Susannah E. Motl

Pharmacokinetic considerations in the treatment of CNS tumours.

Despite aggressive therapy, the majority of primary and metastatic brain tumour patients have a poor prognosis with brief survival periods. This is because of the different pharmacokinetic parameters of systemically administered chemotherapeutic agents between the brain and the rest of the body. Specifically, before systemically administered drugs can distribute into the CNS, they must cross two membrane barriers, the blood-brain barrier (BBB) and blood-cerebrospinal fluid (CSF) barrier (BCB). To some extent, these structures function to exclude xenobiotics, such as anticancer drugs, from the brain. An understanding of these unique barriers is essential to predict when and how systemically administered drugs will be transported to the brain. Specifically, factors such as physiological variables (e.g. blood flow), physicochemical properties of the drug (e.g. molecular weight), as well as influx and efflux transporter expression at the BBB and BCB (e.g. adenosine triphosphate-binding cassette transporters) determine what compounds reach the CNS. A large body of preclinical and clinical research exists regarding brain penetration of anticancer agents. In most cases, a surrogate endpoint (i.e. CSF to plasma area under the concentration-time curve [AUC] ratio) is used to describe how effectively agents can be transported into the CNS. Some agents, such as the topoisomerase I inhibitor, topotecan, have high CSF to plasma AUC ratios, making them valid therapeutic options for primary and metastatic brain tumours. In contrast, other agents like the oral tyrosine kinase inhibitor, imatinib, have a low CSF to plasma AUC ratio. Knowledge of these data can have important clinical implications. For example, it is now known that chronic myelogenous leukaemia patients treated with imatinib might need additional CNS prophylaxis. Since most anticancer agents have limited brain penetration, new pharmacological approaches are needed to enhance delivery into the brain. BBB disruption, regional administration of chemotherapy and transporter modulation are all currently being evaluated in an effort to improve therapeutic outcomes. Additionally, since many chemotherapeutic agents are metabolised by the cytochrome P450 3A enzyme system, minimising drug interactions by avoiding concomitant drug therapies that are also metabolised through this system may potentially enhance outcomes. Specifically, the use of non-enzyme-inducing antiepileptic drugs and curtailing nonessential corticosteroid use may have an impact.

Delayed-Onset Grade 4 Neutropenia Associated with Rituximab Therapy in a Patient with Lymphoma: Case Report and Literature Review

A 53‐year‐old man developed delayed‐onset neutropenia 6 weeks after completing first‐line therapy with rituximab, cyclophosphamide, mitoxantrone, vincristine, and prednisone for high‐grade B‐cell lymphoma. Bone marrow biopsy demonstrated hypercellular marrow with normal maturation. He also developed interstitial pneumonitis, an adverse event associated with rituximab use. Infiltrates of T cells were found in the patients lungs. For the next 6 months, the patient required subcutaneous granulocyte colony‐stimulating factor 300 μg twice/week to maintain a granulocyte count above 1000 cells/mm3. He also received oral antibiotics for mouth sores and thrush. Based on the existing evidence, monitoring blood counts for as long as 8 weeks after rituximab therapy may be advisable, although the literature reports that neutropenia can develop up to 1 year after treatment. The development of a registry and uniform testing may help uncover the cause of this delayed‐onset neutropenia.

Evaluation of Accuracy of Health Studies Reported in Mass Media

OBJECTIVE To evaluate communication of clinical research in the written media for completeness and accuracy. DESIGN Observational assessment. SETTING United States. PARTICIPANTS Not applicable. INTERVENTIONS Content of media articles discussing randomized controlled trials was assessed by three reviewers on the basis of the Consolidated Standards of Reporting Trials (CONSORT) criteria modified for the mass media. Reports from October 1 through December 31, 2002, published in the top two U.S. daily newspapers (USA Today and Wall Street Journal), weekly news magazines (Time and Newsweek), and daily news Web sources (CNN.com and MSNBC.com) and the corresponding published RCTs were analyzed. MAIN OUTCOME MEASURES Total score and score in 10 specific content areas, leading to classification of coverage as poor, fair, or excellent. RESULTS A total of 60 media reports discussing results of 25 RCTs appeared in these media during the study period. All reports were categorized as fair, and no content area was rated excellent. Several content areas received poor rankings in all and/or most media, including reporting of adverse effects, outcomes data, and statistical tests used. Media reports written by newswire services were rated more highly than were those prepared by nonnewswire services, but only 1 of 10 criteria had statistically significant differences. CONCLUSION Mass media reports of RCTs are often incomplete. This type of reporting may misinform the lay public and may lead to questions about the applicability of the results to individual patients.

Trastuzumab for the Treatment of Non—Small-Cell Lung Cancer:

OBJECTIVE: To evaluate trastuzumab for the treatment of advanced non—small-cell lung cancer (NSCLC). DATA SOURCES: Clinical literature was accessed through MEDLINE (1966–January 2003), EMBASE (1974–January 2003), International Pharmaceutical Abstracts (1970–January 2003), Proceedings of the American Society of Clinical Oncology (1995–January 2003), and Genentech. Key search terms included trastuzumab, lung cancer, Herceptin, and NSCLC. DATA SYNTHESIS: Research has revealed that NSCLC specimens may express the protein HER-2/neu. The monoclonal antibody against HER-2/neu, trastuzumab, could prove valuable for patients. An evaluation of the studies exploring trastuzumab for management of NSCLC was conducted. Phase II clinical trials reveal variable response rates from no improvement to a partial response rate of 42%. Due to a lack of clinical trials and deficiencies in the literature, the ultimate benefit of this agent remains to be proven. CONCLUSIONS: Clinical data from ongoing trials indicate potential synergy when trastuzumab is added to standard chemotherapy. The ultimate benefit in NSCLC remains to be proven.

Recurring Chemotherapy‐Associated Alopecia Areata: Case Report and Literature Review

A 52‐year‐old woman with stage IIIC ovarian cancer and stage IA uterine cancer experienced recurring alopecia areata of her eyebrows, eyelashes, arms, legs, and pubic area beginning 5 months after completing chemotherapy with paclitaxel and carboplatin. The condition recurred in a cyclic fashion over the ensuing months. Alopecia is a well‐recognized adverse event associated with chemotherapy; however, to our knowledge, this cyclic pattern of alopecia has not been reported in a patient with cancer. Our report of a cancer survivor who experienced cyclic alopecia areata indicates that this condition may be related to autoimmune changes instigated by chemotherapy. Oncology health care practitioners should evaluate unusual clinical cases of alopecia for underlying pathology.

Health Information Web Sites by Therapeutic Category for Healthcare Professionals

Objective: To compile and evaluate health information Web sites to aid healthcare professionals in locating information on select therapeutic categories. Data Sources: Therapeutic categories were chosen based on questions that pharmacists may receive in the community and institutional setting for which they might lack adequate resources to answer. Categories included adverse drug reactions, alternative medicine, cardiology, drug dosing in renal failure, drug interactions, foreign drug identification, geriatrics, immunology/vaccines, intravenous stability/compatibility, investigational drugs, oncology, pediatrics, pregnancy/lactation, legal and regulatory, monographs/medication usage evaluations, new drug approvals, shortages, tablet/capsule identification, therapy/therapeutics, and toxicology/poisoning. Web sites were chosen by searching www.google.com, as this search engine currently indexes over 3 billion Web pages. Data Synthesis: Resulting Web sites were reviewed, selected, and evaluated using published criteria to assess the quality of each Web site, focusing on the authorship, disclosure, currency, and content. Conclusions: The top Web sites in each category are presented, with details on their quality rating, sponsor, content, and special features or directions.