Gynecologic cancers in pregnancy: guidelines of a second international consensus meeting.

REVIEW ARTICLE

Gynecologic Cancers in Pregnancy Guidelines of a Second International Consensus Meeting Fre´de´ric Amant, MD, PhD,* Michael J. Halaska, MD, PhD,Þ Monica Fumagalli, MD,þ Karina Dahl Steffensen, MD,§ Christianne Lok, MD, PhD,|| Kristel Van Calsteren, MD, PhD,¶ Sileny N. Han, MD,* Olivier Mir, MD,# Robert Fruscio, MD, PhD,** Cathe´rine Uzan, MD, PhD,ÞÞ Cynthia Maxwell, MD,þþ Jana Dekrem, MSc,* Goedele Strauven, MSc,* Mina Mhallem Gziri, MD, PhD,* Vesna Kesic, MD, PhD,§§ Paul Berveiller, MD, PhD,|||| Frank van den Heuvel, MD, PhD,¶¶ Petronella B. Ottevanger, MD, PhD,## Ignace Vergote, MD, PhD,* Michael Lishner, MD, PhD,*** Philippe Morice, MD, PhD,ÞÞ and Irena Nulman, MD, PhDÞÞÞ on behalf of the ESGO task force ‘Cancer in Pregnancy’ Objectives: This study aimed to provide timely and effective guidance for pregnant women and health care providers to optimize maternal treatment and fetal protection and to promote effective management of the mother, fetus, and neonate when administering potentially teratogenic medications. New insights and more experience were gained since the first consensus meeting 5 years ago. Methods: Members of the European Society of Gynecological Oncology task force ‘‘Cancer in Pregnancy’’ in concert with other international experts reviewed the existing literature on their respective areas of expertise. The summaries were subsequently merged into a complete article that served as a basis for discussion during the consensus meeting. All participants approved the final article. Results: In the experts’ view, cancer can be successfully treated during pregnancy in collaboration with a multidisciplinary team, optimizing maternal treatment while considering fetal safety. To maximize the maternal outcome, cancer treatment should follow a standard treatment protocol as for nonpregnant patients. Iatrogenic prematurity should be avoided. Individualization of treatment and effective psychologic support is imperative to provide throughout the pregnancy period. Diagnostic procedures, including staging examinations and imaging, such as magnetic resonance imaging and sonography, are preferable. Pelvic surgery, either open or laparoscopic, as part of a treatment protocol, may reveal beneficial outcomes and is preferably performed by experts. Most standard regimens of chemotherapy can be administered from *Department of Oncology, Katholieke Universiteit Leuven and Gynecologic Oncology, University Hospitals Leuven, Belgium; †Gynecologic Oncology, 2nd Medical Faculty, Charles University, Prague, Czech Republic; ‡Neonatal Intensive Care, Department of Clinical Sciences and Community Health, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy; §Radiotherapy and Clinical Oncology, Vejle Hospital, Vejle, Denmark; ||Gynecological Oncology, Center for Gynecological Oncology Amsterdam, Amsterdam, The Netherlands; ¶Obstetrics, University Hospitals Leuven, Katholieke Universiteit Leuven, Belgium; #Medical Oncology, Cochin Teaching Hospital, Paris Descartes University, Paris, France; **Obstetrics and Gynecology, Ospedale San Gerardo, Monza, Italy; ††Gynecologic Surgery, Institute de Cance´rologie Gustave Roussy, Villejuif, France; ‡‡Maternal Fetal Medicine Unit, Mt Sinai Hospital, Toronto, Ontario, Canada; §§Obstetrics and Gynecology, Copyright * 2014 by IGCS and ESGO ISSN: 1048-891X DOI: 10.1097/IGC.0000000000000062

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Clinical Center of Serbia, Faculty of Medicine, University of Belgrade, Belgrade, Serbia; ||||Department of Gynecology and Obstetrics, Hoˆpital Trousseau, Assistance-Publique Hoˆpitaux de Paris, Universite´ Pierre et Marie Curie, Paris, France; ¶¶Radiation Oncology, University Hospitals Leuven, Katholieke Universiteit Leuven, Belgium; ##Medical Oncology, Radboudziekenhuis, Nijmegen, The Netherlands; ***Department of Hematology and Bone Marrow Transplantation, Rambam Health Care Campus, Haifa, Israel; and †††Clinical Pharmacology and Toxicology, Motherisk Program, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada. Address correspondence and reprint requests to Fre´de´ric Amant, MD, PhD, Department of Oncology, Katholieke Universiteit Leuven and Gynecologic Oncology, University Hospitals Leuven, Belgium. E-mail: [email protected]. Supplemental digital content is available for this article. Direct URL citation appears in the printed text and is provided in the HTML and PDF versions of this article on the journal’s Web site (www.ijgc.net). The authors declare no conflicts of interest.

International Journal of Gynecological Cancer

& Volume 24, Number 3, March 2014

Copyright © 2014 by IGCS and ESGO. Unauthorized reproduction of this article is prohibited.



Gynecologic Cancers in Pregnancy

14 weeks gestational age onward. Apart from cervical and vulvar cancer, as well as important vulvar scarring, the mode of delivery is determined by the obstetrician. Term delivery is aimed for. Breast-feeding should be considered based on individual drug safety and neonatologistYbreast-feeding expert’s consult. Conclusions: Despite limited evidence-based information, cancer treatment during pregnancy can succeed. State-of-the-art treatment should be provided for this vulnerable population to preserve maternal and fetal prognosis. Supplementary Information: Supplementary data on teratogenic effects, ionizing examinations, sentinel lymph node biopsy, tumor markers during pregnancy, as well as additional references and tables are available at the extended online version of this consensus article, go to http://links.lww.com/IGC/A197. Key Words: Cancer, Pregnancy, Chemotherapy, Consensus, Gynecologic Received August 30, 2013, and in revised form October 31, 2013. Accepted for publication November 10, 2013. (Int J Gynecol Cancer 2014;24: 394Y403)

of cancer during pregnancy is on the rise. T heBaseddiagnosis on an estimation that 0.05% to 0.1% of pregnancies

is affected, it is calculated in Europe that 2500 to 5000 new cases of cancer are diagnosed during pregnancy annually. The concurrence of cancer and pregnancy complicates treatment in each stage, including diagnostic, treatment, delivery, postpartum, and neonatal periods. Management of gynecologic cancer is one of the most complicated and requires a team of dedicated experts. The ultimate goal of cancer treatment during pregnancy is to achieve a prognosis similar to that of nonpregnant women. Because treatment of cancer in pregnancy is a tremendous therapeutic challenge, and given the scarcity of evidence-based information and clear guidelines, clinicians have long been reluctant to treat pregnant patients with cancer. A physician’s survey in 2011 showed that contrary to new evidence, termination of pregnancy, delay of treatment, and also iatrogenic preterm delivery are often preferred mainly by physicians in nonacademic hospitals.1 It is of paramount importance to disseminate experts’ knowledge, updated treatment protocols, new evidence-based information, and appropriate treatment techniques to optimize treatment success of pregnancies complicated with cancer. An international consensus meeting of leading experts was first held on the third of July 2008 to create a comprehensive protocol.2 Since 2008, our knowledge on the management of cancer in pregnancy has increased considerably. These include better documentation of the pharmacokinetics of chemotherapy, as well as maternal and fetal outcomes, more individualized clinical experience, and new treatment techniques. Moreover, we now have a wider consensus incorporating the French guidelines, which differed in the first protocol. Such knowledge is essential for a more confident approach to cancer treatment during pregnancy. We organized a second international consensus meeting to review the novel information in the field and to adjust the existing protocols. In preparation for the second consensus meeting, we identified the experts based on their scientific and clinical focus or active membership in the ‘‘cancer

in pregnancy’’ task force of the European Society of Gynecological Oncology (ESGO). We also consulted more experts in related fields, including those who are residing outside Europe, resulting in an additional emphasis on teratogenic, obstetric, and neonatal aspects. The members were divided into small groups and assigned a topic based on their area of expertise. Each group reviewed the literature, and the information collected was used for a first draft on each particular topic. These contributions were merged into 1 draft that was circulated to all participants before the meeting scheduled on the 17th of May 2013 in Leuven, Belgium. The article was systematically discussed, and changes were made in accordance to agreements made during the meeting. Final changes were made after the meeting, and the article circulated among the experts until consensus was obtained. All participants of the meeting also coauthored the article.

GENERAL MANAGEMENT Psychologic Support The diagnosis of cancer in pregnancy is a dramatic event that poses difficult dilemmas for the pregnant patient, her family, and treating physicians. Therefore, the importance of psychologic support for those who are undergoing or have undergone cancer-complicated pregnancies should not be underestimated. Previous studies, despite slight flaws in methodology, have shown both a significant portion of female patients with cancer who require and desire psychologic support do not receive it as well as the positive effect of psychologic intervention observed in behavioral and social changes in the remainder of patients.

Staging Examinations Staging examinations are performed as in nonpregnant women and are important as far as they will alter and determine appropriate therapeutic procedures that optimally treat

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the mother while maximally protecting the fetus. Ultrasonography and magnetic resonance imaging (MRI) techniques are preferred. Magnetic resonance imaging in patients with cervical cancer can help determine tumor size in 3 dimensions, stromal invasion, degree of healthy stroma, vaginal and parametrial invasion, and also lymph node infiltration. As stated by the American College of Radiology, present data have not documented any deleterious effects of MRI exposure on the developing fetus in any trimester of pregnancy.3 Previously inconclusive information on gadolinium for imaging during MRI scans has been updated since the first consensus meeting. Gadolinium (a category C drug according to the US Food and Drug Administration) should only be used if absolutely essential. No adverse effects to the neonate have been found after gadolinium exposure in all 3 trimesters. However, gadolinium crosses the placenta and is excreted by the fetal kidney into amniotic fluid; it remains unknown how long it stays in this space with the potential for dissociation of gadolinium ion from its chelate molecule (which then becomes toxic).3 An MRI without gadolinium can also provide sufficient information on parametrial invasion. In small series, MRI features of pregnant patients with cervical cancer were comparable with nonpregnant patients and allowed for tailored treatment planning. A good correlation between MRI findings and pathology specimens was also found.4 In addition, intravenous gadolinium is not essential for examination of an adnexal mass in pregnancy because this is mainly applied to document the presence of solid components in a cystic adnexal mass, but this can easily be seen by grayscale and Doppler sonography.5 Additional information on ionizing examinations, sentinel lymph node biopsy, and tumor markers during pregnancy can be found in the extended online version, http://links.lww.com/IGC/A197.

follow cesarean delivery. For cases where surgery cannot be avoided or postponed, we present the following protocol.

Treatment

Precautions During Surgery

Treatment should be similar to nonpregnant patients with cancer whenever possible with adaptations and concerns explained in detail later. A checklist of standard care for high-risk pregnant women can be found in the extended online version (Table 1, at http://links.lww.com/IGC/A197). Supportive care at home is highly recommended.

A stable maternal condition is the best guarantee for fetal well-being. Knowledge of the risks associated with surgery during pregnancy and careful monitoring of the maternal condition during surgery is vital for maternal and fetal health. Significant risks of surgery during pregnancy include preterm delivery, miscarriage, and fetal distress. In addition to the risk of fetal loss, surgery may cause hypercapnia, perforation of enlarged uterus, and reduced blood flow due to both increased abdominal pressure and use of carbon dioxide. Furthermore, the hemodynamic and physiologic changes in pregnancy have important consequences for perioperative monitoring.8 Monitoring of hemodynamic parameters is crucial to prevent hypoxia, hypotension, and hypoglycemia. A pregnant patient is also at risk for aspiration because of the pregnancy-associated gastroesophageal reflux. The placenta lacks the ability to autoregulate flow, and its perfusion is determined primarily by maternal blood pressure. Hypotension will therefore result in a shunting of blood away from the placenta/fetus, and fetal hypoxia will occur shortly after the onset of hemorrhage or hypovolemia. One of the earliest signs of maternal distress is fetal distress, and the fetal condition can be critical by the time maternal hypotension manifests.8 Cardiotocography monitoring during

Radiotherapy Radiotherapy for cancers of the abdomen and pelvic regions is contraindicated because of the serious adverse effects to the fetus. Therapeutic doses of radiation can induce microcephaly, mental retardation, microphthalmia, cataracts, iridial defects, skeletal anomalies, and fetal death.

Surgery Surgery is an essential part of oncological treatment, particularly for gynecologic cancers. Surgery during pregnancy is not rare, with approximately 0.5% to 2% of pregnant women undergoing nonobstetric surgery. Surgery methodology and outcome are dependent on gestational age and the stage of fetal development. If the expected delivery date is forthcoming, one could consider delaying surgery until postpartum. In specific cases, operations could directly

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Surgery Protocol Standard anesthetic procedures are safe during pregnancy. Regarding surgery during the first trimester, reports have shown an association between surgery during gastrulation (between third and fifth week after conception) and neural tube defects.6 Therefore, surgery during this period should be avoided. In general, abdominal surgery should be undertaken in the second trimester because the risk of miscarriage is decreased and the size of the uterus still allows a certain degree of access. Every procedure after 20 weeks gestational age should be performed in the ‘‘left lateral tilt’’ position to avoid vena cava compression and maintain cardiac preload. In the past 5 years, additional research has been conducted concerning laparoscopic surgery during pregnancy. Pregnant patients may undergo laparoscopic surgery safely during pregnancy (G26Y28 weeks). Depending on the procedure and experience of the surgeon, laparoscopic surgery for more advanced gestational ages is possible and a comparable complication rate to laparotomy. There are no randomized controlled trials that compare laparoscopy and laparotomy for benign ovarian masses in pregnancy.7 There is an increased risk for fetal loss after laparoscopy for appendectomy (pooled relative risk [RR] of 1.91 [1.31Y2.77]), but it is unknown whether those results can be applied to a laparoscopic approach for gynecologic surgery. We recommend 4 prerequisites for surgical interventions during pregnancy; these are as follows: a maximal laparoscopic procedure time of 90 minutes, a pneumoperitoneum with a maximal intraabdominal pressure of 10 to 13 mm Hg, open introduction, and an experienced surgeon. These conditions will allow for an effective surgery while minimizing potential risks to the fetus.





surgery (vulvar cancer or laparoscopy) is therefore advisable in case intervention is needed for fetal distress (depending on gestational age, local policy, and parent’s consent). A fetal sleep pattern should be discerned from fetal distress.

Postoperative Care Postoperatively, fetal well-being needs to be assessed by cardiotocography or ultrasound. After surgery, adequate analgesia (paracetamol, nonsteroidal anti-inflammatory drugs, tramadol, and morphine) and antiemetics (metoclopramide, meclizine, alizapride, and ondansetron) can be prescribed.9,10 Nonsteroidal anti-inflammatory drugs administered in the third trimester of pregnancy may be associated with premature closure of the ductus arteriosus and possible pulmonary hypertension in the neonate in 50% to 80% of cases.11 Although data are limited, there is a consensus that tocolytic agents are indicated when manipulation of the pregnant uterus is unavoidable. Pregnancy is a procoagulant state. Therefore, a prophylaxis with either unfractionated or lowYmolecular weight heparin is advisable.

Chemotherapy During pregnancy, multiple physiologic changes occur, affecting the major pharmacokinetic processes including absorption, distribution, metabolism, and excretion. Changes in drug metabolism begin at 4 weeks of gestation, progressively increase, and are more pronounced in the third trimester of pregnancy. Physiologic pharmacokinetic changes have been shown in humans to result in a decrease in plasma drug exposure (area under the curve) and peak plasma concentration and an increase in distribution volume and clearance.12 In the largest follow-up study in breast cancer, there was no survival difference between women with cancer treatment during pregnancy and stage-matched nonpregnant women.13 Thus, despite the ‘‘dilution’’ of chemotherapy during pregnancy, current data do not show worse outcomes in pregnant women who receive chemotherapy compared with nonpregnant women. Therefore, we advocate that chemotherapy dosages are based on actual patients’ weight and height during pregnancy. Chapters on teratogenic effects and also pharmacokinetics and transplacental passage of chemotherapy (Table 2) can be found in the extended online version, http://links.lww.com/IGC/A197.


Recently, a disharmonious intelligence profile (median followup of 22.3 months) was reported, but an important bias by prematurity was suggested.17 Moreover, internalizing and externalizing psychologic problems were also observed. These findings support the hypothesis that more subtle changes in neurodevelopment are possible and need to be prospectively investigated. Behavioral and emotional issues deserve further attention because maternal health status during early development might also affect child’s behavior. A chapter on anthracyclines and supportive drugs during pregnancy (Table 3) can be found in the extended online version, at http://links.lww.com/IGC/A197.

Monitoring of Pregnant Patient With a Gynecological Cancer At diagnosis, it is important to determine the exact gestational age and exclude preexisting fetal anomalies by ultrasonography.

Medical Assessment It is important to assess the direct and indirect (treatment linked) cancer effects on the general maternal health and pregnancy. Special attention is needed for cardiac assessment (electrocardiogram, echocardiogram, and Holter monitoring) in women exposed to anthracyclines and/or chest radiation, as well as pulmonary function testing for women exposed to bleomycin or chest radiation. Renal and liver functioning and evaluation of neuropathy and ototoxicity in case of exposure to platinum-based therapy are other important things for medical personnel to consider to better assess the situation and appropriate solutions. Regarding prenatal diagnosis, we note that noninvasive testing is preferable. However, in case an invasive test is indicated, the tumor site should be taken into account and avoided in the determination of the access way (transvaginal/cervical or transabdominal).

Obstetrical Management In pregnancies complicated by cancer, the standard of care for high-risk pregnant women should be adhered to (see also extended online version Table 1, at http://links.lww.com/ IGC/A197). Consultation with neonatologists and proper counseling are recommended to better understand the course of pregnancy, feto-neonatal outcomes, and possible complications.

Effects of Chemotherapy Exposure Further evidence has accumulated on the effects of chemotherapy during pregnancy. The recent information supports the previous evidence that chemotherapy after the first trimester is not associated with increased rates of birth defects above the rate in the general population (3%).13Y17 In addition, intrauterine growth restriction and transient myelosuppression have been reported and need to be investigated at birth.14 Major concerns arise over the possible effects of chemotherapy on the developing brain, which is potentially vulnerable to damage throughout the entire gestation. Longterm neurobehavioral outcomes remain undefined because of limited and mainly retrospective follow-up data, although reassuring findings have been reported in small series.18

CERVICAL CANCER Diagnosis and Staging of Cervical Cancer The diagnostic approach to cervical cancer during pregnancy is similar to that of nonpregnant women.4 Lymphadenectomy (laparoscopic or laparotomic) can safely be performed between the 13th and 22nd weeks of pregnancy. Based on 32 published cases (extended online version Table 4, http://links.lww.com/IGC/A197), it seems that most patients have been operated on before the 22nd week of pregnancy, yielding a median of 19 lymph nodes (range, 6Y72). Increasing gestational age represents an obstacle for satisfactory lymphadenectomy in minimal number of 10 lymph nodes suggested by International Federation of Gynecology and



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FIGURE 1. Yielded number of pelvic lymph nodes versus gestational age for cervical cancer treated during pregnancy. (References can be found in the extended online version.) Obstetrics (Fig. 1). The technical procedure is dependent on the surgeon’s experience and preference. Based on these considerations, we divide management based on the potential to perform a pelvic lymphadenectomy at around 22 to 25 weeks of pregnancy.

Management of Invasive Cancer Pregnancy-Nonpreserving Management In case pregnancy preservation is not aimed for, management is similar to nonpregnant women. Especially for advanced-stage disease, termination of pregnancy and subsequent standard treatment are advocated. Radical hysterectomy should be performed with fetus in utero during early pregnancy or after hysterotomy to reduce the volume of the uterus (during the same procedure). Pelvic radiotherapy causes spontaneous abortion during the first trimester and fetal death within the first month after external beam radiation during the second trimester. The advantages and disadvantages of hysterotomy before radiotherapy should individually be balanced. When hysterotomy is performed before initiating radiotherapy, there is no replanning of the radiation field, there are less obstetrical complications (bleeding and diffuse intravascular coagulation), and there is less psychologic distress.19 However, the procedure may be associated with postoperative adhesions that enhance radiotherapy toxicity, a potential delay of treatment in case of wound infection, and a risk of wound metastasis.

Pregnancy-Preserving Management Treatment of cervical cancer during pregnancy remains experimental, especially in case of large-volume tumors. Pregnancy-sparing treatment should only be offered, in carefully selected cases, to motivated patients after sufficient explanation of the limited experience.

Cancer Diagnosed Before 22 to 25 Weeks of Pregnancy If microscopic invasion after colposcopy is suspected, diagnostic conization is preferably performed at 12 to 20 weeks of pregnancy. In stage IA1, conization alone is a sufficient and

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relatively safe treatment during pregnancy. For higher stages of cervical cancer, pelvic lymphadenectomy is proposed to diagnose the high-risk disease (with positive nodes) that may necessitate termination of pregnancy and application of standard treatment. In stage IA2 and IB1 tumors, smaller than 2 cm and with negative nodes, a simple trachelectomy or large conization is proposed (Fig. 2; similar to fertility-sparing surgery), whereas several studies in nonpregnant patients have shown rates of parametrial involvement to be less than 1%, thereby justifying this less radical surgery.20,21 In the absence of obstetrical safety data of such a procedure during pregnancy, we propose to tailor the resection volume according to the tumor diameters. Regarding radical trachelectomy (abdominal or vaginal), several cases are described during pregnancy (extended online version Table 5, at http://links.lww.com/IGC/A197, Supplemental Digital Content). Apart from the technically challenging procedure, which is associated with significant blood loss and prolonged surgery, the obstetrical results are poor when 6 (32%) of 19 described cases result in early abortions related to the procedure. Thus, based on these data, we cannot recommend a radical trachelectomy during pregnancy. For patients with a stage IB1 tumor, larger than 2 cm and with negative pelvic lymph nodes, neoadjuvant chemotherapy (NACT) is proposed until fetal maturity (Fig. 2). Alternatively, the chemotherapy can be administered without performing a lymphadenectomy, followed by surgical staging after delivery. Recent updates in literature suggest that delay of treatment until after delivery is a possibility when the lymph nodes are negative. In a recent review, 76 stage IB1 cases of delayed treatment are reported with a 95% rate of survival at a mean follow-up of 37.5 months.22 The median delay is 16 weeks, and no recurrences are reported for patients with microscopically proven negative pelvic nodes. When progressive disease is observed, either by clinical examination or MRI, termination of pregnancy or NACT is advocated. In stage IB2 and higher stage tumors, NACT is the only way to preserve pregnancy (Fig. 2). The therapeutic value of * 2014 IGCS and ESGO





FIGURE 2. Treatment strategy for cervical cancer, smaller than 2 cm (left) or larger than 2 cm (right), diagnosed before 22 to 25 weeks of pregnancy. *PALND is only recommended for tumors measuring 4 cm and above.PLND, pelvic lymph node dissection; PALND, para-aortic lymph node dissection; NACT, neoadjuvant chemotherapy; TOP, termination of pregnancy. a pelvic staging lymphadenectomy before the start of the chemotherapy is unknown, but the procedure can add in the decision-making process to continue the pregnancy or not. Depending on the gestational age and pelvic nodal status on imaging, a paraaortic lymph node sampling can also be performed. Data on the oncological safety of NACT for these tumors during pregnancy are still sparse, especially in patients with stage IIA2, IIB, and higher-stage disease in the early second trimester. The goal of NACT is to stabilize the tumor while simultaneously preventing tumor dissemination.23 Concerning newly reviewed literature on NACT, 50 cases are identified in English literature including half of patients with stage IB1 disease (extended online version Table 6, at http://links.lww.com/IGC/A197, Supplemental Digital Content). The average age of patients is 32.4 years, with cancer diagnosed at 19.2 weeks of pregnancy. Chemotherapy allows the pregnancy to be continued until 33.2 weeks on average. The response to chemotherapy in 6.25% of the patients was complete, in 62.5% partial, in 28.1% the disease stabilized, and in 3.1% the disease progressed. The chemotherapy used was always platinum based, alone or in combination with paclitaxel, vincristine, 5-fluorouracil, cyclophosphamide, or bleomycin. Chemotherapy was administered at a 3-week interval. Overall survival rate is 79% (34/43 patients) at a median follow-up of 24 months. The survival rate is 94% (15/16 patients) in IB1 stage at a median follow-up of 12 months (1 patient with small cell cancer died). In stage IB2, the overall survival rate is 70% (12/17 patients), and progression-free survival is 58.9% at a median follow-up of 27 months (extended online version Table 7, at http://links.lww.com/IGC/A197, Supplemental Digital Content).

Patients with higher-stage disease have a survival rate of 70% (7/10 patients) at a median follow-up of 14 months (extended online version Table 8, at http://links.lww.com/IGC/A197, Supplemental Digital Content). These oncological results need to be interpreted cautiously because the follow-up is short and variable chemotherapy regimens have been used. The currently recommended regimen is platinum-based chemotherapy (cisplatin 75 mg/m2), preferably with paclitaxel (175 mg/m2) at a 3-week interval.24 In view of recent contradictory data on weekly schedules of paclitaxel, a 3-weekly schedule of paclitaxel 175 mg/m 2 seems preferable. This schedule is used with an acceptable short-term safety in 27 pregnant patients in the literature.25 An alternative to cisplatin that has a better maternal toxicity profile is carboplatinum (area under the curve, 5Y6). There is no evidence of a difference in the effect of NACT on survival by dose intensity.23 When analyzing response during pregnancy to NACT using a single platin agent versus platin + paclitaxel, a statistically significant difference in favor of combination therapy is found (Cochran-Armitage trend test at P = 0.049); therefore, a combination therapy is preferred. This is in concordance with data of nonpregnant patients (extended online version Fig. 3, at http://links.lww.com/IGC/A197, Supplemental Digital Content). Regarding the dose of platinum agents, cisplatin is used in pregnant patients at doses ranging from 20 mg/m2 for 5 days, up to 75 mg/m2 (given on day 1, day 1 = day 21), with cumulated doses up to 500 mg/m2. Data on the use of gemcitabine, vinorelbine, and topotecan during pregnancy are very limited, and the use of these drugs should be avoided in pregnant patients.



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Cancer Diagnosed After 22 to 25 Weeks of Pregnancy At this gestational age, a complete pelvic and/or paraaortic lymphadenectomy is difficult to perform; therefore, the decision making cannot rely on the nodal status. In stage IA2 and IB1 tumors smaller than 2 cm, we propose delay of treatment until fetal maturity, with delivery after discussion with a neonatologist. When progressive disease is observed, early delivery or NACT is advocated. Alternatively, NACT can be started straight away. For higher stages, NACT is the only way to preserve pregnancy and reach fetal maturity.

OVARIAN CANCER Most ovarian cysts during pregnancy are physiologic and will disappear naturally. In case of a persisting cyst, ultrasonography is performed. When the cyst is benign and asymptomatic, we opt for watchful waiting. The risk of complications such as torsion has been found to be around 8%. A staging procedure is proposed when there is high suspicion for preinvasive or invasive cancer. Surgical procedures should be performed with utmost care. The key point of the surgery is to avoid cyst rupture. An adnexectomy instead of cystectomy is thus preferred. If possible, surgery is performed after 14 to 16 weeks of gestation. At this stage, the placenta is capable of sufficient hormonal supply in case of bilateral adnexectomy.

Borderline As in fertility-sparing surgery, when a borderline tumor is suspected or confirmed by frozen section, surgical staging consists of unilateral salpingo-oophorectomy, infracolic omentectomy, appendectomy (only for mucinous tumors), and peritoneal biopsies. A recent study discovered a high incidence of advanced-stage tumors, with 20% of the patients finally diagnosed as stage II to III disease. Because the pelvic peritoneum and pouch of Douglas cannot be reliably examined during pregnancy, the authors recommended up-front salpingo-oophorectomy with planned restaging surgery postpartum. During follow-up, there was no progression to invasive cancer.

Invasive Early Stage Invasive epithelial ovarian cancer during pregnancy is uncommon, and the evidence is mainly based on case reports or small series ranging from 10 to 27 cases.26 Because most cases are diagnosed at an early stage, surgical staging with preservation of the uterus and contralateral ovary is indicated. Standard treatment as for nonpregnant women should be strived for. Patients with stage IA grade 2 to 3, IB, IC, and IIA disease additionally require a lymphadenectomy and platinum-based chemotherapy, although the order can be discussed. When staging is not complete after the first surgery, chemotherapy can be initiated during pregnancy with completion of staging postpartum, thereby avoiding risks of a second surgery during pregnancy. Recent findings show that in mucinous tumors, grading is not reliable and the treatment is determined using the microscopic growth patterns. Although an expansive growth pattern relates to an excellent outcome after extirpation of the cyst only, tumors with infiltrative growth are high grade.

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Invasive Advanced Stage Standard treatment (debulking to no residual tumor) for advanced-stage ovarian cancer is not possible when the pregnancy is continued. With poor maternal prognosis and limited experience, termination of pregnancy remains an appropriate option. When maintaining pregnancy, a suboptimal cytoreduction during pregnancy will unnecessarily jeopardize fetal health and is therefore not recommended. Therefore, NACT until fetal maturity and complete cytoreduction after delivery is the best way to treat advanced-stage ovarian cancer during pregnancy. Combination therapy for paclitaxel and carboplatin should be the choice of treatment, as used by nonpregnant patients with ovarian cancer.27 In the absence of data on the systemic use of bevacizumab, we do not recommend its use during pregnancy. Bevacizumab is an immunoglobulin that may theoretically cross the placenta, depending on the stage of pregnancy. One report describes early pregnancy loss after intraocular bevacizumab.

Nonepithelial Ovarian Tumors Nonepithelial ovarian neoplasms (germ cell, sex cord stromal tumors) are usually stage I when diagnosed in pregnancy and are primarily treated by surgical resection. Indications for adjuvant chemotherapy are the same as for nonpregnant patients. The number of cycles of chemotherapy for yolk sac tumors cannot be based on the tumor marker; 6 cycles of chemotherapy are recommended. In nonpregnant patients, the combination of bleomycin-etoposide-cisplatin is used for nonepithelial ovarian tumors. Alternatively, during pregnancy, paclitaxel-carboplatin or cisplatin-vinblastin-bleomycin can be used. Paclitaxel is an active drug in germ cell tumors, whereas vinca alkaloids have been used for a long time, and many reports cite their use as relatively safe during pregnancy.14,28

VULVAR CANCER During pregnancy, the standard surgical treatment should be provided, depending on the tumor diameter, stage of disease, and gestational age. In patients with clinically negative node, radical local excision or radical vulvectomy with unilateral or bilateral lymph node dissection or sentinel node procedure is performed. The surgical margins need to be radical (2 cm macroscopically and 8 mm microscopically) to avoid the need for postoperative radiotherapy. Because genital vascularization is markedly increased in the third trimester, surgery may result in higher blood loss, and the treatment of cases diagnosed after 36 weeks of gestation might be delayed in the postpartum period. Patients with sentinel node metastasis require additional treatment. In patients with isolated tumor cells in the sentinel lymph node and negative inguinal nodes, adjuvant radiotherapy might be avoided. When nodal involvement is evident after inguinofemoral lymphadenectomy, pregnancy is terminated or delivery is planned, depending on the gestational age followed by postpartum irradiation. Delay of radiotherapy by 6 to 8 weeks is within the safety limits. When preoperative examinations suggest inguinal lymph node involvement, the prognosis is less favorable and inguinal * 2014 IGCS and ESGO




radiotherapy to prevent local groin recurrence becomes vital. Immediate treatment is then mandatory, and termination of the pregnancy in the first and second trimester is indicated. In the third trimester, a cesarean delivery is performed followed by standard treatment. Neoadjuvant chemotherapy to reduce tumor size for locally advanced disease remains experimental.

DELIVERY PLANNING Timing of Delivery A 3-week interval between the last cycle of chemotherapy and the delivery avoids problems associated with hematopoietic suppression in both the mother and the child (bleeding, infections, and anemia) and avoids presence of cytotoxic drugs in the neonate. For all patients, a term delivery (937 weeks gestation) is preferred. However, deterioration of maternal condition or the need for radiotherapy may indicate a need for preterm delivery. When a patient is diagnosed after 30 weeks gestation, 1 cycle of chemotherapy during pregnancy (maximum of 35 weeks), followed by term delivery of more than 37 weeks, is preferable to a late preterm delivery without chemotherapy during pregnancy.

Mode of Delivery A natural vaginal birth is normally preferred whenever possible in the absence of complicating factors. However, in which cases cesarean delivery is necessary, it has been debated. Since the 2009 protocol, some progress has been made in delivery methods, leading to the following recommendations. Advantages of a vaginal birth also apply to the oncological population and include reduced blood loss, operative and infection risk, shorter duration of hospitalization, and better preservation of reproductive future. This is especially important for patients with myelosuppression after chemotherapy. Cesarean delivery is indicated in case of cancer metastasis to the long bones to avoid the risk of fractures by lithotomy position. Active pushing can also be contraindicated in central nervous system metastasis causing increased intracranial pressure. Assisted vaginal delivery can then be safely offered in most cases. Cervical intraepithelial neoplasia is not an indication for cesarean delivery.29 The overall impact of mode of delivery on the oncological outcome of cervical cancer is controversial. In the presence of cervical cancer, abdominal delivery may contribute to a higher risk of lymphovascular dissemination, major bleeding, birth canal obstruction, infection, cervical laceration, and cancer cell implantation at the episiotomy site. Reviewing the published cases of episiotomy recurrences, we encountered 7 fatal cases after abdominal delivery (extended online version Table 9, at http://links.lww.com/IGC/A197, Supplemental Digital Content). Cesarean delivery is therefore recommended in case cervical cancer is still present. A corporeal uterine incision avoiding the lower uterine part to prevent wound metastasis is preferred. In addition, cesarean delivery enables complementary surgical treatment of the cancer, when indicated. In patients operated for vulvar cancer during pregnancy, vulvar scarring and the risk for vulvar trauma can be an indication for


cesarean delivery. Abdominal delivery in the presence of vulvar cancer needs individual consideration. The placenta should be examined for metastatic disease. Metastasis to the fetus is exceptional. For gynecologic malignancies, only 1 case report of placental metastasis of cervical cancer, 1 case of vaginal angioblastic sarcoma, and 1 case of vulvar melanoma were reported in literature.30 We recommend microscopic examination by a pathologist; if metastases are present, follow-up of the infant for development of malignant disease is advised.

Postpartum Management Breast-feeding during chemotherapy is not completely contraindicated. Breast-feeding safety should be considered based on individual drugs according to their pharmacokinetic properties. The LactMed Web site, which is updated biweekly, and neonatologistYbreast-feeding experts should be consulted. In case of doubt, breast-feeding is not advisable, especially because a safe alternative is available. Oncological treatment can be continued immediately after abdominal delivery and 1 week after uncomplicated cesarean delivery.

NEONATOLOGIST/PEDIATRICIAN PERSPECTIVE The duration of gestation, the maternal disease, and the toxicity of treatments in conjunction with the timing of the interventions are factors that may affect early postnatal and long-term outcomes of children born to mothers with cancer. All neonates need to be examined at birth by a neonatologist to assess the neonate’s transition from intrauterine to extrauterine life and to detect congenital malformations and actual or potential diseases. Anthropometric measurements (weight, length, and head circumference) should be obtained to assess fetal growth according to gestational age. In cases of chemotherapy exposure, the neonates need to be investigated for hematologic, immunologic, cardiac, and neurologic disorders, all of which have to be monitored long-term. Infants and children should be screened for cancer development and reproductive development. A chapter on effects of prematurity can be found in the extended online version, http://links.lww.com/IGC/A197.

CONCLUSIONS Effective treatment of gynecologic cancers during pregnancy is achievable. The presence of cancer during pregnancy creates a challenging conflict between maternal care and fetal well-being. Oncological treatment needs to be individualized while placing an emphasis on optimal maternal care by adhering to standard (nonpregnant) treatment protocols with consideration for fetal safety. The treatment and prognosis of cervical cancer during pregnancy need further research. A matched case-control study of 132 women with cervical cancer during pregnancy is currently being performed by members of the ESGO task force. The crucial role of lymphadenectomy as part of staging in particular is a large step toward individualization of treatment based on more accurate staging and risk assessment. How this will be



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implemented in clinical practice and whether it will improve maternal prognosis is certainly an area of future research. In addition, the long-term maternal prognosis and health of the children need to be better documented. The ESGO ‘‘Cancer in Pregnancy’’ task force aims to explore this field and welcomes more international collaborators (http://www.esgo.org/ task_forces/Pages/CancerinPregnancy.aspx). The complexities that arise with treating cancer in pregnancy demand for a supportive multidisciplinary team that includes a neonatologist, perinatologist, oncologist, obstetrician, teratologist, and toxicologist and provides psychologic support throughout the entire pregnancy and postpartum. Neonatal prematurity has been identified as the most common adverse outcome associated with cancer-complicated pregnancies; guidelines on prematurity prevention were provided in the present report. Current related research and expert knowledge, which support and strengthen recommendations from our previously guidelines published in 2009, are included. An extended version of this article is available as Supplemental Digital Content (http://links.lww.com/IGC/A197).

ACKNOWLEDGMENTS Fre´de´ric Amant is senior clinical researcher for Research Foundation Flanders (FWO). The organization of the consensus meeting was endorsed by the ESGO. Irena Nulman is the senior author and is an expert in reproductive toxicology and behavioral teratology. The authors thank Marie-Astrid Van Hoorick for the administrative support.

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