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.

Breast cancer during pregnancy: a literature review.

Breast cancer during pregnancy is relatively uncommon. However, the incidence is expected to increase as more women delay childbearing. A challenging situation emerges for all persons involved ­ patient, family and medical care workers ­ since two lives are at risk with contradicting priorities. Breast cancer treatment is possible during pregnancy. The treatment plan needs to adhere as closely as possible to standardised protocols for nonpregnant patients, with some considerations to minimize fetal exposure and risks. This concerns mainly limiting radiation exposure and timing of chemotherapy to start in the second trimester. The prognosis of pregnant women does not seem to differ from that of nonpregnant patients when matched for age and stage of the disease. This literature review concentrates on the diagnosis, treatment and outcome of patients diagnosed with breast cancer during pregnancy.

Transplacental transfer of anthracyclines, vinblastine, and 4-hydroxy-cyclophosphamide in a baboon model.

OBJECTIVE: The paucity of data on the fetal effects of prenatal exposure to chemotherapy prompted us to study transplacental transport of chemotherapeutic agents. METHODS: Fluorouracil-epirubicin-cyclophosphamide (FEC) and doxorubicin-bleomycin-vinblastine-dacarbazine (ABVD) were administered to pregnant baboons. At predefined time points over the first 25 h after drug administration, fetal and maternal blood samples, amniotic fluid (AF), urine, fetal and maternal tissues, and cerebrospinal fluid (CSF) were collected. High-performance liquid chromatography (HPLC) and liquid chromatography-mass spectrometry (LC-MS) were used for bioanalysis of doxorubicin, epirubicin, vinblastine, and cyclophosphamide. RESULTS: In nine baboons, at a median gestational age of 139 days (range, 93-169), FEC 100% (n = 2), FEC 200% (n=1), ABVD 100% (n = 5), and ABVD 200% (n = 1) were administered. The obtained ratios of fetal/maternal drug concentration in the different simultaneously collected samples were used as a measure for transplacental transfer. Fetal plasma concentrations of doxorubicin and epirubicin averaged 7.5 ± 3.2% (n = 6) and 4.0 ± 1.6% (n = 8) of maternal concentrations, respectively. Fetal tissues contained 6.3 ± 7.9% and 8.7 ± 8.1% of maternal tissue concentrations for doxorubicin and epirubicin, respectively. Vinblastine concentrations in fetal plasma averaged 18.5 ± 15.5% (n=9) of maternal concentrations. Anthracyclines and vinblastine were neither detectable in maternal nor in fetal brain/CSF. 4-Hydroxy-cyclophosphamide concentrations in fetal plasma and CSF averaged 25.1 ± 6.3% (n = 3) and 63.0% (n = 1) of the maternal concentrations, respectively. CONCLUSION: This study shows limited fetal exposure after maternal administration of doxorubicin, epirubicin, vinblastine, and 4-hydroxy-cyclophosphamide.

CMV pneumonia in HIV-infected ventilated infants.

BACKGROUND: The contributing role of cytomegalovirus (CMV) in infants treated for Pneumocystis jiroveci pneumonia (PJP) is unknown. High dose steroids used in the treatment of PJP may further immunocompromise these infants contributing to the development of CMV pneumonia. AIM: The aim of this study was to determine the role of CMV pneumonia in infants being ventilated for suspected PJP. METHODS: In this prospective study HIV infected infants being treated with trimethoprim-sulfamethoxazole (TMP/SMX) and ventilated for suspected PJP were included if they had not responded to treatment. Open lung biopsy was performed if there was no improvement in ventilatory requirements. RESULTS: Twenty-five HIV positive infants with a mean age of 3.3 months were included. Lung biopsy was performed in 17 (68%) and post-mortem lung tissue was obtained in 8 (32%). After evaluation of the histology, immunohistochemistry, and viral cultures from lung tissue, the most likely causes of pneumonia were: CMV and PJP dual infection 36% (n = 9), CMV pneumonia 36% (n = 9), and PJP 24% (n = 6). The pp65 test for CMV antigen was falsely negative in 24%. The mean blood CD4 count was 287/microl. There was an association between the CD4 lymphocyte status and the final diagnosis, with the CMV and PJP group (CD4 110/microl) having the lowest CD4 status (P = 0.0128). Pediatric Intensive Care Unit (PICU) mortality was 72% (n = 18) and in hospital mortality 88%. CONCLUSION: Of the ventilated infants failing to respond to treatment, 72% had histologically confirmed CMV pneumonia, probably accounting for the high mortality in this cohort. The incidence of CMV disease in HIV infected infants being ventilated for severe pneumonia warrants that ganciclovir is used empirically until CMV disease is excluded. The role of lung biopsy in these circumstances needs to be researched.

Management of children with tuberculosis admitted to a pediatric intensive care unit.

OBJECTIVES: To review the incidence, clinical features, ventilatory support and outcome of children with tuberculosis (TB) admitted to a Pediatric Intensive Care Unit (PICU) in a region with an high incidence of TB. MATERIALS AND METHODS: The study was performed in a PICU situated in a province with a extremely high incidence of TB (> 700 new cases/ 100000/year). This is a retrospective descriptive study of TB admissions to the PICU in a 4-year period. Data regarding indications for admission, clinical picture, duration of ventilation, PICU and hospital stay were collected from patient files. Outcome measures included mortality and long term morbidity. RESULTS: Of the 1862 children admitted to the hospital for TB during the 4 years, 57 (3.1%) required PICU admission (1 to 6% of annual admissions). Of these 57 children 41 (72%) were admitted for respiratory failure. In 12 cases TB was the cause of the respiratory failure, 17 cases suffered from other respiratory diseases and in 12 cases the cause was nonrespiratory disease of which TB meningitis (n=8) was the most common. Mechanical ventilation was indicated in 43 (75%) patients who were ventilated for 7.3+/-11.5 days. The duration of PICU admission was 10.2+/-2.4 days whereas the duration of hospitalization was 70.3+/-148.9 days. The PICU mortality was 23% with TB meningitis having the highest mortality of 75%. CONCLUSIONS: In a region with a high incidence of TB, tuberculous patients constitute up to 6% of PICU admissions. A high degree of suspicion for the diagnosis is needed because in 30% of our cases the diagnosis was not initially considered.