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    Amant. Gynecological Cancers in Pregnancy - Guidelines of An International Consensus Meeting PDF

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    Derrick Davis

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    SPECIAL ARTICLE =r Gynecologic Cancers in Pregnancy: Guidelines of an International Consensus Meeting Frédéric Amant, MD, PhD,* Kristel Van Calsteren, MD,* Michael J. Halaska, MD,* Jos Beijnen, MD, PhD,¢ Walter Vanden Bogaert, MD, PhD,** La even Lagae, MD, PhD,§ Myriam Hanssens, MD, PhD,// Liesheth Heyns, MSe,* Lore Lannoo, MD,|/ Nelleke P. Ottevange': MD, PhD. Ungar, MD, PhD. Ignace Vergote, MD, PhD,* and Andreas du Bois, MD, PhD3é Background: Gynecologi oF its treatment may affect not ancer during pregnaney is nly the pregnant women special challenge because cancer reneral but directly involve the reproductive tract and fetus, Currently, there are no guidelines on how to deal with this special coincidence. Methods: An international consensus meeting on staging and treatment of gynecological ‘malignancies during pregnaney was organised including a systematic literature search, and interpretation followed by a physical meeting of all participants with intensive discussion, Im the absence of large trials and randomized studies, recommendations were based on available Titerature data and personal experience thus representing a low but best achievable level of evidence, ws: Randomized trials and prospective studies ey are lacking. Gynecological cancer during pregnancy isa demanding problem, anxl multidiseiplin: expertise should be available. Counseling both parents on the maternal prognosis and fetal seeded. When there is a firm desire to continue the pregnancy, gynecological eancer ean be treated in selected cases. The staging and treatment should follow the standard approach as ‘much as possible. Guidelines for rgery during pregnancy are presented, Mainly in cervical and ovarian cancer, chemotherapy and an alternative surgical approach need to be considered. Administration of chemotherapy during the second or thinl trimester may probably not inerease the incidence of congenital malformations. Until nov, the long-term outcome of children in utero exposed to oncological treatment modalities is. poorly documented, but preterm birth on its own is associated with cognitive impairment. Delivery should be postpotied preferably until after a gestational age of 35 weeks, Interpretation: Further research including international registries for eynecologic cancer in pregnaney is urgently needed. The gathering of both available literature and personal experience allowed only suggesting models for treatment of gynecologic cancer in pregnancy. fon cancer treatment during prea “Gynaevolosic oncology, Leuven Cancer Inte (LKD), UZ Gasthisbe, Katholicke Universitet Leusen, Belg: $Divison of Oncogynaccolo Deparment of Gynaccology and Obst, Charles Univers iP 2nd Medical Faculty, Czsch Republi: :Depanment of Pharmacy an Pharmacology, The” Netherkans Cancer Instute’Skoteraaet_ Most The Netheriands: $Peiatics, |Obscies, UZ Gashustery, Katholcke Universitit Leuven, Delguins #Department of Maia! Oncol, ‘ogy, Radboud University Nijmegen Medical Cert, Nimgzen, The Nett lands: **Radiation oncology, Leuven Cancer Insite (LKD. UZ Gosthuiserg, Katholike Universitet Lewen,Netgum, | 1Gynaecologi oncology, National Cancer Insite, Budapest, Hungary. {Deparment of ascology and Gynaecoogic Oncol. HSK, Dr. Horst Schailt Klink Wiesbaden, Gemany Received Fetny 19,2000 ‘Accepted for publication February 19,2009, Aas cmrespondence and epi requests to Fede Amant, MD, PAD. Division of Gynaecolosial Oncology, Deparment of Obscires& Gyraccology, U2 Gasuishers, Katholieke Unnersiet Leuven, eres 49,2000 Leuven, Belgian, E-mu Frederic aman uwztulewonas be Frsdri Amant is clinical researcher fo Research Fourtion anders (WO. Kristel Van Calsteren is aepirat for Research Foundation-Flandets(F WO.) Lieve Lagi sold ofthe UCB chair in Cognitive dystincons in Childhood Copyrgt © 2009 by 1GCS aid ESO. ISSR IOASOIX DO 10.11111GC-O4D13e318atedce Intemational Journal of Gynecological Cancer * Volume 19, Number $1, May 2009 sl Amant et al Key Words: Cancer, Pregn Neonatal, Offspring, Cognitiv (Unt J Gynecol Cancer 2009;19; $1-$12) ‘he estimation of worldwide cancer burden indicates that gynecological cancers (ie, eancer of the vulva, vagina, cervix uteri, uterine corpus, ovary, and fallopian tube) account for 19% of the 5.1 million estimated new cancer eases andl 2.9 million can deaths in 2002." They account for 22% of all new cancer cases among women in developing counties compared with 15" ofall new eases among women in developed countries. Canes cervin isthe because it is the, most common gynecological canoer in the developing world.' In unscreened populations, the peak isk of invasive cervical cancers occurs earlier than for most adult cancers, Peaking or reaching a plateau from about 35 10 $5 years? The Increase starts in the second and early in the third decade-? This Paral overlap with the reproductive era renders pregnant women, susceptible to cervical eancer, Because information on the pregnant slate is frequently missing in cancer registries, figures on cancer incidence during pregnancy are approximative only. Whereas abnormal cervical cytology complicates approximately S% of pregnancies, the incidence of cervical cancer during pregnancy is «estimated to be around 1/10,000.’ The incidence of adnexal masses during pregnancy vaties between 2% and 4%"? It is estimated that {6% ofall operated adnexal masses are malignant,’ inciing epithelial (49%-75%), sex eord stromal (%%-16Y%), and 8 tumors (6%- 40%)" The incidence of ovarian eancer ‘during gestation Auctuates around I/10,000 to 100,000. Cancer affecting the reproductive system during pregnancy is 8 complex situation that endangers at least 2 lives, the pregnant ‘woman and the fetus, The tremendous therapeutic challenge ted by this coincidence on one hand and the sparse ‘experience of individual clinicians on the other hand. demand clinical guidance. However, literature data on eancers of the pelvic female reproductive system during pregnancy mainly consist of ‘anecdotal case reports or small series only. We expected that ithering and summarizing all available data could help to provide a usefil toon this situation. Therefore, we oxganized an International Consensus meeting on the 3rd of July 2008 in Leuven, Belgium, Participants were selected based on their expertise and all related fields were covered, gynecological oncology, “medical ‘oncology, clinical pharmacology, obsetries, pediatris, and radiation ‘oncology. A basic manuserine and 2 CD-tom including 263 articles ‘vas sent to all partieipants before the meeting. These articles were Identified during a PUBMED search looking for keywords including pregnancy, surgery, offspring, cancer, chemotherapy, radiotherapy, id ovarian. Articles before 1990 were ‘only included if considered important, Some articles were hand searched based on reference lists, Endometrial eancer and cancers ‘iagnosed in the postpartum are excluded. Malignant trophoblastic disease was not included. All participants were assigned to comment and review the topic of their experience. This new manuscript served as a basis for sliscussion during the meeting. The discussion during the meeting resulted in a new version that circulated 6 times. All participants seed with the final recommendations. Questions we sought 10 ‘answer in particular include the identification of stages that exclude pregnancy preservation as a safe option, requirements for safe surgery for pelvic cancer during pregnancy, alternative surgical International journal of Gynecological Cancer * Volume 19, Number S1, May 2009 jynecologic, Cervieal, Ovarian, Chemotherapy, Vulvar ‘reatment options that aim to preserve the pregnancy, choice of chemotherapy timing of delivery, and the nedmatal outcome, IMAGING AND ONCOLOGICAL TREATMENT MODALITIES DURING PREGNANCY ‘The risk of fetal damage (eg, by surgery-related hyporia, radiation, or chemotherapy) al hence the possibility 1 stage and tweat cancer during pregnancy will kigely depend on the exposure Period in pregnancy. With regatd to this, the pregnancy can be Aivided into 3 stages: fertilization implantation, organogenesis, and the fetal phase. During the frst 10 days posteonception (Ferilizaton/implan- tation) cells are omnipotent and. can develop 3 diferent cembryologial layers. Viability will depend on the number of cells that is Killed daring treatment, and this will result in an “allor nothing” phenomenon, The most vulnerable phase expands from 10 days to 8 wi after conception (organogenesis). The potential for fetal damage is the highest during this period but varies depending on the agents used. The use of radia organogenesis. will i Therefore, radiation or chemotherapy until 10 wecks gestational age (= dutation of amenorthea) is contraindicated, However, some systems including the eyes, genitals, hematopoietic system, and the nal nervous system continue to develop afterward. We propagate 4 2-to 4-week “safety period” in order to allow teatment from 1210 | weeks pregnancy (ie, 10-12 weeks alter conception). Proper dating is erucial to plan safe treatment. During the second and third trimesters, radiotherapy of the upper part of the body al limbs as ‘well as chemotherapy can be administered safely.”* Chemotherapy is administered until a gestational age of 35 weeks or preferably an interval of at least 3 weeks before delivery is aimed for, When the interval is too short, there isa risk for dlivery-related maternal etal infection or bleeding, whereas an inadequate elimination of cytotoxic drugs by the immature fetal organs may contribute to an increased fetal sk, Imaging and Diagnosis During Pregnancy Staging should be as compre Ultrasonography and- magnetic resonance ina relatively sate and widely used during pregnancy" The safety for the later, however, is not proven" Int contrast to previo bel also gadolinium-enhanced magnetic resonance imaging is possible during pregnaney.! X-ay studies eypose the fetus to radiation, ad the highest dosages are generated by computed tomography (CT) ‘Table 1). Although the fetal dase doesnot reach the threshold dose for deterministic effects, stochastic effects need 10 be considered because fetuses have a high proportion of dividing cell.™ In children, this results na higher lifetime risk for cancer after «exposure to ration!” The risk for childhood cancer is highest after adomino-pelvie imaging (but not other sites) with exposure daring the third trimester” Position emission tomography combined with CTexposed the fetus to 19 mGy and might be considered if itis the only tool to make & proper diagnosis." Staging examinations 1 2009 IGCS and ESGO Intemational Journal of Gynecological Cancer + Volume 19, Number $1, May 2009. TABLE 1. Approximate fetal absorbed doses during imaging studies!” Fetal dose, Procedure f Procedure Chest x-ray 0.00006 Lumbosacral spine 0.2 (posteroanterior and lateral) Abdominal x-ray 0.15-0.26 Mammography 0401-0.04 Pelvie x-ray 02-035 CT thorax 001-13 Intravenous 04-09 CTabdomen 083 yclography Barium enema 03-4 CT pelvis, 2589 Dorsal spine <0001 —TChone scan ———0.15-6.20 Lumbar spine 04-06 Tie theshol dose for fal dam 20 eG, e estimated vary baween TO and during pregnaney are possible, but fetal protection with abdominal shieking is advised, The sentinel Iymph node procedure with "Te can safely be performed during pregnaney. Studies in breast cance show that after injection of 18,5 MBq "Te, the fetal dosage approximately ranges between 0.0 and 0.05 mGy' which is far below the deterministic threshold dosage." Ths igmainly due to the low dosages that are ‘administered and because "Te is captured in the lymph nodes luring a period during which radioactivity decreases considerably The exposure afer sentinel node procedure isin the same level 3 few day dosages of natural background iradation In vulvar sancer,a dosage of 0 or 80 MBq is often used to detect the sentinel Iymph node. Approximately 80% of a theoretical dosage of 100 MBq remains in the pelvis (injetion location and some Iymph nodes). The distance from the fetus iat east 10 em. In this situation, fetal exposure can be estimated to be 100 Sv (or 0.1 mGy). According, to the Intemational Commission on Radiological Protection! fetal risk starts from 100 mS (or mGy) The fetal exposure is thus 1000 times lower, and the fetal sk is negligible \when a sentinel node procedure is used for vulvar cancer (after a Personal communication with Ate Van det Zee). Anaphylactic Feaeton to patent ble hasbeen deseibed.*""* However, treatment of this sid effet during pregnaney is hazardous, and fetal well being is put into danger, There are also repons of possible skeletal and reurologie defects in rat models.” ‘The use of patent blue for the detection ofthe sentinel node is therefore not recommended Diagnosis of cervical pathology during pregnancy deserves special altention, Both cervical glands and stroma undergo Physiologic alterations during pregnancy that aller cytologic" and colposcopie interpretation. However, if the eytologist and aware of the pregnant state, ther reliability isnot Moreover, a eolposcopieuided biopsy should not be postpone because the colposcopie cytologic concordance can be ‘worse in the postpartum." Indications foe eolpescopy are the same as for nonpregnant patients and also the same’ morphoogical alterations in ease of abnormality ae present, Progression or missed Aiagnosis of microinvasive disease until the postpartum period was noted in 0.0%, 1.1%, 2.4%, 80%, and 9.7% of eases Inthe absence of progression to invasive cervical cance no treatment oF CIN 23 lesions during pregnaney is nceasary, Diagnosis shoul be made by an experienced colposcopist. There is only very limited indication for conization in pregnancy in patients in whom the © 2009 IGS and ESGO Gynecologic Cancers in Pregnancy previously mentioned measures cannot rule out invasive disease Then, conization refers to the excision of the transformation zone, iekness oF at least S mm is recommended, Inthe presence of ‘vaginal delivery is allowed. However this will, ind a preinvasive disease ‘ot inetease regression rates when compared with cesarean delivery. Surgery During Pregnancy Overall, 0.75% to 39% of pregnant women will undergo surgery during pregnancy. Surgery and anesthesia are safe during pregnancy if physiologic adaptations are considered. "2" Adequate ‘maternal monitoring is crucial in preventing hypoxia, hypotension, and hypoglycemia. Pregnant patents should be positioned in lef later tito prevent eaval compression, Peroperaive fetal monitar- ing is always difficult to interpret and is only useful if clinically ‘elevant, Fetal monitoring during surgery for gynecological cancers is mostly not feasible. A eardotocography, dope, or ultasound {ust before and afer the surgery maybe useful exelade direc etal damage timely associated with surgery. With repant to fetal resuscitation, the local policy needs to be followed Cohet-Kerem etal” reviewed over 12,000 cases of surgery daring pregnaney. The data suggest that surgery does not increase the risk for miscarriage and congenital anomalies. Only in cases of peritonitis, fetal loss rate was increased, However, most of the ‘reported surgeries did not include the reproductive tract or were indicated for cancer treatment. Therefore, conclusion shoul be interpreted cautiously. ‘Surgery might slighty inerease preterm delivery but numbers ae lificlt fo interpret because no comparison was made with & normal pregnant population. There is no literature supporting the prophylactic use of tocolysis in eases of surgery during pregnancy. When preterm labor is diagnosed perioperatively, tocolytic agens like. nifedipine, atosiban, or indomethacin (<32 weeks) should be considered. Laparoscopic surgery during pregnancy is safe and effective when performed in experienced: hands." The carbon oxide Pneuio-peritoneum and carbon monoxide production during «letro-coagulation does not seem to be hazardous wo the fetis a6 long as the maximal pressure (oor 10-13 toy Hig: maximum, 15mm Hg) and operation time (25-90 minutes) are respected.” The use of a Vertes needle puts the pregnant wertstrsk. An «nen laparoscopic procedure is sate fram oncological point of view in experienced. hands that minimize the risk for spilling, ideally between Toth and 2th week of pregnancy." ‘Systemic Anticancer Treatment During Pregnancy Most anticancer drugs exhibit a narrow therapeutic window with small_margins between toxic and therapeutic exposure Inierindividual pharmacokinetic and pharmacodynamic vaviabil- ies are usually substantial and may be augmented by pregnancy. During pregnaney, multiple changes in physiology oveur affecting the major pharmacokinetic processes of drug: absorption, distribution, metabolism, and excretion This may have thera- peutic and foxie consequences for bath the pregnant woman and the Fetus. Because of the changes in pharmacokinetic processes the ‘pregnant patent may be exposed to subtherapeutic or toxie drug levels, and an unwanted amount of deug may be delivered to the fetus, Only 1 report compared maternal doxorubicin levels during and after pregnancy. The results in a single ease point toa lower drug exposure and decreased tissue toxicity when doxorubicin is aulministered during pregnancy. Despite the putative emer pharmacokinetic changes of chemotherapeutics during pre there are, however, so far no indications that pregnant cancer Patients when treated with standard heightaveight based dosed 83 fmant et al chemotherapy higher risk for reduced efficacy or more toxicity than nonpregnant patients treated with the same drugs and dosags The effect onthe fetus is another aspect. The term “placental barrier isa misnomer and a false notion because the placenta is not a true hartier forthe transfer of most substances from mother 10 fetus.” Instead the placenta isthe entry through which the Fetus is «exposed to chemicals. Placental transfer of drugs from the maternal to the fetal side occurs predominantly via passive diffusion and 10a lesser extent via active transport and facilitated diffusion, Concom- itant administration of drugs that block these wansporters or imeslulate the metabolizing enzymes, harnor the risk of leading 10 unintended exposure ofthe Fetus to chemotherapy and thus alertness ‘is advised when drug combinations are used, Specific cytotoxie drug elfects are dificult to describe because combinations ate frequently used and because anal antiemetics, and growth factors are administered as well, How chemotherapeutis should be dased in pregnant women is uncertain and needs further research, Up tll now, the same schemes are used a5 in nonpregnant women. Table 2 compares combinations used in nonpregnant and pregnant women. Cytotoxic drugs used in gynecologic cancer include plat, paclitaxel, bleomycin, etoposide, and vinblastn Based on 37 reported cases, we calculate that cisplatin ‘exposure resulted in moderate bilateral heating loss in 1/37 (2. and ventriculomegaly e causa ignota in 1/37 2,72)" ° This later Patient received I eycle of bleomycin, cisplatin, and etoposide at a ‘gestational age of 26 weeks. Apart from significant manipulation of the uterus to remove the uterus and the development of a pelvie hematoma requiring blood transfusion that might have been associated with fetal hypoxia, a direct neurotoxic effect must be considered.” In another ease, maternal sepsis after bleomycin, cisplatin, and, etoposide administration occurred, result preterm ‘labor The premature neonate (1190 'g) devel respiratory distess syndrome, myelosuppression, ment, and alopecia. Although eisplatin might have contebted to the sensorineural hearing loss, prematurity and postnatal treatment with, gentamyein were confounding factors. Taking these considerations into account, administration of cisplatin and regimens during pregnancy resulted in. absen anomalies and nionmal neurological development in 35 (95 Tenses Carboplatin has been administered during pregnancy in 8 cases (of which 4 in association with paclitaxel) and a normal ‘neonatal outcome was noted in each.” ”" Based on a better toxi profile, we recommend carboplatin instead of cisplatin if evaluated in the respective tumor entity. Unil more data ate available on the pharmacokinetics during pregnancy, we recommend 10 dose as usu for ovarian tumors in nonpregrant women (area under cutve, $7.5). TABLE 2. Recommended combinations of chemotherapy in nonpregnant and pregnant women Nonpregnant Pregnant Ovarian cancer Epithelial Paclitaxelcarboplatin Paclitaxel-carboplatin Germ cell Bleomycin-etoposide-Pacltaxel-carboplatin or Cisplatin-vinblastin- bleomycin Paclitaxel cisplatin Paclitaselcarboplatin cisplatin Cervical eancer Platin based International journal of Gynecological Concer + Volume 19, Number S1, May 2009 ‘Area under curve is based on the glomeruk safety upper limit of carboplatin of 800 mg, be planned according to blood counts subsequ ‘Tiventy ease eports were found document the use of taxanes during pregnancy: 13 on paclitaxel" and 7 on docetaxel." * In 17 of the 20 cases, taxanes were administered after other eytotoxi drugs (patients with breast cancer) of in combination with other cytotoxic devas (patents with ovarian of lung cancer). Except for 1 hydrocephalia in patent given docetaxel with doxorubicin-cyclophosphamide but with normal outcome of the child after 28 months," no fetal or neonatal problems have been observed after the use of taxanes during pregnancy. Atleast cases of a combination of bleomycin, cisplatin, and etoposide (BEP) during pregnancy for treatment of germ eel tumors hhave been described:*°"5°56388? Although reports deseribe a filtration rate, with a Dose escalations can hormal neonatal outcome, 1 child with a significant ventriculome- aly with cerebral atrophy was born after 1 eycle of BEP and! | case Of hearing impairment (See discussion above).""* Based on this oor neonatal outcome and given the pas tumors,"*™ paclitaxel and carboplatin alkaloids are already in use fora fon their use is relatively sate in pregnancy may replace etoposide because cis been used in 4 eases without matemal or Fetal complications.” Based on a possible fetal risk and the high risk of leukemia ater loposide administration, esplatin-vinblastin-bleomycin or palitanel- carboplatin is advised in pregnant women with germ cell tumors (instead of BEP), [New targeted therapy iS not recommended for pregnant patients with pelvie cancers because ofthe limited experience and because Inge randomized phase IIT tials ae sill awaited to prove their efficacy. therapy During Pregnancy Therapeutic pelvic radiation induces severe or lethal Sand Is not consistent with preservation of the el activity in germ eal e administered." Vinca and many reports cite tn addition, vinblastin in-vinblastin-bleommyein has pregoaney. Supportive Therapy and Symptom Control in the Pregnant Patient Supportive treatment of chemotherapy canbe piven mainly acconting to the general recommendations.” Regarding the use of comicoids, methyrednsolone and hydrocortisone are extensively metabolized in the placenta and litle crosses ito the fetal compgrtment. They are therefore referred over dexa-orbetamethae sone.” Repeated antenatal exposte o dexarbetamethasone resulted imvanimal models in dooteased bod and rain W inthe maturation timetable, and hormonal disturbances." This eoncem vwas_ raised, subsequently in the National Insitutes of Health Consensus” More children with attention problem and higher rates of erebral palsy have been described °**” Granulocyte colony-st Factor have been used sae ant patents, and their use should follow current guidelines for growth factor support during chemotherapy.” A list of the most important supportive drugs and their safety profil is presente in Table 3 MONITORING PREGNANCY AND NEONATAL OUTCOME Monitoring of the Pregnancy, Complicated With a Gynecological Cancer In general the mother and fetus should monitored withthe stundard prenatal care established Tor hi © 2009 IGCS and ESGO {International foual of Gynecological Cancer * Volume 19, Number $1, May 2009 Gynecologic Cancers in Pregnancy TABLE 3, Most important supportive drugs and their fetal safety profile?” upportive drugs Fetal safety data Antiemeties| Metoclopramide/alizapride Metoclopramide be used in all stages of pregnancy. Its methoxy-2-benvamide-derivate, alizapride, is probably’ also safe, S-HT antagonists (granisetron, topisetron, Should nat be withheld because ofthe pregnancy. Animal data sugges low risk, Case eporis ondansetron} ‘on ondansetron show its effectiveness in the control of vomiting in pr maney and m0 adverse effects wete observed inthe children, KI antagonist aprepitant) suggest lo risk Conticoids Growin factors Granulocyte colony-stinulating factors (peefilgrastim,filgastrim,lenograstim) Erythropoetins Pain medication Paracetamol Nonsteroidal inflammatory drugs Should not be with Pregnaney-rlated complications should he treated according to the ‘standard obstetrical eae. ery should take place ina hospital with neonatal care unit, When possible, the delivery should be delayed until 35 10 37 wot before 32 weeks. Sequciae associated with preterm birth, of which neurodevelopmental im: Pairments and cerebral palsy are the most important, increase with decreasing gestational age."*-"* The risk for long-term neurologic sequelae should be avoided if possible and discussed. with the Parents. When delivery is planned before 34 weeks, fetal lung mat luration must be considered. The placenta should be examined for metastases, but fetal involvement has never been described for gynecological can- cers." Breastleeding during chemotherapy is contraindicated, 88 most ofthe agents used can be exereted in breast milk. Neonatal and Long-Term Outcome After in Utero Exposure to Chemotherapy Available studies on he outcome ofthe offspring lack ether a etd methodology ora systematic examination, thetefore, data on the long-term outcome ofthese children ae very limited. fn the largest and recent literature review on this topic, Cardenic and Iacobucci” desribed 376 cases of in utero exposure to chemother ‘py. In this series, 5% intrauterine deaths and 19% neonatal dats were registered, All but 3 deaths oscurred with maternal hemato. logical malignant disease. Tw ofthese 3 eases had been exposed to idarubicin for breast cancer. The authors encountered 11 cases Of ital_ malformation “of which 9 cases were exposed to notherapy’ in the first timeste. More recent publications so described no particular problems wien chemotherany was ad istered aller the fist timeste."""" Hahn etal! doserbed $7 Patents that were tated for breast cancer during. pregnancy Although telephone call or mail was used to contact the parents suardian or teacher, the outcome was encouraging. One smell study applied systematically a hanery of neuropsyshological testing in 1D shilen. Morbidity ater ntaurine eyposue to cyeoxie dues mainly appeared to be related to prsterm neonates" If poss delivery should be planned after'35 weeks gestational age. This strategy has shown tobe beneficial 2009 IGCS and ESGO ‘an be used after the first rimester of pregnancy. Pre Should not be withheld because ofthe pre Should not be withheld because of the pregnancy. No human data available, animal data isolone or hydrocortisone are preferred cld because ofthe pregnancy. Is crossing the placenta, ane. Is probably not crossing the placenta Drug of preference (til 4 gid) Can be use between 12 and 32 weeks of gestation Echocardiographie follow-up data suggest a normal cardiac Function, in children who were in utero exposed. to cytotoxic ddrugs.""'"* Ina small series, Van Calsteren et all”? used echocardiographie quantification ‘of eardiae function using both conventional and newer techniques. in all children, a normal cardiac performance without morphological abnormalities could be ob. served, However, a tend toward a lower wall thickness and lef ventricular mass was recorded. The authors believe this could be due {o chemotherapy as this influences myocyte replieation and geowth, Whether the different methodology that was used can explain the difference is subject for further study. The limited data did not show an excessive increase risk for ‘congenital malformations when compared with the background risk for fetal anomalies after intrauterine exposure 10 chemotherapy “during the second and tied trimester. However, long-term fallow -up data are urgently needed. ORGAN PATHOLOGY Invasive Cervical Cancer The treatment of cervieal cancer during pregnaney is determined by the gestational age, stage of disease, and the Wish ‘of the patient to preserve the pregnanes, ‘The limited experince with an invasive cervieal cancer siagnosed during pregnancy renders every treatment proposal other than established standard therapy’ for nonpregnant patients exper ‘mental, Radical hysterectomy ofa pregnant wens is posible. From the second trimesier onward, surgical delivery by hysterotomy will improve the accessibility of the pelvis, The inereased blood supply deserves an experienced surgeon. Aitematively, chemoradiation can be used, Radiation ofthe pelvis during the fis trimester will in spontaneous abortion. During the second trimester, abortion may bbe protracted and interfere with the radiotherapy. Prior wterine evacuation (hysterotomy or suction curettage) will facilitate subsequent chemoradiotherapy ‘When maintenance of pregnancy is desired, the experimental nature of the cancer treatment during pregnancy and the pote risks should be discussed with the patient concemed. The Amant etal Send wer | Trtelstomy FIGURE 1. Algorithm for treatment of cervical cancer stage IBy, less than 2 cm treated during the second trimester of pregnancy in patients wishing to preserve the pregnancy and Tertity. NACT, neoadjuvant chemotherapy. during pregnancy primarily depends on the gestational age at which cervical cancer is diagnosed ‘When cervical cancer is diagnosed during the frst arimester ‘ofa wanted pregnancy, a conservative approach is proposed to reach the second trimester. During the shird mimester, fetal maturity is avaited and a cesarean delivery followed by standard treatment is Proposed, Treatment of cervical cancer during the second trimester is determingd by the stage. Stave IAI disease is treated by a flat cone biopsy." Treatment options for higher stages during the second trimester ane presented in Figures 1 to 3. Interventions including International Journal of Gynecological Cancer * Volume 19, Number $1, May 2009 |ymphadensstoms; neoadjuvant chemotherapy (NACT), and trache: Jeetomyy during pregnancy can be considered, ‘A lymphadenectomy is performed duting gestation when pregnaney or fertlty saving surgery is possible, Pelvic Iymphad Dectomy i performed to identify high-risk disease that-would exclude a pregnancy swing policy, A reimopeitonea laparotonic approach of laparoscopy’ could potentially help to minimize ‘uterine manipulation and hence contractility. The pathologist should bee aware of the pregnant slate, as decidual changes in the pelvic Iymph nodes may mimic malignant disease.!"* Neoadjuvant chemotherapy during pregnancy’ can be used to stabilize or reduce the size of cervical cancer: "2 q summary of 9 reported cases is presented in Table 4, 1 should be noted that 2 matemal deaths were treatmentrclted, The neonatal ‘outcome was normal inal eases. Chemotherapy for cervical cancer should be platinum based but the addition of paclitaxel wil increase response rates.” During pregnancy, paltaxel-carboplatin may be considered a allerative to eisplatinchased regimens ecause of ts favorable toxicity profile as shown in small serie." The number cycle of chemotherapy is nee policy is preferred. i Trachelectomy, has been described as an abdominal!” or \aginal procedure." Experience during pregnancy is, however, very limited, and the technique requires sufficient surgical skills, may be associated with large volumes of blood loss (irespective of | the approach), and the risk of pregnancy loss is considerable." The experimental nature ofthis approach needs to be disc These data suggest that Iymphadenecto trachelectomy can be used to teat cervical cary we pregnancy Their use depends on the stage of cervical cancer. An algorithm for stage 1A2-IBI less than 2 em is presented in Figure 1. In the absence ‘of nodal metastasis, NACT followed by’ conservative surgery (ez, trachelectomy) can be considered. Standant weatment depends on the local policy and is radical hysterectomy’ of chemoradiation (Fig. 1). An algorithm forstage BI 2 to 4 em tumors is presented in comet | CCL] [cee | Ensen sel — ee Pees |eelemane FIGURE 2. Algorithm for treatment of cervical cancer stage IB|, 2 to 4 cm treated during the second trimester of pregnancy in patients wishing to preserve the pregnancy and fertility. NACT, neoadjuvant chemotherapy. S6 2009 IGCS and ESGO Intemational joual of Gynecological Cancer + [wert Cs Sen] (eiiiaets] [Taeteteciomy | FIGURE 3, Algorithm for treatment of cervical cancer stage '8241B treated during the second trimester of pregnancy in patients wishing to preserve the pregnancy and fertility. NACT, neoadjuvant chemotherapy. Figure 2. Lymphadenectomy is mandatory but ean be performed after NACT. The potential to preserve the pregnancy de fn the nodal status and the response to NACT. Av Sage 1B2-IB is presented in Figure 3. For these tumors, fertility sparing surgery has not been sufficiently evaluated. Definitive treatment is performed after delivery: Neoadjuvant chemothempy during pregnancy can be applied until fetal maturity, preferably longer than 35 weeks. Cesarean delivery precekes final treatment. tn case of a good response to NACT (residual tumor <4 em), frit sparing surgery can be considered in experienced hands though in an experimental seting. Alternatively, standard treatment is proposed In selected cases, radical hysterectomy at the time of cesaean delivery maybe indicated. ‘Standard treatment is mandatory in nonresponders to NACT. Thus, for stage IB2-II, lymphadenectomy is postponed until after delivery, when radical trachelectomy. or radical hysterectomy; is opted fa ‘The route of delivery is determined by the presence or absence of tumor, When the cervix i cleared from tumor, a vaginal Uclivery is possible. Inthe presence of tamor, a cesarean delivery is the prefered route of delivery to prevent (fatal) recurrences in the Volume 19, Number $1, May 2009 Gynecologic Cancers in Pregnancy episiotomy sear?" Because abdominal wall ecurre (but less) have been described after a cesarean delivery, a ‘wound protective system of a corporeal uterine incision might be Uusefl when the tumor is large, Vulvar Cancer Ubvar intraepithelial neoplas skinning or surgical excision at every stage of pregnancy. For invasive vulvar cancer, the potential 10 preserve the pregnancy Adepends on the nodal stage. Invasive (> Imm) vulvar cancer with clinical negative nodes during pregnancy’ should be tated in nonpregnant women with hemi- oF total vulvectomy’ and unilateral of bilateral inguinofemoral lymphadenectomy or sentinel. proce. dure." Recurrence during peegnaney has heen described. Narrow margins should be avoided because postoperative tadio- therapy to reduce recurrence rates during. pre indicated. The increased vascularization of the pelvis during ‘regnaney increases the peroperatve blood loss. After surgery for vulvar caneer, the route of delivery should be discussed with the gynecological oncologist. Problematic wound healing, important Scarring, periuretral or perianal sear are considered. telative ‘contraindication for a vaginal delivery ‘The prognosis is poor if inguinal nodes are involved, Adequate teatment is needed without delay. Evidence tor the bbenelt of chemotherapy is low. Termination of pregnancy with immediate treatment is advocated during the fist and. second trimester in patents with metastatic inguinofemoral Iymph nodes, Daring the third trimester, delivery followed by standard eaten Suggested in these patients. Given the potential for spilling in the episiotomy wound and subsequent risk for an episiotomy scat currence, a cesarean delivery is preferred. Vulvar melanoma deserves the same treatment as in nonpregnant patients. Patients harboring poor prognosis. disease should be informed about the high risk of relapse and death Metastatic melanoma caries a risk for placental with an approximate risk for fetal metastasis of 22%." can be treated with laser Ovarian Neoplasm Malignant ovarian tumors are more likely to present at early sage because of frequent obstetrical examinations in asymptomatic patients" 'Nonepithelial neoplasms (germ cell, sex-cord stromal tumors) are usually stage 1 and ean be treated during midline laparotomy ‘ith unilateral salpingo-oophorectoms, omentetoms, penton TABLE 4. Summary of published reports on the use of NACT for cervical cancer during pregnancy Outcome Outcome Ave Stage Di (w) Chemotherapy’ Surgery (9) FU (mts) mother ehild Giacalone, 1996 34 TBE 17-75 mgin® PG courses) 2 2 NED) NI Tewari, 1998 34 A 16 mg/m? ¥, 50 mgim? P (6 courses) 4 5 bopy Ni 36 IRR 1 me’ ieim’ P (4 courses) 32 ey NED NI Marna, 2001 26 UB. 30 mg/m? B, 0 mgim" P (2 courses) 38 12 boo' NI Caluwaers, 2006 28 1B 75 mg/m’, P (6 courses) 2 10 NED NI Bader, 2007 38 A 1 mgm? \, 50 mg/m? P (4 courses) 8 0 NED NI Benhaim, 2006 30 mB 50 mg/m? P (2 courses) 28 10 bop M Palaia, 2007 30 IB 2075 maim? P3 courses) 35 0 NED NI Karam, 200728 1B2__23.—_ 40 mpim? P (6 courses) 33 W NED N {This patient developed an absominal wound wsurenee aller wre Gv This pation sefased Further etment Dia © 2009 1GCS and ESGO ess (D) wecks (w), months mts), fllowsup (FU), normal (I), dead of disease (DOD), no evidence of disease (NED), s7 Amant etal cytology, and blind biopsies during pregnancy, Uterine manip lations should be limited in order to prevent preterm contractions Lymphadeneetomy is not indicated, unless enlarged nodes were noticed during staging or intraoperatively. Adjuvant chemotherapy is ‘ot indicated for FIGO stage I grade | imasatue teratoma or FIGO stage I dysgerminoma, For higher stages or nondysgerminoma ‘tumors adjuvant chemotherapy is needed. Close surveillance instead ‘of adjuvant chemotherapy has been propagated,” however, tumor ‘markers during pregnancy are less reliable If continuation of pregnancy is desired, tumor markers are not useful to determine the number of cycles and 6 cycles of paclitaxel-carboplatin are recommended (bieomycin-coposide-cisplatin second choice) (See paragraph on chemotherapy). Restaging after delivery should be ‘considered based on imaging findings and tumor markers Borderline epithelial cancers during pregnaney are likely to be stage I and can be treated during pregnancy. Stang laparotomy ‘ith unilateral salpingo-oophorectomy, omentevtomy, and peritone- al biopsies is needed, In seleced eases, laparoscopic procedure can be executed, For higher stages, removal of the adnexa during pregnancy is aimed for with completion ofthe surgery afer delivery A vaginal delivery is allowed. For invasive epithelial ovarian carcinoma, the potential to preserve the pregnancy and the type of surgery and chemotherapy ‘depend onthe stage and grade. Forstage 1A, grade I surgical staging is similar to borderline tumors. Postdclivery restaging may be considered because staging during pre stage IA grade 2-3, 1B, IC and IIA, additionally, lymphadenectomy nd adjuvant platin based chemotherapy is mandatory. I he patient is upstaged, chemotherapy during pregnancy and final surgery after elivery are needed. ‘Advanced stage ovarian cancer during pregnancy was treated with differen treatment strategies, including primary debulking with termination, of prognancy°S!" or delivery, ="? expectant mane agement,°™"™ surgery during pregnancy followed by posipartal chemotherapy."*'** surgery (including. cytoreductive. surgery) followed by chemo during preenaney with final surgery during after delivery.'31940!s-7076158155 These ease reports show that ovarian cancer treatment during pregnancy is an option, After considering the matemal prognosis and wish to preserve the pregnancy, stage of disease and the westational age will determine i treatment plan. Advanced stage ovarian cancer before 20 weeks is mostly incompatible with maintenance of pregnancy. Debulking surgery with removal ofthe pregnancy and subsequent chemother- apy are recommended, After 20 weeks, preservation of pregnancy is experimental though possible, Surgery should be limited to establish the diagnosis. Any debulking procedire would be incomplete when preservation of the pregnancy is aimed for. Incomplete debulking during pregnancy should be avoided because the fetus would be exposed unnecessarily to major surgery not accomplishing the goal of complete resection of the tumor, Pacitaxel-carboplatin chemo- therapy until fetal maturity isthe regimen of choice for pre-operative chemotherapy. Vaginal delivery followed by final surgery in the Postpartum period or planned laparotomy for cesarean delivery and (interval)-debulking may be considered ney is not complet. For Psychosocial and Ethical Concerns of Cancer Diagnosis During Pregnancy Most regan women diagnosed with cancer experincs high emotional distress and even long-term emotional sequelae Cancer diagnosis brings fear of death, wort about continuation of the pregnaney, anxiety about the impact of cancer talent on the fous, fear fr not being able to raise the child into adulthood, and anwety about ature ety, Emotional and psychological supports imperative Ii avisable to engage the experts of ther members S8 Intemational journal of Gynecological Cancer + Volume 19, Number $1, May 2009 of the health care team such as psychologists, social workers, and depending on patients religion, a pastoral worker, especially while treatment decisions are being made. Such a decision comprises a balance between the (disadvantages for mother and child, The prognosis, treatment modalities, gestational age, and the patients preference are pivotal in the decision making process on treatment uring pregnancy or termination of pregnancy. Although most studies report that the prognosis of cancer during pregnancy’ is similar t0 the nonpregnant state, these statements should. be interpreted cautiously. The series are not large enough 10 ental for all prognostic factors and to draw firm conclusions." Ethically, a delivery before 28 weeks isan undue risk for the fetus but a suboptimal treatment is an undue risk for the mother. The parents shouldbe informed abou the different treatment options and the possible consequences forthe patent and the fetus. CONCLUSIONS Individvalization is crucial when gynecological cancer is diagnosed during pregnancy, Oncological surgery and chemothe apy afer the first timester seem to be relatively safe from a fetal point of view. 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