Sileny Han

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.

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.

Prognosis of Women With Primary Breast Cancer Diagnosed During Pregnancy: Results From an International Collaborative Study

PURPOSE We aimed to determine the prognosis of patients with breast cancer diagnosed during pregnancy (BCP). PATIENTS AND METHODS In this cohort study, a multicentric registry of patients with BCP (from Cancer in Pregnancy, Leuven, Belgium, and GBG 29/BIG 02-03) compiled pro- and retrospectively between 2003 and 2011 was compared with patients who did not have associated pregnancies, using an age limit of 45 years. Patients with a diagnosis postpartum were excluded. The main analysis was performed using Cox proportional hazards regression of disease-free survival (DFS) and overall survival (OS) on exposure (pregnant or not), adjusting for age, stage, grade, hormone receptor status, human epidermal growth factor 2 status, histology, type of chemotherapy, use of trastuzumab, radiotherapy, and hormone therapy. RESULTS The registry contained 447 women with BCP, mainly originating from Germany and Belgium, of whom 311 (69.6%) were eligible for analysis. The nonpregnant group consisted of 865 women. Median age was 33 years for the pregnant and 41 years for the nonpregnant patients. Median follow-up was 61 months. The hazard ratio of pregnancy was 1.34 (95% CI, 0.93 to 1.91; P = .14) for DFS and 1.19 (95% CI, 0.73 to 1.93; P = .51) for OS. Cox regression estimated that the 5-year DFS rate for pregnant patients would have increased from 65% to 71% if these patients had not been pregnant. Likewise, the 5-year OS rate would have increased from 78% to 81%. CONCLUSION The results show similar OS for patients diagnosed with BCP compared with nonpregnant patients. This information is important when patients are counseled and supports the option to start treatment with continuation of pregnancy.

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.).

Physiologic variations of serum tumor markers in gynecological malignancies during pregnancy: a systematic review

BackgroundRecent insights provide support for the treatment of cancer during pregnancy, a coincidence that poses both mother and fetus at risk. Our aim was to critically review studies on the physiologic variations during pregnancy, the most common tumor markers used in diagnosis and follow-up of gynecological cancers.MethodsWe conducted a systematic review of six tumor markers during normal pregnancy: carbohydrate antigen (CA) 15-3 (breast cancer); squamous cell carcinoma antigen (cervical cancer); and CA 125, anti-Müllerian hormone, inhibin B and lactate dehydrogenase (ovarian cancer).ResultsFor CA 15-3, 3.3% to 20.0% of all measurements were above the cut-off (maximum 56 U/mL in the third trimester). Squamous cell carcinoma antigen values were above cut-off in 3.1% and 10.5% of the measurements (maximum 4.3 µg/L in the third trimester). Up to 35% of CA 125 levels were above cut-off: levels were highest in the first trimester, with a maximum value up to 550 U/mL. Inhibin B, anti-Müllerian hormone and lactate dehydrogenase levels were not elevated in maternal serum during normal pregnancy.ConclusionDuring normal pregnancy, tumor markers including CA 15.3, squamous cell carcinoma antigen and CA 125 can be elevated; inhibin B, anti-Müllerian hormone and lactate dehydrogenase levels remain below normal cut-off values. Knowledge of physiological variations during pregnancy can be clinically important when managing gynecological cancers in pregnant patients.

Management of cancer in pregnancy

A multidisciplinary discussion is necessary to tackle a complex and infrequent medical problem such as cancer occurring during pregnancy. Pregnancy does not predispose to cancer, but cancers occurring in women of reproductive age are encountered during pregnancy. Ultrasonography and magnetic resonance imaging are the preferred staging examinations, but also a sentinel node staging procedure is possible during pregnancy. Standard cancer treatment is aimed for. Operations can safely be performed during pregnancy, but surgery of genital cancers can be challenging. The observation that chemotherapy administered during the second or third trimester of pregnancy, that is, after the period of organogenesis, has little effect on the long-term outcome of children adds to the therapeutic armamentarium during pregnancy. Cancer treatment during pregnancy adds in the continuation of the pregnancy and the prevention of prematurity.

Optimizing anticancer drug treatment in pregnant cancer patients: pharmacokinetic analysis of gestation-induced changes for doxorubicin, epirubicin, docetaxel and paclitaxel

BACKGROUND Pregnant patients with cancer are increasingly treated with anticancer drugs, although the specific impact of pregnancy-induced physiological changes on the pharmacokinetics (PK) of anticancer drugs and associated implications for optimal dose regimens remains unclear. Our objectives were to quantify changes in PK during pregnancy for four frequently used anticancer agents doxorubicin, epirubicin, docetaxel and paclitaxel, and to determine associated necessary dose adjustments. PATIENTS AND METHODS A pooled analysis of PK data was carried out for pregnant (Pr) and nonpregnant (NPr) patients for doxorubicin (n = 16 Pr/59 NPr), epirubicin (n = 14 Pr/57 NPr), docetaxel (n = 3 Pr/32 NPr) and paclitaxel (n = 5 Pr/105 NPr). Compartmental nonlinear mixed effect models were used to describe the PK and gestational effects. Subsequently, we derived optimized dose regimens aiming to match to the area under the concentration-time curve (AUC) in nonpregnant patients. RESULTS The effect of pregnancy on volumes of distribution for doxorubicin, epirubicin, docetaxel and paclitaxel were estimated as fold-change of <1.32, <2.08, <1.37 and <4.21, respectively, with adequate precision [relative standard error (RSE) <37%]. For doxorubicin, no gestational effect could be estimated on clearance (CL). For epirubicin, docetaxel and paclitaxel, a fold-change of 1.1 (RSE 9%), 1.19 (RSE 7%) and 1.92 (RSE 21%) were, respectively, estimated on CL. Calculated dose adjustment requirements for doxorubicin, epirubicin, docetaxel and paclitaxel were +5.5%, +8.0%, +16.9% and +37.8%, respectively. Estimated changes in infusion duration were marginal (<4.2%) except for paclitaxel (-21.4%). CONCLUSION Clinicians should be aware of a decrease in drug exposure during pregnancy and should not a priori reduce dose. The decrease in exposure was most apparent for docetaxel and paclitaxel which is supported by known physiological changes during pregnancy. The suggested dose adaptations should only be implemented after conduct of further confirmatory studies of the PK during pregnancy.

Lung cancer in pregnancy: Report of nine cases from an international collaborative study

OBJECTIVE Lung cancer is an uncommon diagnosis during pregnancy. The combination of smoking in young women, increased maternal age during pregnancy, and increasing incidence of lung cancer worldwide may cause an increase of pregnancy associated lung cancer. The aim of this study was to describe all cases of lung cancer during pregnancy, registered in the international Cancer in Pregnancy registration study (CIP study; www.cancerinpregnancy.org). MATERIALS AND METHODS We present nine cases, all advanced lung cancer during the course of pregnancy. Collected data included demographic features of the study patients, cancer treatment, pregnancy outcome as well as maternal and fetal outcomes. RESULTS AND CONCLUSION Nine pregnant patients from 4 European centres with a median age of 33 years old (range, 26-42) were included. The median gestational age at diagnosis was 17 weeks (range, 6-28). All patients presented with metastatic disease including bone, lung, brain, spinal cord, pleura, lymph nodes, adrenal and liver. Histopathology was compatible with adenocarcinoma in 4 patients, non-small cell lung cancer with unidentified subtype in 2 patients and squamous-cell, large-cell and a poorly differentiated carcinoma in 3 patients, respectively. Eight patients were treated with systemic therapy, five of them during gestation. No responses were seen. The maternal postpartum outcome was poor with less than one year survival following delivery. One patient experienced a spontaneous abortion and three pregnancies were terminated. Five infants were all born premature due to poor maternal status by cesarean section, with a median gestational age of 30 weeks (range 26-33). To summarize, lung cancer in pregnancy has a dismal maternal outcome in our series. We add nine new cases and discuss both therapeutic and prognostic results.

Chemotherapy during pregnancy: effect of anthracyclines on fetal and maternal cardiac function.

Chemotherapy and especially anthracyclines are associated to cardiotoxicity. To assess this potential risk during pregnancy a clinical case–control trial was conducted. Maternal cardiac function, fetal Doppler and fetal cardiac function were evaluated before and after chemotherapy. Maternal cardiac function was assessed by echocardiography before and after the third cycle of anthracyclines and compared with a control group of 10 non‐pregnant women matched for age, type of cancer and anthracycline treatment. Ten fetuses exposed to chemotherapy were compared with 10 control fetuses matched for gestational age and gender. Biometry, amniotic fluid index, fetal Doppler and cardiac function were assessed before and after each cycle of chemotherapy. In all, 108 fetal ultrasounds scans were performed before and after 36 cycles of chemotherapy. Anthracycline exposure did not result in acute maternal and fetal cardiac dysfunction in this small cohort study.

Weekly Paclitaxel/Carboplatin in the Treatment of Locally Advanced, Recurrent, or Metastatic Vulvar Cancer

Objective To evaluate efficacy of weekly paclitaxel/carboplatin chemotherapy in patients with locally advanced, metastatic, or recurrent vulvar squamous cell carcinoma. Method A prospective, single-arm, single-center pilot study was initiated to study response rate of 9 weekly courses of paclitaxel (60 mg/m2) and carboplatin (area under the curve, 2.7). We used this regimen in the neoadjuvant or metastatic setting when surgery would cause serious morbidity or was not an option owing to distant metastases. Primary outcome was response rate, measured according to Response Criteria in Solid Tumors criteria. Treatment toxicity, surgical morbidity, and type of surgery were also evaluated. Results We treated 6 patients in the period between May 2009 and May 2011, of which 4 patients had a diagnosis of locally advanced disease and 2 patients had a diagnosis of recurrent disease. A median number of 7.5 cycles of paclitaxel/carboplatin weekly was administered (range, 3–9). No objective response was observed. Paclitaxel/carboplatin weekly was discontinued after a mean of 4.3 weekly cycles in 3 patients owing to local disease progression. After a median follow-up of 4.2 months (range, 1–29 months), 3 patients died owing to progressive disease and 1 patient died owing to intercurrent disease. The 2 remaining patients underwent radical vulvectomy + bilateral inguinofemoral lymphadenectomy after neoadjuvant chemotherapy. The main chemotherapy-related toxicity was anemia and could be managed conservatively with erythropoietin and intravenous iron therapy. Conclusion Weekly administration of paclitaxel-carboplatin has limited clinical benefit in the treatment of vulvar squamous cell carcinoma.