Assessment of ifosfamide pharmacokinetics, toxicity, and relation to CYP3A4 activity as measured by the erythromycin breath test in patients with sarcoma

BACKGROUND: Ifosfamide is a chemotherapeutic agent that requires cytochrome P450 3A (CYP3A) for bioactivation and metabolism. To the authors' knowledge, the correlation between dose, pharmacokinetics, CYP3A, and toxicity has not been fully evaluated. A randomized Phase II trial was performed on 22 soft tissue sarcoma patients treated with doxorubicin (60 mg/m(2)/cycle) and either high-dose ifosfamide (12 g/m(2)/cycle) or standard-dose ifosfamide (6 g/m(2)/cycle). The pharmacokinetics of ifosfamide and CYP3A measurements observed are reported. METHODS: Pharmacokinetic parameters for ifosfamide, 2-dichloroethylifosfamide (2-DCE), and 3-dichloroethylifosfamide (3-DCE) were collected after the first ifosfamide infusion in 13 patients. Bayesian designed limited pharmacokinetic data were collected from an additional 41 patients. The erythromycin breath test (ERMBT) was performed on 81 patients as an in vivo phenotypic assessment of CYP3A activity. RESULTS: Fourteen-hour (peak) plasma levels of ifosfamide, 2-DCE, and 3-DCE were found to correlate strongly with the respective area under the curve (AUC) 0-24 values (r=0.97, 0.94, and 0.95; P<.0001). Patients who experienced a grade 3-4 absolute neutrophil count (ANC), platelet, or creatinine toxicity (using the National Cancer Institute Common Toxicity Criteria [version 2]) were found to have statistically significantly higher median 14-hour plasma levels of ifosfamide, 2-DCE, and 3-DCE compared with patients with grade 0-2 toxicity. ERMBT was not found to correlate with pharmacokinetic parameters of ifosfamide and metabolites or toxicity. CONCLUSIONS: The 14-hour plasma level of ifosfamide, 2-DCE, and 3-DCE is a simple and appropriate substitute for describing the AUC of ifosfamide after 1 day of a 1-hour to 2-hour infusion of drug. Fourteen-hour plasma levels of ifosfamide and metabolites are useful predictors of neutropenia, thrombocytopenia, and creatinine toxicity. ERMBT was not found to accurately correlate with ifosfamide pharmacokinetics or clinical toxicity.     

Active surveillance for favorable risk prostate cancer: rationale, risks, and results

Active surveillance for favorable risk prostate cancer has become increasingly popular in populations where prostate cancer screening is widespread, due to evidence that prostate cancer screening results in the detection of disease that is not clinically significant in many patients (i.e., untreated, would not pose a threat to health). This approach is supported by data demonstrating that patients who fall into the category of clinically insignificant disease can be identified with reasonable accuracy, and that patients who are initially classified as low risk who reclassify over time as higher risk and are then treated more aggressively are in most cases still cured. An active surveillance approach means (1) identifying patients who have a low likelihood of disease progression during their lifetime, based on clinical and pathologic features of the disease and patient age and comorbidity; (2) monitoring closely over time, (3) establishing reasonable criteria for intervention, which will both identify more aggressive disease in a timely fashion, and not result in excessive treatment, and (4) meeting the communication challenge to reduce the psychological burden of living with untreated cancer. The results of active surveillance, the criteria for patient selection, and the appropriate triggers for intervention are reviewed.     

Perceptions in 7700 patients with rheumatoid arthritis compared to their families and physicians

ObjectiveTo compare perceptions of patients with rheumatoid arthritis (RA) to those of their families and usual physicians regarding pain and subjective experience of the disease.MethodsQuestionnaires were mailed to patients listed in the files of a non-profit patient organization (Association Française des Polyarthritiques). Each patient, one family member (or close friend), and the usual physician were each asked to complete a questionnaire. Concordance among replies made by patients, family/friends, and physicians was evaluated using the kappa coefficient.ResultsQuestionnaires were sent to 20,468 patients, among whom 7702 (38%) mailed back adequate data. The family member was usually the spouse (70%) and the usual physician a rheumatologist (68%). Joint pain was described by patients as variable (80%) and unpredictable (68%). Patients reported a need to push themselves (86%), frustration (86%), anxiety about possible disease progression (89%), and being prevented from making plans for the future (6%). A negative impact was reported on recreational activities (84%), work (56%), and family life and sexuality (51%). Concordance was excellent for pain severity (kappa > 0.90) and good for the main joint-pain characteristics and experience of the disease (kappa > 0.70), although family members tended to overestimate, and physicians to underestimate, the intensity of the pain.ConclusionWe found good overall agreement between perceptions of patients, their families, and their physicians, despite differences between these last two groups. Our qualitative analysis showed not only a major physical impact of the disease, but also marked negative psychosocial effects.