Michael Halaska

Cancer During Pregnancy: An Analysis of 215 Patients Emphasizing the Obstetrical and the Neonatal Outcomes.

PURPOSE The aim of this study was to assess the management and the obstetrical and neonatal outcomes of pregnancies complicated by cancer. PATIENTS AND METHODS In an international collaborative setting, patients with invasive cancer diagnosed during pregnancy between 1998 and 2008 were identified. Clinical data regarding the cancer diagnosis and treatment and the obstetric and neonatal outcomes were collected and analyzed. RESULTS Of 215 patients, five (2.3%) had a pregnancy that ended in a spontaneous miscarriage and 30 (14.0%) pregnancies were interrupted. Treatment was initiated during pregnancy in 122 (56.7%) patients and postpartum in 58 (27.0%) patients. The most frequently encountered cancer types were breast cancer (46%), hematologic malignancies (18%), and dermatologic malignancies (10%). The mean gestational age at delivery was 36.3 +/- 2.9 weeks. Delivery was induced in 71.7% of pregnancies, and 54.2% of children were born preterm. In the group of patients prenatally exposed to cytotoxic treatment, the prevalence of preterm labor was increased (11.8%; P = .012). Furthermore, in this group a higher proportion of small-for-gestational-age children (birth weight below 10th percentile) was observed (24.2%; P = .001). Of all neonates, 51.2% were admitted to a neonatal intensive care unit, mainly (85.2%) because of prematurity. There was no increased incidence of congenital malformations. CONCLUSION Pregnant cancer patients should be treated in a multidisciplinary setting with access to maternal and neonatal intensive care units. Prevention of iatrogenic prematurity appears to be an important part of the treatment strategy.

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

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 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 neonatologist–breast-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.

Long-term cognitive and cardiac outcomes after prenatal exposure to chemotherapy in children aged 18 months or older: an observational study

BACKGROUND Chemotherapy for the treatment of maternal cancers during pregnancy has become more acceptable in the past decade; however, the effect of prenatal exposure to chemotherapy on cardiac and neurodevelopmental outcomes of the offspring is still uncertain. We aimed to record the general health, cardiac function, and neurodevelopmental outcomes of children who were prenatally exposed to chemotherapy. METHODS We did an interim analysis of a multicentre observational cohort study assessing children who were prenatally exposed to maternal cancer staging and treatment, including chemotherapy. We assessed children at birth, at age 18 months, and at age 5-6, 8-9, 11-12, 14-15, or 18 years. We did clinical neurological examinations, tests of the general level of cognitive functioning (Bayley or intelligence quotient [IQ] test), electrocardiography and echocardiography, and administered a questionnaire on general health and development. From age 5 years, we also did audiometry, the Auditory Verbal Learning Test, and subtasks of the Childrens Memory Scale, and the Test of Everyday Attention for Children, and we also completed the Child Behavior Checklist. This study is registered with ClinicalTrials.gov, number NCT00330447. FINDINGS 236 cycles of chemotherapy were administered in 68 pregnancies. We assessed 70 children, born at a median gestational age of 35·7 weeks (range 28·3-41·0; IQR 3·3; 47 women at <37 weeks), with a median follow-up period of 22·3 months (range 16·8-211·6; IQR 54·9). Although neurocognitive outcomes were within normal ranges, cognitive development scores were lower for children who were born preterm than for those born at full term. When controlling for age, sex, and country, the score for IQ increased by an average 11·6 points (95% CI 6·0-17·1) for each additional month of gestation (p<0·0001). Our measurements of the childrens behaviour, general health, hearing, and growth corresponded with those of the general population. Cardiac dimensions and functions were within normal ranges. We identified a severe neurodevelopmental delay in both members of one twin pregnancy. INTERPRETATION Fetal exposure to chemotherapy was not associated with increased CNS, cardiac or auditory morbidity, or with impairments to general health and growth compared with the general population. However, subtle changes in cardiac and neurocognitive measurements emphasise the need for longer follow-up. Prematurity was common and was associated with impaired cognitive development. Therefore, iatrogenic preterm delivery should be avoided when possible. FUNDING Research Foundation-Flanders; Research Fund-K U Leuven; Agency for Innovation by Science and Technology; Stichting tegen Kanker; Clinical Research Fund-University Hospitals Leuven; and Belgian Cancer Plan, Ministery of Health.

Breast cancer in pregnancy: recommendations of an international consensus meeting.

PURPOSE To provide guidance for clinicians about the diagnosis, staging and treatment of breast cancer occurring during an otherwise uncomplicated pregnancy. METHODS An international expert Panel convened to address a series of questions identified by a literature review and personal experience. Issues relating to the diagnosis and management of breast cancer after delivery were outside the scope. RESULTS There is a paucity of large and/or randomized studies. Based on cohort studies, case series and case reports, the recommendations represent the best available evidence, albeit of a lower grade than is optimal. RECOMMENDATIONS In most circumstances, serious consideration should be given to the option of treating breast cancer whilst continuing with the pregnancy. Each woman should ideally be referred to a centre with sufficient expertise, given a clear explanation of treatment options. Most diagnostic and staging examinations can be performed adequately and safely during pregnancy. Treatment should however be adapted to the clinical presentation and the trimester of the pregnancy: surgery can be performed during all trimesters of pregnancy; radiotherapy can be considered during the first and second trimester but should be postponed during the third trimester; and standard chemotherapies can be used during the second and third trimester. Since neonatal morbidity mainly appears to be related to prematurity, delivery should not be induced before 37 weeks, if at all possible. CONCLUSIONS The treatment of breast cancer in pregnancy should be executed by experienced specialists in a multidisciplinary setting and should adhere as closely as possible to standard protocols.

Treatment of breast cancer during pregnancy: an observational study

BACKGROUND Little is known about the treatment of breast cancer during pregnancy. We aimed to determine whether treatment for breast cancer during pregnancy is safe for both mother and child. METHODS We recruited patients from seven European countries with a primary diagnosis of breast cancer during pregnancy; data were collected retrospectively if the patient was diagnosed before April, 2003 (when the registry began), or prospectively thereafter, irrespective of the outcome of pregnancy and the type and timing of treatment. The primary endpoint was fetal health for up to 4 weeks after delivery. The registry is ongoing. The study is registered with ClinicalTrials.gov, number NCT00196833. FINDINGS From April, 2003, to December, 2011, 447 patients were registered, 413 of whom had early breast cancer. Median age was 33 years (range 22-51). At the time of diagnosis, median gestational age was 24 weeks (range 5-40). 197 (48%) of 413 women received chemotherapy during pregnancy with a median of four cycles (range one to eight). 178 received an anthracycline, 15 received cyclophosphamide, methotrexate, and fluorouracil, and 14 received a taxane. Birthweight was affected by chemotherapy exposure after adjustment for gestational age (p=0·018), but not by number of chemotherapy cycles (p=0·71). No statistical difference between the two groups was observed for premature deliveries before the 37th week of gestation. 40 (10%) of 386 infants had side-effects, malformations, or new-born complications; these events were more common in infants born before the 37th week of gestation than they were in infants born in the 37th week or later (31 [16%] of 191 infants vs nine [5%] of 195 infants; p=0·0002). In infants for whom maternal treatment was known, adverse events were more common in those who received chemotherapy in utero compared with those who were not exposed (31 [15%] of 203 vs seven [4%] of 170 infants; p=0·00045). Two infants died; both were exposed to chemotherapy and delivered prematurely, but both deaths were thought not to be related to treatment. Median disease-free survival for women with early breast cancer was 70·6 months (95% CI 62·1-105·5) in women starting chemotherapy during pregnancy and 94·4 months (lower 95% CI 64·4; upper 95% CI not yet reached) in women starting chemotherapy after delivery (unadjusted hazard ratio 1·13 [95% CI 0·76-1·69]; p=0·539). INTERPRETATION Although our data show that infants exposed to chemotherapy in utero had a lower birthweight at gestational age than did those who were unexposed, and had more complications, these differences were not clinically significant and, since none of the infants was exposed to chemotherapy in the first trimester, were most likely related to premature delivery. Delay of cancer treatment did not significantly affect disease-free survival for mothers with early breast cancer. Because preterm birth was strongly associated with adverse events, a full-term delivery seems to be of paramount importance. FUNDING BANSS Foundation, Biedenkopf, Germany and the Belgian Cancer Plan, Ministry of Health, Belgium.

Pediatric Outcome after Maternal Cancer Diagnosed during Pregnancy.

BACKGROUND Data on the long-term outcome of children who are exposed to maternal cancer with or without treatment during pregnancy are lacking. METHODS In this multicenter case-control study, we compared children whose mothers received a diagnosis of cancer during the pregnancy with matched children of women without a cancer diagnosis. We used a health questionnaire and medical files to collect data regarding neonatal and general health. All children were prospectively assessed (by means of a neurologic examination and the Bayley Scales of Infant Development) at 18 months, 36 months, or both. A cardiac assessment was performed at 36 months. RESULTS A total of 129 children (median age, 22 months; range, 12 to 42) were included in the group whose mother had cancer (prenatal-exposure group) with a matching number in the control group. During pregnancy, 96 children (74.4%) were exposed to chemotherapy (alone or in combination with other treatments), 11 (8.5%) to radiotherapy (alone or in combination), 13 (10.1%) to surgery alone, 2 (1.6%) to other drug treatments, and 14 (10.9%) to no treatment. Birth weight was below the 10th percentile in 28 of 127 children (22.0%) in the prenatal-exposure group and in 19 of 125 children (15.2%) in the control group (P=0.16). There was no significant between-group difference in cognitive development on the basis of the Bayley score (P=0.08) or in subgroup analyses. The gestational age at birth was correlated with the cognitive outcome in the two study groups. Cardiologic evaluation among 47 children at 36 months of age showed normal cardiac findings. CONCLUSIONS Prenatal exposure to maternal cancer with or without treatment did not impair the cognitive, cardiac, or general development of children in early childhood. Prematurity was correlated with a worse cognitive outcome, but this effect was independent of cancer treatment. (Funded by Research Foundation-Flanders and others; ClinicalTrials.gov number, NCT00330447.).

Less radical surgery than radical hysterectomy in early stage cervical cancer: a pilot study.

OBJECTIVE The purpose of this pilot study was to evaluate the feasibility and safety of a less radical surgery; laparoscopic lymphadenectomy followed by a simple vaginal hysterectomy in sentinel lymph node (SLN) negative early cervical cancer patients. Treatment-associated morbidity and oncological outcome were evaluated. PATIENTS AND METHODS From December 2000 to September 2007, 60 patients (50 squamous and 10 adenocarcinoma patients) in stages 3-IA1, 11-IA2 and 46-IB1 with median age of 44.6 years (range 33-64 years) were enrolled. Patients were selected based on favorable cervical tumors (IA1 with lymph-vascular space invasion [LVSI], IA2 and IB1 with tumor size less than 20 mm and less than half of stromal invasion). All patients underwent laparoscopic SLN identification using frozen section (FS). Negative SLN patients underwent complete pelvic laparoscopic lymphadenectomy and vaginal hysterectomy. FS positive patients underwent radical hysterectomy with low paraaortic lymphadenectomy. RESULTS The average number of sentinel nodes per side was 1.4 with detection rate per side of 95%. The average number of removed nodes was 23.2. Five patients (8.3%) were SLN positive. There were two false negative FS results (both were micrometastases in SLN). Median follow-up was 47 months (range 12-92). There were no recurrences in 55 SLN negative patients and in 5 SLN positive patients. CONCLUSION Lymphatic mapping and SLN identification improved safety in less radical surgery in early stage cervical cancer. This preliminary study showed that it is both feasible and safe to reduce the radicality of parametrial resection for small tumor volume in SLN negative patients. Results also indicated that treatment-associated morbidity is low.

Pharmacokinetics of chemotherapeutic agents in pregnancy: a preclinical and clinical study

Objective. To determine the impact of physiologic changes of pregnancy on pharmacokinetics of chemotherapeutic agents. Design. A preclinical and a clinical case–control trial. Setting. Institute of Primate Research Nairobi and collaborating hospitals in Belgium, the Netherlands and Czech Republic. Population. Pregnant and nonpregnant women and baboons receiving chemotherapy. Methods. Chemotherapy pharmacokinetics was compared between the pregnant and nonpregnant state. Standard‐dosed chemotherapy regimens were administered in pregnant and nonpregnant baboons/women, followed by serial blood samplings. Drug plasma levels were determined using high performance liquid chromatography and atomic absorption spectrometry. Main outcome measures. Area under the curve (AUC), maximal plasma concentration, terminal elimination half‐life, clearance and distribution volume of each drug in pregnant and nonpregnant state. Results. Intraindividual comparative pharmacokinetic data were obtained for doxorubicin and paclitaxel/platinum in three and two baboons, respectively. In the clinical trial, two patients were exposed to doxorubicin and one patient was exposed to paclitaxel/platinum during and after pregnancy. Furthermore, a pooled analysis was performed based on 16 cycles of pregnant and 11 cycles of nonpregnant women. Numbers of pregnant/nonpregnant patients were 5/2, 7/5, 4/4 and 2/2 for paclitaxel, doxorubicin, epirubicin and platinum, respectively. For all drugs tested in the preclinical and clinical study, a decreased AUC and maximal plasma concentration and an increased distribution volume and clearance were observed in pregnancy. Conclusions. Although numbers were too small for statistical significance, pregnancy‐associated physiologic alterations appear to lead to a decrease in plasma exposure of chemotherapeutic drugs. The importance of long‐term follow‐up of women treated with chemotherapy during pregnancy is underscored.

A prospective study of sentinel lymph node status and parametrial involvement in patients with small tumour volume cervical cancer

OBJECTIVE The purpose of prospective study is to determine incidence and distribution of pelvic lymph node (LN) involvement, sentinel lymph node (SLN) involvement and pathologic parametrial involvement (PI) in stage Ia2 and small Ib1 cervical cancer. PI is defined as positive parametrial LN or discontinuous malignant cells in parametrium. METHODS After radical abdominal hysterectomy, 158 women patients were stratified into two groups based on tumour size: In Group 1 (91 women) tumours were less than 20 mm and less than half of stromal invasion. In Group 2 (67 women) tumours were between 20 and 30 mm and infiltration was not more than 2/3 of cervical stroma. RESULTS In Group 1 positive SLN was detected in 11(12.1%) patients; of these, 3 (27.3%) had positive PI. In 80 women with negative SLN PI was not detected. In Group 2 positive SLN was detected in 14 (20.9%) patients: PI was found in four (28.6%) of these 14 patients. No PI was detected in 53 women with negative SLN. CONCLUSION No PI was observed in early cervical cancer if SLNs were negative. However, we found PI in 28.0% of women with positive SLN. Statistical analysis revealed that the results were highly significant. Based on our results, radical removal of parametrium in SLN negative patients is questionable.

Gynaecologic cancer complicating pregnancy: An overview

Cancer complicating pregnancy endangers two lives. Any approach should look at both maternal and foetal safety. Maternal prognosis will not improve by terminating the pregnancy. Imaging for staging purposes is possible, and sonar and magnetic resonance imaging are the preferred examinations. Abdominopelvic computed tomography exposes the foetus to the highest doses radiation and should be avoided. Provided a thorough maternal monitoring to ensure a stable uteroplacental blood flow and foetal oxygenation, surgical techniques that are used in non-pregnant patients are also safe for pregnant patients. Radiotherapy of the upper part of the body is possible during pregnancy, but during the third trimester the close distance may put the foetus at risk. Chemotherapy during the second or third trimester can be administered without increasing the incidence of congenital malformations. A systematic analysis, especially on the long-term outcome of the offspring after cancer treatment during pregnancy is still lacking. Here, we present a summary of issues related to the diagnosis and treatment of gynaecological malignancies during pregnancy. Firstly, we describe general diagnostic and cancer-treatment-related problems. In the second part, organ pathology including breast, cervical, ovarian, endometrial and vulvar cancer is discussed.