mass (arrow) after 2nd NACT cycle.
      A multidisciplinary team including a gynecologic oncologist, obstetrician, radiation oncologist, radiologist, neonatologist, pathologist, and psychologist counseled the patient regarding treatment options, each balancing the potential risks and outcomes for the patient, her cancer and her pregnancy.
      The decision to proceed with neoadjuvant chemotherapy (NACT) until fetal maturity was made after thorough discussion with the patient, considering her strong desire to preserve pregnancy, and to reduce risks for fetal survival and health. She underwent 2 cycles of cisplatin (75 mg/m2) and paclitaxel (135 mg/m2) at three-week intervals. Chemotherapy was well tolerated. Fetal health was assessed by obstetric US and Doppler velocimetry before and after each cycle.
      After two cycles, MRI demonstrated partial response, with a reduction in the tumor size down to 4.0 × 2.2 × 3.4 cm (vol. 16 cm3) (Fig. 1B). At 35 weeks of pregnancy, three weeks after completing the second cycle of NACT, and after fetal pulmonary induction with steroids, she underwent radical Cesarean hysterectomy (Type C1, according to Querleu and Morrow classification) [
      • Querleu D.
      • Morrow C.P.
      Classification of radical hysterectomy.
      ] with bilateral salpingectomy, ovarian transposition, and pelvic and infra-mesenteric lymphadenectomy (Fig. 2). No immediate post-operative complications were noted.
      Fig. 2
      Fig. 2Radical type C1 Cesarean hysterectomy. A) Residual tumor after NACT; B) vaginal cuff; C) hysterotomy incision; D) proximal paracervix.
      Surgical pathology revealed residual poorly differentiated, invasive squamous-cell carcinoma, 2.5 cm in diameter, infiltrating 1.1 cm of 1.8 cm (61%) the cervical stroma, with extratumoral LVSI, and negative margins (Fig. 3A and B) In detail, microscopic examination revealed the presence of residual neoplastic cells organized in nests and solid sheets, without evidence of keratin pearls formation. Tumor cells displayed a scant eosinophilic cytoplasm with distinct cell borders, and round to oval hyperchromatic nuclei with coarse chromatin. Moreover, the neoplasm showed a brisk mitotic activity of 10/10 HPF and highly positive p16 nuclear staining by immunohistochemistry. Thirty-nine lymph nodes and the placenta were negative for metastases. Adjuvant external beam radiation therapy (4500 cGy in 180 cGy fractions) and concomitant chemosensitization with cisplatin (20 mg/m2) and 5-FU (100 mg/m2) was performed.
      Fig. 3
      Fig. 3H&E stained slides. A) Deep invasion from the superficial squamous cervical epithelium (*) through the cervical stroma (arrow) is depicted. B) Lymphovascular spaces are filled with residual neoplastic squamous nests (arrows).
      A healthy male was born, weighing 2450 g, with an Apgar score of 8/9. At 22 months of age, the baby experienced acute myeloid leukemia (AML) ex- FAB (French-American-British)-M7 subtype and received bone marrow transplantation. At the time of this publication, the mother and her child have remained free from disease.

      2. Impact of pregnancy on the biology of cervical cancer

      In developed societies, cervical cancer is one of the most common malignancies in pregnancy, with an estimated incidence of 0.8 to 1.5 cases per 10,000 births [
      • Ruiz R.
      • Herrero C.
      • Strasser-Weippl K.
      • et al.
      Epidemiology and pathophysiology of pregnancy-associated breast cancer: a review.
      ,
      • De Simone V.
      • Pagani O.
      Pregnancy after breast cancer: hope after the storm.
      ,
      • PDQ Adult Treatment Editorial Board
      Breast Cancer Treatment and Pregnancy (PDQ®): Health Professional Version.
      ,
      • Abdalla N.
      • Bizoń M.
      • Piórkowski R.
      • Stanirowski P.
      • Cendrowski K.
      • Sawicki W.
      Does chemotherapy for gynecological malignancies during pregnancy cause fetal growth restriction?.
      ]. This is also due to a raising number of women delaying their age for pregnancy. Up to 3% of women affected by cervical cancer are pregnant or postpartum at the time of diagnosis [
      • Knabben L.
      • Mueller M.D.
      Breast cancer and pregnancy.
      ,
      • Gerstl B.
      • Sullivan E.
      • Ives A.
      • et al.
      Pregnancy outcomes after a breast Cancer diagnosis: a systematic review and meta-analysis.
      ]. Most patients are diagnosed at an early stage of disease [
      • Yu H.H.
      • Cheung P.S.
      • Leung R.C.
      • et al.
      Current management of pregnancy-associated breast cancer.
      ,
      • Ngu S.F.
      • Ngan H.Y.
      Chemotherapy in pregnancy.
      ]. Although a different behavior of autoimmune diseases during pregnancy has been described, due to a new cooperation among diverse T-cell subtypes in pregnant patients [
      • Bonney E.A.
      Alternative theories: pregnancy and immune tolerance.
      ], there is no evidence in the literature supporting pregnancy as a trigger event for HPV-related carcinogenesis [
      • Frega A.
      • Verrone A.
      • Manzara F.
      • et al.
      Expression of E6/E7 HPV-DNA, HPV-mRNA and colposcopic features in management of CIN2/3 during pregnancy.
      ].
      As there are no data from large randomized trials that provide guidelines for the treatment of cervical cancer during pregnancy, management takes in account: i) treatment in non-pregnant women; ii) findings from case series and case reports and observational studies of pregnant women; and iii) the unique medical and ethical considerations underlying each individual case. Existing guidelines for preserving pregnancy in cervical cancer pregnant women are shown in Table 1 [
      • Amant F.
      • Halaska M.J.
      • Fumagalli M.
      • et al.
      Gynecological cancers in pregnancy: guidelines of a second international consensus meeting.
      ,
      • Peccatori F.A.
      • Azim H.A.J.R.
      • Orecchia R.
      • et al.
      Cancer, pregnancy and fertility: ESMO clinical practice guidelines for diagnosis, treatment and follow-up.
      ,
      • Boere I.
      • Lok C.
      • Vandenbroucke T.
      • et al.
      Cancer in pregnancy: safety and efficacy of systemic therapies.
      ,
      • Amant F.
      • Han S.N.
      • Gziri M.M.
      • et al.
      Management of cancer in pregnancy.
      ]. Due to the low incidence of cervical cancer in pregnancy, centralization in well- equipped facilities is compulsory.
      Table 1Current guidelines for treatment of cervical cancer during pregnancy – preserving management (modified from Gynecologic Cancers in Pregnancy. Guidelines of a Second International Consensus Meeting, 2014) [
      • Amant F.
      • Halaska M.J.
      • Fumagalli M.
      • et al.
      Gynecological cancers in pregnancy: guidelines of a second international consensus meeting.
      ].
      Stage IA2 – IB1 < 2 cmSafety and role of SLN unclear [
      • Dostálek L.
      • Zikan M.
      • Fischerova D.
      • et al.
      SLN biopsy in cervical cancer patients with tumors larger than 2 cm and 4 cm.
      ]

      Pathological retroperitoneal lymph node assessment is encouraged based on gestational age
      • If positive: fertility preserving options are not indicated
      • If negative: simple trachelectomy or cone biopsy can be considered
      Delay treatment up to delivery
      Stage 1B > 2 cm or higherPathological retroperitoneal lymph node assessment is unclear

      Any suspect nodal involvement: fertility preserving options not indicated

      NACT is used to preserve pregnancy until maturity and delivery.

      3. Cervical cancer staging, and the implications of pregnancy on these procedures

      Staging of cervical cancer during pregnancy should follow the same approach as cases of non-pregnant patients, and includes a bimanual gynecological examination for the assessment of locoregional diffusion of disease. There is no evidence that the large dimensions of the gravid uterus and the hormone-related changes of parametrial tissues can affect such evaluation. Imaging is often utilized to establish radiographic disease distribution, and abdominopelvic imaging is optimally performed using MRI [
      • Khan S.R.
      • Arshad M.
      • Wallitt K.
      • et al.
      What's new in imaging for gynecologic cancer?.
      ,
      • Zagouri F.
      • Dimitrakakis C.
      • Marinopoulos S.
      • et al.
      Cancer in pregnancy: disentangling treatment modalities.
      ] without contrast. Endovaginal ultrasound is an easily available, affordable and low-risk option for evaluating cervical dimensions [
      ]. Recently, a multi-centric prospective trial has demonstrated a higher accuracy of ultrasound than MRI in detecting parametrial diffusion of disease and tumor diameter [
      • Epstein E.
      • Testa A.
      • Gaurilcikas A.
      • et al.
      Early-stage cervical cancer: tumor delineation by magnetic resonance imaging and ultrasound - a European multicenter trial.
      ].The use of (18-FDG) PET-CT scan is contraindicated during pregnancy due to the high fetal uptake of radioactivity [
      • Morice P.
      • Uzan C.
      • Gouy S.
      • et al.
      Gynaecological cancers in pregnancy.
      ].
      The pathologic assessment of the lymph nodal status before starting any treatment adds important prognostic information. A laparoscopic LND is feasible until the late second trimester, beyond which the dimension of the gravid uterus may preclude the ability to access the pelvic lymph nodes [
      • Amant F.
      • Han S.N.
      • Gziri M.M.
      • et al.
      Management of cancer in pregnancy.
      ]. The role of SLN in early and locally advanced cervical cancer is debated, but promising data have been recently reported. [
      • Dostálek L.
      • Zikan M.
      • Fischerova D.
      • et al.
      SLN biopsy in cervical cancer patients with tumors larger than 2 cm and 4 cm.
      ,
      • Cibula D.
      • Kuzel D.
      • Sláma J.
      • et al.
      Sentinel node (SLN) biopsy in the management of locally advanced cervical cancer.
      ] Papadia et al. [
      • Papadia A.
      • Mohr S.
      • Imboden S.
      • et al.
      Laparoscopic indocyanine green sentinel lymph node mapping in pregnant cervical cancer patients.
      ] described two cases of pregnant patients with early-stage cervical cancer that underwent cervical injection of indocyanine green (ICG) and successful identification of SLN. It has been already reported that ICG does not cross the placenta after intravenous injection up to 5 mg/kg of body weight [
      • Rudolf H.
      • Goretzlehner G.
      • Brugmann E.
      • et al.
      Assessment of liver function using indocyanine green (Ujoviridin) during normal pregnancy, during labor and in puerperium.
      ,
      • Probst P.
      • Paumgartner G.
      • Caucig H.
      • et al.
      Studies on clearance and placental transfer of indocyanine green during labor.
      ], but further studies are needed to assess the feasibility and safety of this technique during pregnancy. At this time, ICG carries a Category C rating during pregnancy, and the package insert states that it “should be given to a pregnant woman only if clearly indicated”.
      Our patient received gynecological oncology examination, abdominopelvic MRI (Fig. 1) and pelvic ultrasound. No pathologic evaluation of lymph node status was performed due to her gestational age and the challenges of accessing her retroperitoneum. As a result, she was staged as IB2 cervical cancer with radiographically negative nodes.

      4. Therapies for early-stage cervical cancer patient later in pregnancy

      Given the diagnosis of early cervical cancer concurrent with a viable pregnancy, the following therapeutic options were explored: i) immediate Cesarean radical hysterectomy or Cesarean section followed by chemoradiation; ii) immediate chemoradiation with fetus in uterus; iii) delaying treatment until fetal viability and then chemoradiation; iv) neoadjuvant chemotherapy (NACT) followed by Cesarean radical hysterectomy.
      Literature suggests that immediate treatment is appropriate and often proposed in patients with a diagnosis of cervical cancer at 2nd or 3rd trimester of pregnancy [
      • Amant F.
      • Halaska M.J.
      • Fumagalli M.
      • et al.
      Gynecological cancers in pregnancy: guidelines of a second international consensus meeting.
      ,
      • Peccatori F.A.
      • Azim H.A.J.R.
      • Orecchia R.
      • et al.
      Cancer, pregnancy and fertility: ESMO clinical practice guidelines for diagnosis, treatment and follow-up.
      ,
      • Boere I.
      • Lok C.
      • Vandenbroucke T.
      • et al.
      Cancer in pregnancy: safety and efficacy of systemic therapies.
      ,
      • Amant F.
      • Han S.N.
      • Gziri M.M.
      • et al.
      Management of cancer in pregnancy.
      ]. However, the survival rate among live birth infants born at 27 weeks of gestational age (GA) is lower than at term, and the risk of developing cerebral palsy, hearing and visual impairment, developmental delay and psychological disorders is high [
      • Ehret D.Y.
      • Patterson J.K.
      • Bose C.L.
      Improving neonatal care: a global perspective.
      ,
      • EPICure Study Group
      EPICure: facts and figure: why preterm labour should be treated.
      ]. Conversely, since the fetus is extremely sensitive to ionizing radiation, chemoradiation can induce fetal death [
      • Findeklee S.
      Overview tumour disease and oncologic therapy during pregnancy.
      ].

      5. Rationale for NACT for early-stage cervical cancer independent of and during pregnancy

      Due to the patient's strong desire to preserve her pregnancy and deliver at near-term, options were restricted to treatment delay, with or without NACT.
      The risk of delaying definitive treatment of her cervical cancer until at least 34 weeks gestation for reducing extreme preterm-associated neonatal mortality and morbidity has its own risks. Retrospective reviews [
      • Perri T.
      • Issakov G.
      • Ben-Baruch G.
      Effect of treatment delay on survival in patients with cervical cancer: a historical cohort study.
      ,
      • Shen S.C.
      • Hung Y.C.
      • Kung P.T.
      • et al.
      Factors involved in the delay of treatment initiation for cervical cancer patients: a nationwide population-based study.
      ] report conflicting results on survival of non- pregnant patients with cervical cancer who experience treatment delays, mainly related to the duration of delay. Recent data suggests that delay of treatment for pre-invasive disease and small invasive carcinomas without lymph node involvement a valid option during pregnancy [
      • Ribeiro F.
      • Correia L.
      • Paula T.
      • et al.
      Cervical cancer in pregnancy: 3 cases, 3 different approaches.
      ,
      • Karam A.
      • Feldman N.
      • Holschneider C.H.
      Neoadjuvant cisplatin and radical Cesarean hysterectomy for cervical cancer in pregnancy.
      ]. Data on the impact of delay on advanced stage cervical cancer are lacking, but it is reasonable to assume that the higher the stage, the quicker and more likely is progression over time. We decided to begin neoadjuvant chemotherapy immediately rather than delaying treatment with delivery after 34 weeks gestation to decrease the potential risk of local progression and distant metastases. This concept was initially described more than twenty years ago [
      • Tewari K.
      • Cappuccini F.
      • Gambino A.
      • et al.
      Neoadjuvant chemotherapy in the treatment of locally advanced cervical carcinoma in pregnancy: a report of two cases and review of issues specific to the management of cervical carcinoma in pregnancy including planned delay of therapy.
      ], and other cases have been described subsequently.
      The role of primary chemotherapy followed by radical surgery in LACC has been studied, reported and utilized for more than a decade [
      • Minig L.
      • Colombo N.
      • Zanagnolo V.
      • et al.
      Platinum-based neoadjuvant chemotherapy followed by radical surgery for cervical carcinoma international federation of gynecology and obstetrics stage IB2-IIB.
      ,
      • Benedetti-Panici P.
      • Greggi S.
      • Colombo A.
      • et al.
      Neoadjuvant chemotherapy and radical surgery versus exclusive radiotherapy in locally advanced squamous cell cervical cancer: results from the Italian multicenter randomized study.
      ]. Theoretically, by shrinking the size of the primary disease, it improves local control given by subsequent irradiation or surgical resection. In addition, systemic chemotherapy offers a better control of micrometastases in distant sites as well as in regional lymph nodes. Independent of pregnancy, a randomized trial of NACT with carboplatin and paclitaxel for 3 cycles followed by radical surgery was shown to have inferior progression-free survival and similar overall survival compared with radiation and concurrent cisplatin in women with early-stage cervical cancer, and in particular in women with stage IIB disease [
      • Gupta S.
      • Maheshwari A.
      • Parab P.
      • et al.
      Neoadjuvant chemotherapy followed by radical surgery versus concomitant chemotherapy and radiotherapy in patients with stage IB2, IIA, or IIB squamous cervical cancer: a randomized controlled trial.
      ]. Similarly designed EORTC 55994 (ClinicalTrials.gov Identifier: NCT00039338) is still awaiting survival results [

      EORTC GCG 55994: Randomized phase III study of neoadjuvant CT followed by surgery vs concomitant RTX + CT in FIGO stage Ib2, IIa > 4 cm or IIb cervical cancer. Ongoing trial.

      ]. There have been no clinical trials of neoadjuvant chemotherapy as a means to delay delivery in women with invasive cervical cancer during pregnancy.

      6. Role of chemotherapy, and potential drug-related risks during pregnancy

      Chemotherapy has been used to treated cancer in pregnancy since the early 1950s. Drugs used in the past to treat cervical cancer include cisplatin, vincristine, bleomycin, cyclophosphamide and 5-fluorouracil [
      • Cardonick E.
      • Iacobucci A.
      Use of chemotherapy during human pregnancy.
      ]. Most chemotherapeutic drugs can cross the placenta because of their relatively small molecular weight; consequently, the main concern is the potential teratogenic effects and the risk of miscarriage. The most vulnerable period appears to be the time of organogenesis, 2 to 8 weeks after conception [
      • Ngu S.F.
      • Ngan H.Y.
      Chemotherapy in pregnancy.
      ,
      • Ilancheran A.
      Neoadjuvant chemotherapy in cervical cancer in pregnancy.
      ], when risk of major malformations has been reported up to 20% [
      • Weisz B.
      • Meirow D.
      • Schiff E.
      • et al.
      Impact and treatment of cancer during pregnancy.
      ].
      Few studies have analyzed the materno-fetal passage of cisplatin, and have demonstrated a significantly lower level of the drug in the umbilical cord blood and amniotic fluid compared to maternal blood [
      • Marnitz S.
      • Kohler C.
      • Oppelt P.
      • et al.
      Cisplatin application in pregnancy: first in vivo analysis of 7 patients.
      ,
      • Köhler C.
      • Oppelt P.
      • Favero G.
      • et al.
      How much platinum passes the placental barrier? Analysis of platinum applications in 21 patients with cervical cancer during pregnancy.
      ]. Data on placental transfer of carboplatin [
      • Mir O.
      • Berveiller P.
      • Ropert S.
      • et al.
      Use of platinum derivatives during pregnancy.
      ] from maternal to fetal circulation are available from ex vivo placental studies, showing no significant placental transfer, fetal exposure or fetal toxic effects at an AUC of <7.5 mg/ml/min [
      • Smith J.A.
      • Gaikwad A.
      • Mosley S.
      Utilization of an ex vivo human placental perfusion model to predict potential fetal exposure to carboplatin during pregnancy.
      ]. However, in baboon and murine models, the passage through the placenta is shown to be high for carboplatin (60%) [
      • Calsteren K.V.
      • Verbesselt R.
      • Devlieger R.
      • et al.
      Transplacental transfer of paclitaxel, docetaxel, carboplatin and trastuzumab in a baboon model.
      ]. The different models used in these studies likely explain inconsistent results about transplacental passage of carboplatin. There are, however, reassuring clinical data with long-term follow up regarding fetal outcome following carboplatin exposure during pregnancy [
      • Zagouri F.
      • Dimitrakakis C.
      • Marinopoulos S.
      • et al.
      Cancer in pregnancy: disentangling treatment modalities.
      ,
      • Zagouri F.
      • Sergentanis T.N.
      • Chrysikos D.
      • et al.
      Platinum derivatives during pregnancy in cervical cancer: a systematic review and meta-analysis.
      ] Experience with taxanes is even more limited than with platinum compounds. Animal studies [
      • Calsteren K.V.
      • Verbesselt R.
      • Devlieger R.
      • et al.
      Transplacental transfer of paclitaxel, docetaxel, carboplatin and trastuzumab in a baboon model.
      ] and data from retrospective registry-based studies and case reports [
      • Cardonick E.
      • Bhat A.
      • Gilmandyar D.
      • et al.
      Maternal and fetal outcomes of taxane chemotherapy in breast and ovarian cancer during pregnancy: case series and review of the literature.
      ] have demonstrated the relative safety of giving taxanes during the second and third trimesters of pregnancy [
      • Li J.
      • Wang L.J.
      • Zhang B.Z.
      • Peng Y.P.
      • et al.
      Neoadjuvant chemotherapy with paclitaxel plus platinum for invasive cervical cancer in pregnancy: two case report and literature review.
      ,
      • Zagouri F.
      • Sergentanis T.N.
      • Chrysikos D.
      • et al.
      Taxanes for ovarian cancer during pregnancy: a systematic review.
      ]. Large observational database studies, however, do suggest a relationship between platinum-based chemotherapy (OR 3·12, 95% CI 1·45–6·70) and taxanes (OR > 2) and small for gestational age babies [
      • de Haan J.
      • Verheecke M.
      • Van Calsteren K.
      • et al.
      Oncological management and obstetric and neonatal outcomes for women diagnosed with cancer during pregnancy: a 20-year international cohort study of 1170 patients.
      ]. In our case, the patient was treated with cisplatin (75 mg/m2) with paclitaxel (135 mg/m2) every 21 days [
      • Knabben L.
      • Mueller M.D.
      Breast cancer and pregnancy.
      ] (Table 2).
      Table 2NACT in cervical cancer during pregnancy.
      Regimen
      Dose calculationDose calculation should follow the standard procedures outside the pregnancy setting, acknowledging that the pharmacokinetics of some cytotoxic drugs might be altered during pregnancy
      Targeted therapyStill unclear and therefore discouraged.

      Anti-angiogenetic drugs are contraindicated due to teratogenic effect in animal models.
      Timing of deliveryA 3-week period should be allowed between the last chemotherapy dose and the expected date of delivery, to reduce the risk of bleeding, infection and anemia for both mother and child.
      Supportive therapyMethylprednisolone or hydrocortisone are often chosen instead of betamethasone or dexamethasone. If needed, the antiemetics, ondansetron and metoclopramide, appear safe to use during pregnancy.

      Growth factor use has been shown feasible during pregnancy.
      The counseling of the mother about the major risks associated with NACT at 28 weeks of gestation included:
      • i)
        3–5% increase in risk of fetal malformations above the general population when chemotherapy is administered beyond the first trimester [
        • Yu H.H.
        • Cheung P.S.
        • Leung R.C.
        • et al.
        Current management of pregnancy-associated breast cancer.
        ].
      • ii)
        Up to a 25% increase in risk of intrauterine growth restriction and a low birth weight when the drugs are administered in the second and third trimester, depending on timing of exposure and type and dosage of chemotherapy [
        • Yu H.H.
        • Cheung P.S.
        • Leung R.C.
        • et al.
        Current management of pregnancy-associated breast cancer.
        ].
      • iii)
        Between 35.6% and 67.1% risk of prematurity (higher than the 4% risk reported in the general population [
        • Yu H.H.
        • Cheung P.S.
        • Leung R.C.
        • et al.
        Current management of pregnancy-associated breast cancer.
        ]), even though most of the patients in the literature receive elective preterm labor induction or Cesarean section to allow a quicker completion treatment of the mother's disease. However, post-natal growth seems to be unaffected, as most small-for-gestational-age children catch-up on their growth shortly after birth [
        • 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.
        ,
        • Amant F.
        • Vandenbroucke T.
        • Verheecke M.
        • et al.
        Pediatric outcome after maternal cancer diagnosed during pregnancy. International network on cancer, infertility, and pregnancy (INCIP).
        ].
      • iv)
        Increased risk of fetal hematologic and non-hematologic toxicities of platinum/taxane therapy, such as 5% risk of ototoxicity [
        • Amant F.
        • Han S.N.
        • Gziri M.M.
        • et al.
        Management of cancer in pregnancy.
        ], 6% risk of transitory fetal creatinine elevation [
        • Köhler C.
        • Oppelt P.
        • Favero G.
        • et al.
        How much platinum passes the placental barrier? Analysis of platinum applications in 21 patients with cervical cancer during pregnancy.
        ], anecdotal hearing loss [
        • Geijteman E.C.
        • Wensveen C.W.
        • Duvekot J.J.
        • et al.
        A child with severe hearing loss associated with maternal cisplatin treatment during pregnancy.
        ] and reduction in cardiac ejection fraction [
        • Karam A.
        • Feldman N.
        • Holschneider C.H.
        Neoadjuvant cisplatin and radical Cesarean hysterectomy for cervical cancer in pregnancy.
        ].
      • v)
        Indeterminate risk of chemotherapy-induced malignancy in the fetus [
        • Avilés A.
        • Neri N.
        Hematological malignancies and pregnancy: a final report of 84 children who received chemotherapy in utero.
        ], and an estimated 8–9% 10-year cumulative risk of treatment-related malignancy in the mother [
        • Greene M.H.
        • Harris E.L.
        • Gershenson D.M.
        • et al.
        Melphalan may be a more potent leukemogen than cyclophosphamide.
        ].
      • vi)
        Risk of maternal chemotherapy-induced toxicities such as nausea, vomiting, allergic reaction, alopecia, and cytopenias.
      Because of the aforementioned risks, the clinical management of this patient before starting therapy included:
      • i)
        Excluding preexisting fetal malformations with ultrasound.
      • ii)
        Evaluating of fetal growth based on gestational age at the time of diagnosis.
      • iii)
        Advising the patient of the recommendation for Cesarean delivery following 34 weeks gestation.
      • iv)
        Counseling the patient regarding the use of supportive care medications to prevent nausea, vomiting and allergic reactions. During the second cycle, our patient experienced a mild allergy to paclitaxel, which was managed with methylprednisolone. Though not required in this patient, growth factors are permitted in pregnancy [
        • Boere I.
        • Lok C.
        • Vandenbroucke T.
        • et al.
        Cancer in pregnancy: safety and efficacy of systemic therapies.
        ,
        • Boxer L.A.
        • Bolyard A.A.
        • Kelley M.L.
        • et al.
        Use of granulocyte colony–stimulating factor during pregnancy in women with chronic neutropenia.
        ].
      • v)
        Planning for monitorng for preterm contractions, and for regular fetal monitoring with ultrasound and umbilical artery Doppler to exclude fetal anemia [
        • 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.
        ].
      • vi)
        Encouraging her regarding breast-feeding, since the expected time between the last cycle of chemotherapy and delivery would be long enough to decrease the chance of fetal exposure of chemotherapy through breast milk [
        • Amant F.
        • Han S.N.
        • Gziri M.M.
        • et al.
        Management of cancer in pregnancy.
        ].

      7. The role and timing of surgery (radical Cesarean hysterectomy)

      Our recommended strategy was for Cesarean radical hysterectomy following neoadjuvant chemotherapy. Delivery was planned at 35 gestational weeks to reduce the risk of extreme preterm-associated neonatal mortality and morbidity; antenatal corticosteroids were administered to the mother prior to delivery to accelerate fetal lung maturation. Chemotherapy was discontinued 3 weeks before delivery to allow for bone marrow recovery in order to minimize the risk of cytopenic complications of maternal and fetal sepsis and hemorrhage.
      Radical surgery is an option in patients with locally advancer cervical cancer (IB2-IIA2) without evidence of extrapelvic disease or bulky lymph node metastasis on imaging studies. Quality of surgery, including type C2 radical hysterectomy (RH) [
      • Querleu D.
      • Morrow C.P.
      Classification of radical hysterectomy.
      ] and systematic pelvic and aortic lymphadenectomy, is of key importance [
      • Khan S.R.
      • Arshad M.
      • Wallitt K.
      • et al.
      What's new in imaging for gynecologic cancer?.
      ]. In patients receiving NACT, radical surgery is tailored according to clinical response [
      • Panici P.B.
      • Di Donato V.
      • Palaia I.
      • et al.
      Type B versus type C radical hysterectomy after neoadjuvant chemotherapy in locally advanced cervical carcinoma: a propensity-matched analysis.
      ]. Our patient had a partial clinical response after 2 cycles of neoadjuvant chemotherapy, with a reduction in the tumor diameter from 7 to 4 cm. A Type C1 radical Cesarean hysterectomy with pelvic and aortic lymphadenectomy was performed. Briefly, the new QM classification [
      • Querleu D.
      • Cibula D.
      • Abu-Rustum N.R.
      2017 update on the Querleu-Morrow classification of radical hysterectomy.
      ], recently updated by Cibula et al., describes the main landmarks of three compartments of the parametrium, to achieve a more tailored surgery. In particular, Type C1 is a Piver III nerve sparing RH, which preserves the hypogastric nerve posteriorly at the level of uterosacral ligament, the caudal part of the lateral parametrium under the deep uterine vein, and the leaf of the anterior parametrium, where parasympathetic trunks run. The length of the vagina is typically preserved. Due to cervical physiological changes during pregnancy, to ensure adequate radical parametrectomy, we performed resection of paracervix after radical hysterectomy, at time of pelvic lymphadenectomy (Fig. 2).
      Based on her age of 35 and the reportedly low risk of ovarian metastases of 0.9% for stage IB2 [
      • Matsuo K.
      • Shimada M.
      • Yamaguchi S.
      • et al.
      Identifying a candidate population for ovarian conservation in young women with clinical stage IB-IIB cervical cancer.
      ] disease, we recommended that she undergo an ovarian preserving surgery; the ovaries were transposed outside the irradiation field to minimize the risk of ovarian failure if adjuvant radiation therapy was necessary [
      • Sedlis A.
      • Bundy B.N.
      • Rotman M.Z.
      • et al.
      A randomized trial of pelvic radiation therapy versus no further therapy in selected patients with stage IB carcinoma of the cervix after radical hysterectomy and pelvic lymphadenectomy: a gynecologic oncology group study.
      ].
      Cesarean radical hysterectomy is safe and feasible with a modest complication rate. The most critical issues in performing surgery on a gravid uterus in the late stage of pregnancy are the size of the specimen occupying the surgical field and the possibility of atonic bleeding. Brunschwig described Cesarean radical hysterectomy for the first time in 1958 [
      • Brunschwig A.
      • Barber H.R.
      Cesarean section immediately followed by radical hysterectomy and pelvic node excision.
      ] resulting in a Cesarean section immediately followed by radical hysterectomy and pelvic node excision. There are few data in literature describing surgical complications of Cesarean radical hysterectomy, with a variety of treatment options described and an overall low number of cases reported. Monk and Montz reported an analysis of surgical outcome of pregnant patients with early stage cervical cancer treated with radical hysterectomy with the fetus in situ or Cesarean radical hysterectomy, showing a greater rate of intraoperative blood loss for the latter procedure [
      • Monk B.J.
      • Montz F.J.
      Invasive cervical cancer complicating intrauterine pregnancy: treatment with radical hysterectomy.
      ]. Leath et al. analyzed operative data and postoperative morbidity comparing pregnant and non-pregnant women submitted to radical hysterectomy or Cesarean radical hysterectomy. Consistent with previous reports, estimated blood loss (1543 vs. 718 mL, p = 0.0002), the rate of transfusion (57 vs. 9%, p = 0.009), and the median length of stay (4.7 vs 3.5 days, p = 0.001) was significantly higher in pregnant women compared with non-pregnant controls. On the other hand, cumulative operative and postoperative morbidity (wound infections, fistula, vascular injury, pneumonia) were similar in both groups [
      • Leath C.A.
      • Bevis K.S.
      • Numnum T.M.
      • et al.
      Comparison of operative risks associated with radical hysterectomy in pregnant and nonpregnant women.
      ]. A Japanese group proposed a surgical strategy to reduce the rate of intraoperative bleeding with the amputation of the uterine corpus after the Cesarean delivery. They reported 3 cases with lower blood loss; concerns regarding the risk of intraoperative cancer exposure to the peritoneal cavity remain [
      • Matsuo K.
      • Enomoto T.
      • Yamasaki M.
      Amputation of uterine corpus as the intraoperative modification during cesarean radical hysterectomy for invasive cervical cancer during pregnancy.
      ].

      8. Information from histopathological findings after NACT, and adjuvant treatment

      After neoadjuvant treatment, some novel histopathological findings have been observed in surgically resected tumors, such as eosinophilic cytoplasm, vacuolation, enlarged nuclei, and chromatin irregularities. Multinucleated giant cells as well as stromal fibrosis and hemosiderin pigment may be also encountered. Pathologic response after neoadjuvant treatment in cervical carcinoma is classified as follows: pR2 (no pathological response); pR1 (partial pathological response) and pR0 (complete pathological response) [
      • Zannoni G.F.
      • Vellone V.G.
      • Carbone A.
      Morphological effects of radiochemotherapy on cervical carcinoma: a morphological study of 50 cases of hysterectomy specimens after neoadjuvant treatment.
      ]. Our patient had a pR2 response, though clinically the size of her primary malignancy decreased during NACT.
      The hysterectomy specimen was notable for a post-gravid uterus, 16 × 11 × 6 cm with an incision in the lower segment. Endometrium and salpinges were negative for cancer. The cervix contained macroscopic residual disease with the largest diameter of 2.5 cm. Vaginal margins measured 2.0 cm at the longest part, and were all free from microscopic tumor invasion. On final pathology, a grade 3 squamous cell cervical carcinoma in the uterine cervix, infiltrating 1.1 cm of 1.8 cm (61%) cervical stroma, with presence of LVSI was shown (Fig. 3). Thirty-nine lymph nodes, the vaginal margin, and the paracervix were negative for malignancy.
      Given that the pathological findings met criteria for adjuvant therapy to reduce the risk of recurrence, a discussion with the patient regarding treatment options was undertaken. Whether pregnancy negatively influences maternal prognosis has been a topic of debate for decades [
      • Amant F.
      • Han S.N.
      • Gziri M.M.
      • et al.
      Management of cancer in pregnancy.
      ]. Theoretically, the physiological changes of pregnancy including an altered immune system, an increased hormonal environment, and hypervascularization have been postulated as factors leading to a poor cancer outcome compared with non-pregnant controls. However, pregnancy does not seem to influence the overall survival of patients diagnosed with estrogen-dependent cancers such as breast cancer [
      • Amant F.
      • von Minckwitz G.
      • Han S.N.
      • et al.
      Prognosis of women with primary breast cancer diagnosed during pregnancy: results from an international collaborative study.
      ] and melanoma [
      • Lens M.B.
      • Rosdahl I.
      • Ahlbom A.
      • et al.
      Effect of pregnancy on survival in women with cutaneous malignant melanoma.
      ] compared with non-pregnant controls in large population based studies.
      A higher stage at time of diagnosis (due to patient or provider delay) can be another cause of poor prognosis in pregnant patients compared with non-pregnant controls. Although most historical case series are underpowered to detect differences in prognosis when compared to stage-matched non-pregnant patients, recent studies have shown a similar prognosis between these groups [
      • Loibl S.
      • Han S.N.
      • von Minckwitz G.
      • et al.
      Treatment of breast cancer during pregnancy: an observational study.
      ,
      • Amant F.
      • Von M.G.
      • Han S.N.
      • et al.
      Prognosis of women with primary breast cancer diagnosed during pregnancy: results from an international collaborative study.
      ]. A large cohort study comparing 516 pregnant women to 42,511 non-pregnant patients with cancer aged between 16 and 49 years showed no difference in the risk of cause-specific death [
      • Stensheim H.
      • Moller B.
      • van Dijk T.
      • et al.
      Cause-specific survival for women diagnosed with cancer during pregnancy or lactation: a registry-based cohort study.
      ], suggesting that the antecedent pregnancy should not impact the recommendation for adjuvant therapy. In our case, the presence of at least 2 pathologic risk factors according to Sedlis criteria [
      • Sedlis A.
      • Bundy B.N.
      • Rotman M.Z.
      • et al.
      A randomized trial of pelvic radiation therapy versus no further therapy in selected patients with stage IB carcinoma of the cervix after radical hysterectomy and pelvic lymphadenectomy: a gynecologic oncology group study.
      ] (i.e. LVSI, stromal invasion deeper than 1/3, tumor size larger than 2 cm) led to our recommendation for adjuvant external beam radiation therapy and concomitant radiosensitizing platinum-based chemotherapy.
      Another consideration when managing cancer during pregnancy is the extremely rare risk of cervical cancer metastatic to placenta; to our knowledge, only one case has been reported in the literature [
      • Can N.T.
      • Robertson P.
      • Zaloudek C.J.
      • et al.
      Cervical squamous cell carcinoma metastatic to placenta.
      ]. In another series of 60 cases of pregnancy complicated by cancer, the placenta was found have metastasis from one case of melanoma and one case of leukemia (3.2%) [
      • Garofalo S.
      • Degennaro V.A.
      • Salvi S.
      • et al.
      Perinatal outcome in pregnant women with cancer: are there any effects of chemotherapy?.
      ]. Additionally, metastases from maternal cancer to the fetus are rare, with only 12 cases of reported from a total of 1134 cancers reported from 1866 to 1987; and, 7 of the fetal metastases occurred in 93 melanoma cases [
      • Dildy 3rd, G.A.
      • Moise Jr., K.J.
      • Carpenter Jr., R.J.
      • et al.
      Maternal malignancy metastatic to the products of conception: a review.
      ]. Considering that the presence of placental metastases should alert the clinician to monitor the infant for development of cancer, we sent the placenta for histologic examination, which was negative. This practice should be considered for patients delivered with an intercurrent malignancy [
      • Weisz B.
      • Meirow D.
      • Schiff E.
      • et al.
      Impact and treatment of cancer during pregnancy.
      ].

      9. Neonatal outcome

      A 2450 g (50th percentile) male was delivered at 35 weeks, with Apgar scores of 8 and 9 at 1 and 5 min, respectively, and normal hematological parameters at delivery. He did not demonstrate any evidence of chemotherapy-related side effects such as ototoxicity, fetal creatinine elevation or hearing loss. He underwent intensive surveillance showing a normal psycho-physical development, until when he was diagnosed with M7 (megakaryoblastic) acute myeloid leukemia (AML) at 22 months of age.
      Although various chemotherapeutic drugs such as alkylating agents, topoisomerases, and platinum compounds can induce secondary leukemia [
      • Reynoso E.E.
      • Shepherd F.A.
      • Messner H.A.
      • et al.
      Acute leukemia during pregnancy: the Toronto leukemia study group experience with long-term follow-up of children exposed in utero to chemotherapeutic agents.
      ], it is difficult to establish the direct causal effect of maternal chemotherapy on in-utero fetal exposure, or to discriminate a primary leukemia from a secondary drug-induced leukemia. Although a few studies have investigated the short and long-term health outcomes of children 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.
      ], data about the fetal risk of developing secondary malignancies following in-utero chemotherapy are generally extrapolated from data derived from cases of ex-utero exposure. Only a few secondary malignancies have been definitively linked to chemotherapy. Specifically, a causal relationship has been established between exposure to alkylating agents and the development of leukemia, and between exposure to cyclophosphamide and the development of bladder cancer. The risk of leukemia peaks around 5–10 years after chemotherapy exposure. Cisplatin has been classified among agents “probably carcinogenic” to humans (IARC Group 2A) [
      • (IARC Group 2A) IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, Volume SO
      Some Pharmaceutical Drugs.
      ] and may act through a mechanism similar to the other alkylating agents. The 8.5% cumulative risk of secondary cancer at 10 years described for women exposed to other alkylating agents (melphalan and cyclophosphamide) [
      • Greene M.H.
      • Harris E.L.
      • Gershenson D.M.
      • et al.
      Melphalan may be a more potent leukemogen than cyclophosphamide.
      ] can be used to estimate the risk of secondary treatment-related malignancies in women treated with cisplatin.
      In our case, the baby's development of AML is unable to be directly attributed to maternal treatment given the absence of a chromosomal translocation such as chromosome 5/5q and/or 7/7q- (frequently seen in secondary AMLs [
      • Masetti R.
      • Vendemini F.
      • Zama D.
      • et al.
      Acute myeloid leukemia in infants: biology and treatment.
      ]), and since no karyotypic abnormalities seen in treatment-related cancers (i.e. complex karyotype, trisomy 8, monosomy 7) were detected. Due to the exposure to cisplatinum in-utero, the baby was assigned to the high-risk prognostic group. The first-line chemotherapy protocol for the treatment of AML in children is based on the cytogenetic characteristics and minimal residual disease clearance [
      • Buldini B.
      • Rizzati F.
      • Masetti R.
      • et al.
      Prognostic significance of flow-cytometry evaluation of minimal residual disease in children with acute myeloid leukaemia treated according to the AIEOP-AML 2002/01 study protocol.
      ]. The baby received multi-drug chemotherapy and achieved a complete flow-cytometry remission after induction. Disease control persisted during the consolidation phase, and haploidentical hemopoietic stem cell transplantation (donor father) was performed.
      Survival of patients with therapy-induced AML overall is significantly inferior to that of patients with de novo AML, due to unfavorable-risk karyotype associated with chemotherapy resistance [
      • Schoch C.
      • Kern W.
      • Schnittger S.
      • et al.
      Karyotype is an independent prognostic parameter in therapy-related acute myeloid leukemia (t-AML): an analysis of 93 patients with t-AML in comparison to 1091 patients with de novo AML.
      ,
      • Kern W.
      • Haferlach T.
      • Schnittger S.
      • et al.
      Prognosis in therapy-related acute myeloid leukemia and impact of karyotype.
      ,
      • Larson R.A.
      Is secondary leukemia an independent poor prognostic factor in acute myeloid leukemia?.
      ] and their median survival ranges from 2 to 8 months. In our case, the response to chemotherapy was complete and 15 months after bone marrow transplantation he remains without evidence of relapse.

      10. Long-term follow-up of the child

      It is well known that prematurity, independent from cancer treatment, is associated with impaired cognitive function. Independent of this factor, long-term prospective studies of children delivered by women diagnosed with cancer during pregnancy have shown no significant effect on childhood learning disabilities or hematological or immunological abnormalities. In a prospective study of 70 children who were exposed to chemotherapy in utero, the general health, cognitive development, and cardiac outcome levels were comparable to those of the general population after a median follow-up of 22 months [
      • 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.
      ]. This was also confirmed by a recent multicenter case–control study [
      • Amant F.
      • Vandenbroucke T.
      • Verheecke M.
      • et al.
      Pediatric outcome after maternal cancer diagnosed during pregnancy. International network on cancer, infertility, and pregnancy (INCIP).
      ], where children whose mothers received a diagnosis of cancer and treatment during pregnancy were compared with matched children of women without a cancer diagnosis (including a neurologic examination, and a cardiac and general health assessment). Follow up in our case is too short to draw any conclusion regarding cognitive function.
      The long-term effect on fetus future fertility needs to be investigated with longer follow up periods, and infants and children should be screened for cancer development [
      • Reynoso E.E.
      • Shepherd F.A.
      • Messner H.A.
      • et al.
      Acute leukemia during pregnancy: the Toronto leukemia study group experience with long-term follow-up of children exposed in utero to chemotherapeutic agents.
      ,
      • Zemlickis D.
      • Lishner M.
      • Erlich R.
      • et al.
      Teratogenicity and carcinogenicity in a twin exposed in utero to cyclophosphamide.
      ].

      11. Summary

      Cervical cancer diagnosed during pregnancy requires multi-disciplinary care to maximize the outcome of both the mother and fetus. The option of delaying delivery until fetal lung maturity by using neoadjuvant chemotherapy until delivery is feasible [
      • Ricci C.
      • Scambia G.
      • De Vincenzo R.
      Locally advanced cervical cancer in pregnancy: overcoming the challenge. A case series and review of the literature.
      ]. The evaluation of the maternal efficacy and safety of neoadjuvant chemotherapy in pregnancy is limited by the inability to perform a randomized trial, the low number of cases reported in literature, and the need for fetal and childhood follow-up to ensure favorable cognitive and functional outcomes.

      Authors' contribution

      Each Author has contributed to the following sections of the manuscript:
      De Vincenzo R*, Gynecologic oncology (case, epidemiology and risk factors, diagnosis and chemotherapy).
      Tortorella L*, Gynecologic oncology (staging and surgery, assessment for adjuvant radiotherapy).
      Ricci C*, Gynecologic oncology (diagnosis and assessment of clinical response, review of the literature).
      Cavaliere AF°, Materno-Fetal Medicine (risk assessment and counseling for premature delivery, and fetal chemotherapy-induced toxicities, clinical management of pregnancy, timing of cesarean section).
      Zannoni GF#, Pathology (histology, assessment of pathological response and risk factors).
      Cefalo MG^, Paediatric Haematology and Oncology (neonatological outcome, diagnosis and treatment of AML, assessment of risk factors for secondary tumor).
      Scambia G*, Gynecologic oncology, Head of the Department (clinical coordination of the MDT).
      Fagotti A*, Gynecologic oncology (staging and surgery, revision of the manuscript).
      All Authors declare no conflict of interest.

      References

        • Querleu D.
        • Morrow C.P.
        Classification of radical hysterectomy.
        Lancet Oncol. 2008 Mar; 9: 297-303https://doi.org/10.1016/S1470-2045(08)70074-3
        • Ruiz R.
        • Herrero C.
        • Strasser-Weippl K.
        • et al.
        Epidemiology and pathophysiology of pregnancy-associated breast cancer: a review.
        Breast. 2017 Oct; 35: 136-141https://doi.org/10.1016/j.breast.2017.07.008
        • De Simone V.
        • Pagani O.
        Pregnancy after breast cancer: hope after the storm.
        Minerva Ginecol. 2017 Jul 10; https://doi.org/10.23736/S0026-4784.17.04113-2
        • PDQ Adult Treatment Editorial Board
        Breast Cancer Treatment and Pregnancy (PDQ®): Health Professional Version.
        PDQ Cancer Information Summaries [Internet]. National Cancer Institute (US), Bethesda (MD)2017 Jun 29 (2002-. Available from) (PubMed PMID: 26389427)
        • Abdalla N.
        • Bizoń M.
        • Piórkowski R.
        • Stanirowski P.
        • Cendrowski K.
        • Sawicki W.
        Does chemotherapy for gynecological malignancies during pregnancy cause fetal growth restriction?.
        Biomed. Res. Int. 2017; 20177543421https://doi.org/10.1155/2017/7543421
        • Knabben L.
        • Mueller M.D.
        Breast cancer and pregnancy.
        Horm. Mol. Biol. Clin. Invest. Special Issue: Breast Cancer: An Update in the management. 2017 October; 32
        • Gerstl B.
        • Sullivan E.
        • Ives A.
        • et al.
        Pregnancy outcomes after a breast Cancer diagnosis: a systematic review and meta-analysis.
        Clin. Breast Cancer. 2018 Feb; 18 (pii: S1526-8209(16)30537-7 (2017 Jul 10)): e79-e88
        • Yu H.H.
        • Cheung P.S.
        • Leung R.C.
        • et al.
        Current management of pregnancy-associated breast cancer.
        Hong Kong Med. J. 2017 Aug; 23: 387-394https://doi.org/10.12809/hkmj166049
        • Ngu S.F.
        • Ngan H.Y.
        Chemotherapy in pregnancy.
        Best Pract. Res. Clin. Obstet. Gynaecol. 2016 May; 33: 86-101https://doi.org/10.1016/j.bpobgyn
        • Bonney E.A.
        Alternative theories: pregnancy and immune tolerance.
        J. Reprod. Immunol. 2017 Sep; 123: 65-71https://doi.org/10.1016/j.jri.2017.09.005
        • Frega A.
        • Verrone A.
        • Manzara F.
        • et al.
        Expression of E6/E7 HPV-DNA, HPV-mRNA and colposcopic features in management of CIN2/3 during pregnancy.
        Eur. Rev. Med. Pharmacol. Sci. 2016 Oct; 20: 4236-4242
        • Amant F.
        • Halaska M.J.
        • Fumagalli M.
        • et al.
        Gynecological cancers in pregnancy: guidelines of a second international consensus meeting.
        Int. J. Gynecol. Cancer. 2014; 24: 394-403
        • Peccatori F.A.
        • Azim H.A.J.R.
        • Orecchia R.
        • et al.
        Cancer, pregnancy and fertility: ESMO clinical practice guidelines for diagnosis, treatment and follow-up.
        Ann. Oncol. 2013; 24: vi160-70
        • Boere I.
        • Lok C.
        • Vandenbroucke T.
        • et al.
        Cancer in pregnancy: safety and efficacy of systemic therapies.
        Curr. Opin. Oncol.S. 2017 Sep; 29: 328-334https://doi.org/10.1097/CCO.0000000000000386
        • Amant F.
        • Han S.N.
        • Gziri M.M.
        • et al.
        Management of cancer in pregnancy.
        Best Pract. Res. Clin. Obstet. Gynaecol. 2015 Jul; 29: 741-753https://doi.org/10.1016/j.bpobgyn.2015.02.006
        • Khan S.R.
        • Arshad M.
        • Wallitt K.
        • et al.
        What's new in imaging for gynecologic cancer?.
        Curr. Oncol. Rep. 2017 Nov 6; 19: 85https://doi.org/10.1007/s11912-017-0640-3
        • Zagouri F.
        • Dimitrakakis C.
        • Marinopoulos S.
        • et al.
        Cancer in pregnancy: disentangling treatment modalities.
        ESMO Open. 2016 May 4; 1 (eCollection 2016)e000016
      1. ESGO-ESTRO-ESP Guidelines for the Management of Patients with Cervical Cancer. 2017 (in press)
        • Epstein E.
        • Testa A.
        • Gaurilcikas A.
        • et al.
        Early-stage cervical cancer: tumor delineation by magnetic resonance imaging and ultrasound - a European multicenter trial.
        Gynecol. Oncol. 2013 Mar; 128: 449-453https://doi.org/10.1016/j.ygyno.2012.09.025
        • Morice P.
        • Uzan C.
        • Gouy S.
        • et al.
        Gynaecological cancers in pregnancy.
        Lancet. 2012 Feb 11; 379 (Review): 558-569https://doi.org/10.1016/S0140-6736(11)60829-5
        • Dostálek L.
        • Zikan M.
        • Fischerova D.
        • et al.
        SLN biopsy in cervical cancer patients with tumors larger than 2 cm and 4 cm.
        Gynecol. Oncol. 2018 Mar; 148 (Epub 2018 Feb 1): 456-460https://doi.org/10.1016/j.ygyno.2018.01.001
        • Cibula D.
        • Kuzel D.
        • Sláma J.
        • et al.
        Sentinel node (SLN) biopsy in the management of locally advanced cervical cancer.
        Gynecol. Oncol. 2009 Oct; 115 (Epub 2009 Jul 31): 46-50https://doi.org/10.1016/j.ygyno.2009.06.017
        • Papadia A.
        • Mohr S.
        • Imboden S.
        • et al.
        Laparoscopic indocyanine green sentinel lymph node mapping in pregnant cervical cancer patients.
        J. Minim. Invasive Gynecol. 2016 Feb 1; 23: 270-273https://doi.org/10.1016/j.jmig.2015.10.001
        • Rudolf H.
        • Goretzlehner G.
        • Brugmann E.
        • et al.
        Assessment of liver function using indocyanine green (Ujoviridin) during normal pregnancy, during labor and in puerperium.
        Zentralbl. Gynakol. 1977; 99: 1548-1553
        • Probst P.
        • Paumgartner G.
        • Caucig H.
        • et al.
        Studies on clearance and placental transfer of indocyanine green during labor.
        Clin. Chim. Acta. 1970; 29: 157-160
        • Ehret D.Y.
        • Patterson J.K.
        • Bose C.L.
        Improving neonatal care: a global perspective.
        Clin. Perinatol. 2017; 44: 567-582
        • EPICure Study Group
        EPICure: facts and figure: why preterm labour should be treated.
        BMJO. 2006 Dec; 113 (10-2)
        • Findeklee S.
        Overview tumour disease and oncologic therapy during pregnancy.
        Z. Geburtshilfe Neonatol. 2018 April; 222: 61-65
        • Perri T.
        • Issakov G.
        • Ben-Baruch G.
        Effect of treatment delay on survival in patients with cervical cancer: a historical cohort study.
        Int. J. Gynecol. Cancer. 2014 Sep; 24: 1326-1332https://doi.org/10.1097/IGC.0000000000000211
        • Shen S.C.
        • Hung Y.C.
        • Kung P.T.
        • et al.
        Factors involved in the delay of treatment initiation for cervical cancer patients: a nationwide population-based study.
        Medicine (Baltimore). 2016 August; 95: e4568
        • Ribeiro F.
        • Correia L.
        • Paula T.
        • et al.
        Cervical cancer in pregnancy: 3 cases, 3 different approaches.
        J. Low. Genit. Tract Dis. 2013 Jan; 17: 66-70https://doi.org/10.1097/LGT.0b013e31824d6fb8
        • Karam A.
        • Feldman N.
        • Holschneider C.H.
        Neoadjuvant cisplatin and radical Cesarean hysterectomy for cervical cancer in pregnancy.
        Nat. Clin. Pract. Oncol. 2007 Jun; 4: 375-380
        • Tewari K.
        • Cappuccini F.
        • Gambino A.
        • et al.
        Neoadjuvant chemotherapy in the treatment of locally advanced cervical carcinoma in pregnancy: a report of two cases and review of issues specific to the management of cervical carcinoma in pregnancy including planned delay of therapy.
        Cancer. 1998 Apr 15; 82: 1529-1534
        • Minig L.
        • Colombo N.
        • Zanagnolo V.
        • et al.
        Platinum-based neoadjuvant chemotherapy followed by radical surgery for cervical carcinoma international federation of gynecology and obstetrics stage IB2-IIB.
        Int. J. Gynecol. Cancer. 2013 Nov; 23: 1647-1654https://doi.org/10.1097/IGC.0b013e3182a616d2
        • Benedetti-Panici P.
        • Greggi S.
        • Colombo A.
        • et al.
        Neoadjuvant chemotherapy and radical surgery versus exclusive radiotherapy in locally advanced squamous cell cervical cancer: results from the Italian multicenter randomized study.
        J. Clin. Oncol. 2002 Jan 1; 20: 179-188
        • Gupta S.
        • Maheshwari A.
        • Parab P.
        • et al.
        Neoadjuvant chemotherapy followed by radical surgery versus concomitant chemotherapy and radiotherapy in patients with stage IB2, IIA, or IIB squamous cervical cancer: a randomized controlled trial.
        J. Clin. Oncol. 2018 Jun 1; 36 (JCO2017759985 (2018 Feb 12)): 1548-1555
      2. EORTC GCG 55994: Randomized phase III study of neoadjuvant CT followed by surgery vs concomitant RTX + CT in FIGO stage Ib2, IIa > 4 cm or IIb cervical cancer. Ongoing trial.

        • Cardonick E.
        • Iacobucci A.
        Use of chemotherapy during human pregnancy.
        Lancet Oncol. 2004 May; 5 (Review): 283-291
        • Ilancheran A.
        Neoadjuvant chemotherapy in cervical cancer in pregnancy.
        Best Pract. Res. Clin. Obstet. Gynaecol. 2016 May; 33 (Epub 2015 Oct 19): 102-107https://doi.org/10.1016/j.bpobgyn.2015.10.008
        • Weisz B.
        • Meirow D.
        • Schiff E.
        • et al.
        Impact and treatment of cancer during pregnancy.
        Expert. Rev. Anticancer. Ther. 2004 Oct; 4: 889-902
        • Marnitz S.
        • Kohler C.
        • Oppelt P.
        • et al.
        Cisplatin application in pregnancy: first in vivo analysis of 7 patients.
        Oncology. 2010; 7972e7
        • Köhler C.
        • Oppelt P.
        • Favero G.
        • et al.
        How much platinum passes the placental barrier? Analysis of platinum applications in 21 patients with cervical cancer during pregnancy.
        Am. J. Obstet. Gynecol. 2015 Aug; 213 (e1-5): 206
        • Mir O.
        • Berveiller P.
        • Ropert S.
        • et al.
        Use of platinum derivatives during pregnancy.
        Cancer. 2008 Dec 1; 113: 3069-3074https://doi.org/10.1002/cncr.23935
        • Smith J.A.
        • Gaikwad A.
        • Mosley S.
        Utilization of an ex vivo human placental perfusion model to predict potential fetal exposure to carboplatin during pregnancy.
        Am. J. Obstet. Gynecol. 2014; 210 (e1-9): 275
        • Calsteren K.V.
        • Verbesselt R.
        • Devlieger R.
        • et al.
        Transplacental transfer of paclitaxel, docetaxel, carboplatin and trastuzumab in a baboon model.
        Int. J. Gynecol. Cancer. 2010; 201456e64
        • Zagouri F.
        • Sergentanis T.N.
        • Chrysikos D.
        • et al.
        Platinum derivatives during pregnancy in cervical cancer: a systematic review and meta-analysis.
        Obstet. Gynecol. 2013 Feb; 121 (Review): 337-343https://doi.org/10.1097/AOG.0b013e31827c5822
        • Cardonick E.
        • Bhat A.
        • Gilmandyar D.
        • et al.
        Maternal and fetal outcomes of taxane chemotherapy in breast and ovarian cancer during pregnancy: case series and review of the literature.
        Ann. Oncol. 2012 Dec; 23: 3016-3023https://doi.org/10.1093/annonc/mds170
        • Li J.
        • Wang L.J.
        • Zhang B.Z.
        • Peng Y.P.
        • et al.
        Neoadjuvant chemotherapy with paclitaxel plus platinum for invasive cervical cancer in pregnancy: two case report and literature review.
        Arch. Gynecol. Obstet. 2011 Sep; 284: 779-783
        • Zagouri F.
        • Sergentanis T.N.
        • Chrysikos D.
        • et al.
        Taxanes for ovarian cancer during pregnancy: a systematic review.
        Oncology. 2012; 83: 234-238
        • de Haan J.
        • Verheecke M.
        • Van Calsteren K.
        • et al.
        Oncological management and obstetric and neonatal outcomes for women diagnosed with cancer during pregnancy: a 20-year international cohort study of 1170 patients.
        Lancet Oncol. 2018 Mar; 19: 337-346
        • 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; 13256e64
        • Amant F.
        • Vandenbroucke T.
        • Verheecke M.
        • et al.
        Pediatric outcome after maternal cancer diagnosed during pregnancy. International network on cancer, infertility, and pregnancy (INCIP).
        N. Engl. J. Med. 2015 Nov 5; 373: 1824-1834
        • Geijteman E.C.
        • Wensveen C.W.
        • Duvekot J.J.
        • et al.
        A child with severe hearing loss associated with maternal cisplatin treatment during pregnancy.
        Obstet. Gynecol. 2014 Aug; 124: 454-456https://doi.org/10.1097/AOG.0000000000000389
        • Avilés A.
        • Neri N.
        Hematological malignancies and pregnancy: a final report of 84 children who received chemotherapy in utero.
        Clin. Lymphoma. 2001 Dec; 2: 173-177
        • Greene M.H.
        • Harris E.L.
        • Gershenson D.M.
        • et al.
        Melphalan may be a more potent leukemogen than cyclophosphamide.
        Ann. Intern. Med. 1986 Sep; 105: 360-367
        • Boxer L.A.
        • Bolyard A.A.
        • Kelley M.L.
        • et al.
        Use of granulocyte colony–stimulating factor during pregnancy in women with chronic neutropenia.
        Obstet. Gynecol. 2015 Jan; 125: 197-203
        • 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 Aug; 126: 192-197
        • Panici P.B.
        • Di Donato V.
        • Palaia I.
        • et al.
        Type B versus type C radical hysterectomy after neoadjuvant chemotherapy in locally advanced cervical carcinoma: a propensity-matched analysis.
        Ann. Surg. Oncol. 2016 Jul; 23: 2176-2182https://doi.org/10.1245/s10434-015-4996-z
        • Querleu D.
        • Cibula D.
        • Abu-Rustum N.R.
        2017 update on the Querleu-Morrow classification of radical hysterectomy.
        Ann. Surg. Oncol. 2017 Oct; 24: 3406-3412
        • Matsuo K.
        • Shimada M.
        • Yamaguchi S.
        • et al.
        Identifying a candidate population for ovarian conservation in young women with clinical stage IB-IIB cervical cancer.
        Int. J. Cancer. 2018 Mar 1; 142 (2017 Oct 16): 1022-1032
        • Sedlis A.
        • Bundy B.N.
        • Rotman M.Z.
        • et al.
        A randomized trial of pelvic radiation therapy versus no further therapy in selected patients with stage IB carcinoma of the cervix after radical hysterectomy and pelvic lymphadenectomy: a gynecologic oncology group study.
        Gynecol. Oncol. 1999 May; 73: 177-183
        • Brunschwig A.
        • Barber H.R.
        Cesarean section immediately followed by radical hysterectomy and pelvic node excision.
        Am. J. Obstet. Gynecol. 1958 Jul; 76: 199-203
        • Monk B.J.
        • Montz F.J.
        Invasive cervical cancer complicating intrauterine pregnancy: treatment with radical hysterectomy.
        Obstet. Gynecol. 1992 Aug; 80: 199-203
        • Leath C.A.
        • Bevis K.S.
        • Numnum T.M.
        • et al.
        Comparison of operative risks associated with radical hysterectomy in pregnant and nonpregnant women.
        J. Reprod. Med. 2013 Jul-Aug; 58: 279-284
        • Matsuo K.
        • Enomoto T.
        • Yamasaki M.
        Amputation of uterine corpus as the intraoperative modification during cesarean radical hysterectomy for invasive cervical cancer during pregnancy.
        Int. J. Clin. Oncol. 2010 Feb; 15: 77-81
        • Zannoni G.F.
        • Vellone V.G.
        • Carbone A.
        Morphological effects of radiochemotherapy on cervical carcinoma: a morphological study of 50 cases of hysterectomy specimens after neoadjuvant treatment.
        Int. J. Gynecol. Pathol. 2008; 27: 274-281
        • Amant F.
        • von Minckwitz G.
        • Han S.N.
        • et al.
        Prognosis of women with primary breast cancer diagnosed during pregnancy: results from an international collaborative study.
        J. Clin. Oncol. 2013 Jul 10; 31: 2532-2539
        • Lens M.B.
        • Rosdahl I.
        • Ahlbom A.
        • et al.
        Effect of pregnancy on survival in women with cutaneous malignant melanoma.
        J. Clin. Oncol. 2004 Nov 1; 22: 4369-4375
        • Loibl S.
        • Han S.N.
        • von Minckwitz G.
        • et al.
        Treatment of breast cancer during pregnancy: an observational study.
        Lancet Oncol. 2012; 13887e96
        • Amant F.
        • Von M.G.
        • Han S.N.
        • et al.
        Prognosis of women with primary breast cancer diagnosed during pregnancy: results from an international collaborative study.
        J. Clin. Oncol. 2013; 312532e9
        • Stensheim H.
        • Moller B.
        • van Dijk T.
        • et al.
        Cause-specific survival for women diagnosed with cancer during pregnancy or lactation: a registry-based cohort study.
        J. Clin. Oncol. 2009; 2745e51
        • Can N.T.
        • Robertson P.
        • Zaloudek C.J.
        • et al.
        Cervical squamous cell carcinoma metastatic to placenta.
        Int. J. Gynecol. Pathol. 2013 Sep; 32: 516-519https://doi.org/10.1097/PGP.0b013e3182763178
        • Garofalo S.
        • Degennaro V.A.
        • Salvi S.
        • et al.
        Perinatal outcome in pregnant women with cancer: are there any effects of chemotherapy?.
        Eur. J. Cancer Care. 2017; 26e12564
        • Dildy 3rd, G.A.
        • Moise Jr., K.J.
        • Carpenter Jr., R.J.
        • et al.
        Maternal malignancy metastatic to the products of conception: a review.
        Obstet. Gynecol. Surv. 1989 Jul; 44: 535-540
        • Reynoso E.E.
        • Shepherd F.A.
        • Messner H.A.
        • et al.
        Acute leukemia during pregnancy: the Toronto leukemia study group experience with long-term follow-up of children exposed in utero to chemotherapeutic agents.
        J. Clin. Oncol. 1987; 5: 1098-1106
        • (IARC Group 2A) IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, Volume SO
        Some Pharmaceutical Drugs.
        International Agency for Research on Cancer, Lyon1991
        • Masetti R.
        • Vendemini F.
        • Zama D.
        • et al.
        Acute myeloid leukemia in infants: biology and treatment.
        Front Pediatr. 2015 Apr 28; 3 (eCollection 2015. Review)https://doi.org/10.3389/fped.2015.00037
        • Buldini B.
        • Rizzati F.
        • Masetti R.
        • et al.
        Prognostic significance of flow-cytometry evaluation of minimal residual disease in children with acute myeloid leukaemia treated according to the AIEOP-AML 2002/01 study protocol.
        Br. J. Haematol. 2017 Apr; 177 (Epub 2017 Feb 27): 116-126https://doi.org/10.1111/bjh.14523
        • Schoch C.
        • Kern W.
        • Schnittger S.
        • et al.
        Karyotype is an independent prognostic parameter in therapy-related acute myeloid leukemia (t-AML): an analysis of 93 patients with t-AML in comparison to 1091 patients with de novo AML.
        Leukemia. 2004; 18: 120-125
        • Kern W.
        • Haferlach T.
        • Schnittger S.
        • et al.
        Prognosis in therapy-related acute myeloid leukemia and impact of karyotype.
        J. Clin. Oncol. 2004; 22: 2510-2511
        • Larson R.A.
        Is secondary leukemia an independent poor prognostic factor in acute myeloid leukemia?.
        Best Pract. Res. Clin. Haematol. 2007 Mar; 20: 29-37
        • Zemlickis D.
        • Lishner M.
        • Erlich R.
        • et al.
        Teratogenicity and carcinogenicity in a twin exposed in utero to cyclophosphamide.
        Teratog. Carcinog. Mutagen. 1993; 13: 139-143
        • Ricci C.
        • Scambia G.
        • De Vincenzo R.
        Locally advanced cervical cancer in pregnancy: overcoming the challenge. A case series and review of the literature.
        Int. J. Gynecol. Cancer. 2016 Oct; 26: 1490-1496https://doi.org/10.1097/IGC.0000000000000795