International Society of Oncology Pharmacy Practitioners (ISOPP) position statement: Role of the oncology pharmacy team in cancer care.

The Oncology Pharmacy Team (OPT), consisting of specialty-trained pharmacists and/or pharmacy technicians, is an integral component of the multidisciplinary healthcare team (MHT) involved with all aspects of cancer patient care. The OPT fosters quality patient care, safety, and local regulatory compliance. The International Society of Oncology Pharmacy Practitioners (ISOPP) developed this position statement to provide guidance on five key areas: 1) oncology pharmacy practice as a pharmacy specialty; 2) contributions to patient care; 3) oncology pharmacy practice management; 4) education and training; and 5) contributions to oncology research and quality initiatives to involve the OPT. This position statement advocates that: 1) the OPT be fully incorporated into the MHT to optimize patient care; 2) educational and healthcare institutions develop programs to continually educate OPT members; and 3) regulatory authorities develop certification programs to recognize the unique contributions of the OPT in cancer patient care.

Safety and efficacy of low-dose sirolimus in the PIK3CA-related overgrowth spectrum.

PURPOSE: PIK3CA-related overgrowth spectrum (PROS) encompasses a range of debilitating conditions defined by asymmetric overgrowth caused by mosaic activating PIK3CA variants. PIK3CA encodes the p110α catalytic subunit of phosphatidylinositol-3-kinase (PI3K), a critical transducer of growth factor signaling. As mTOR mediates the growth-promoting actions of PI3K, we hypothesized that the mTOR inhibitor sirolimus would slow pathological overgrowth. METHODS: Thirty-nine participants with PROS and progressive overgrowth were enrolled into open-label studies across three centers, and results were pooled. For the primary outcome, tissue volumes at affected and unaffected sites were measured by dual energy X-ray absorptiometry during 26 weeks of untreated run-in and 26 weeks of sirolimus therapy. RESULTS: Thirty participants completed the study. Sirolimus led to a change in mean percentage total tissue volume of -7.2% (SD 16.0, p = 0.04) at affected sites, but not at unaffected sites (+1.7%, SD 11.5, p = 0.48) (n = 23 evaluable). Twenty-eight of 39 (72%) participants had ≥1 adverse event related to sirolimus of which 37% were grade 3 or 4 in severity and 7/39 (18%) participants were withdrawn consequently. CONCLUSION: This study suggests that low-dose sirolimus can modestly reduce overgrowth, but cautions that the side-effect profile is significant, mandating individualized risk-benefit evaluations for sirolimus treatment in PROS.

Pharmacogenomics Implementation at the National Institutes of Health Clinical Center.

The National Institutes of Health Clinical Center (NIH CC) is the largest hospital in the United States devoted entirely to clinical research, with a highly diverse spectrum of patients. Patient safety and clinical quality are major goals of the hospital, and therapy is often complicated by multiple cotherapies and comorbidities. To this end, we implemented a pharmacogenomics program in 2 phases. In the first phase, we implemented genotyping for HLA-A and HLA-B gene variations with clinical decision support (CDS) for abacavir, carbamazepine, and allopurinol. In the second phase, we implemented genotyping for drug-metabolizing enzymes and transporters: SLCO1B1 for CDS of simvastatin and TPMT for CDS of mercaptopurine, azathioprine, and thioguanine. The purpose of this review is to describe the implementation process, which involves clinical, laboratory, informatics, and policy decisions pertinent to the NIH CC.

Stability of tacrolimus solutions in polyolefin containers.

PURPOSE: Results of a study to determine the stability of tacrolimus solutions stored in polyolefin containers under various temperature conditions are reported. METHODS: Triplicate solutions of tacrolimus (0.001, 0.01, and 0.1 mg/mL) in 0.9% sodium chloride injection or 5% dextrose injection were prepared in polyolefin containers. Some samples were stored at room temperature (20-25 °C); others were refrigerated (2-8 °C) for 20 hours and then stored at room temperature for up to 28 hours. The solutions were analyzed by stability-indicating high-performance liquid chromatography (HPLC) assay at specified time points over 48 hours. Solution pH was measured and containers were visually inspected at each time point. Stability was defined as retention of at least 90% of the initial tacrolimus concentration. RESULTS: All tested solutions retained over 90% of the initial tacrolimus concentration at all time points, with the exception of the 0.001-mg/mL solution prepared in 0.9% sodium chloride injection, which was deemed unstable beyond 24 hours. At all evaluated concentrations, mean solution pH values did not change significantly over 48 hours; no particle formation was detected. CONCLUSION: During storage in polyolefin bags at room temperature, a 0.001-mg/mL solution of tacrolimus was stable for 24 hours when prepared in 0.9% sodium chloride injection and for at least 48 hours when prepared in 5% dextrose injection. Solutions of 0.01 and 0.1 mg/mL prepared in either diluent were stable for at least 48 hours, and the 0.01-mg/mL tacrolimus solution was also found to be stable throughout a sequential temperature protocol.

Integrating pharmacogenetic information and clinical decision support into the electronic health record.

Pharmacogenetics (PG) examines gene variations for drug disposition, response, or toxicity. At the National Institutes of Health Clinical Center (NIH CC), a multidepartment Pharmacogenetics Testing Implementation Committee (PGTIC) was established to develop clinical decision support (CDS) algorithms for abacavir, carbamazepine, and allopurinol, medications for which human leukocyte antigen (HLA) variants predict severe hypersensitivity reactions. Providing PG CDS in the electronic health record (EHR) during order entry could prevent adverse drug events. Medical Logic Module (MLM) programming was used to implement PG CDS in our EHR. The MLM checks to see if an HLA sequence-based gene test is ordered. A message regarding test status (result present, absent, pending, or test not ordered) is displayed on the order form, and the MLM determines if the prescriber can place the order, place it but require an over-ride reason, or be blocked from placing the order. Since implementation, more than 725 medication orders have been placed for over 230 patients by 154 different prescribers for the three drugs included in our PG program. Prescribers commonly used an over-ride reason when placing the order mainly because patients had been receiving the drug without reaction before implementation of the CDS program. Successful incorporation of PG CDS into the NIH CC EHR required a coordinated, interdisciplinary effort to ensure smooth activation and a positive effect on patient care. Prescribers have adapted to using the CDS and have ordered PG testing as a direct result of the implementation.

Stability of alemtuzumab solutions at room temperature.

PURPOSE: The 24-hour stability of alemtuzumab solutions prepared at concentrations not included in the product label and stored in glass or polyolefin containers at room temperature was evaluated. METHODS: Triplicate solutions of alemtuzumab (6.67, 40, and 120 µg/mL) in 0.9% sodium chloride were prepared in either glass bottles or polyolefin containers and stored at room temperature under normal fluorescent lighting conditions. The solutions were analyzed by a validated stability-indicating high-performance liquid chromatography (HPLC) assay at time zero and 8, 14, and 24 hours after preparation; solution pH values were measured and the containers visually inspected at all time points. Stability was defined as the retention of ≥90% of the initial alemtuzumab concentration. RESULTS: HPLC analysis indicated that the percentage of the initial alemtuzumab concentration retained was >90% for all solutions evaluated, with no significant changes over the study period. The most dilute alemtuzumab solution (6.67 µg/mL) showed some degradation (91% of the initial concentration retained at hour 24), whereas the retained concentration was >99% for all other preparations throughout the study period. Solution pH values varied by drug concentration but did not change significantly over 24 hours. No evidence of particle formation was detected in any solution by visual inspection at any time during the study. CONCLUSION: Solutions of alemtuzumab 6.67 µg/mL stored in glass bottles and solutions of 40 and 120 µg/mL stored in polyolefin containers were stable for at least 24 hours at room temperature.

Improving adherence to research protocol drug exclusions using a clinical alerting system.

OBJECTIVE: To develop a general method for using the alerting function of an electronic health record (EHR) system to warn prescribers when a drug order may be in conflict with the restrictions of a patient's research protocol. METHODS: We examined a sample of clinical research protocols at the National Institutes of Health (NIH) to identify the frequency with which drugs were excluded by protocols. We analyzed two protocols and modeled the exclusions they contained. We then developed a data model to represent the exclusions, expanded the terminology in the NIH's Biomedical Translational Research Information System (BTRIS) to include relevant drug concepts, and wrote a medical logic module (MLM) for the EHR to match terms for ordered drugs with the drug concepts in the protocol. RESULTS: We found that 50% of protocols in our sample included drug exclusions. Our model represented exclusion concepts and also concepts related to exemptions from the exclusions. The MLM was deployed in a test environment where it successfully detected orders for excluded drugs and delivered messages to users explaining the exclusion, providing information about the clinical setting and timing where the exclusion applies. BTRIS reports using the same terminology information were able to identify instances where protocol exceptions occurred. CONCLUSIONS: Drug exclusions are frequent components of research protocols; nonadherenece to these exclusions could result in harm to subjects, erroneous study results or inefficiencies due to disqualification of research subjects. Our approach uses an MLM and a simple knowledge base, together with a controlled terminology, to provide a solution to the detection and prevention of possible protocol violations. Further work is needed to model additional aspects of the exclusions, such as timing and co-occurring conditions, to improve MLM accuracy.

The GYMSSA trial: a prospective randomized trial comparing gastrectomy, metastasectomy plus systemic therapy versus systemic therapy alone.

BACKGROUND: The standard of care for metastatic gastric cancer (MGC) is systemic chemotherapy which leads to a median survival of 6-15 months. Survival beyond 3 years is rare. For selected groups of patients with limited MGC, retrospective studies have shown improved overall survival following gastrectomy and metastasectomies including peritoneal stripping with continuous hyperthermic peritoneal perfusion (CHPP), liver resection, and pulmonary resection. Median survival after liver resection for MGC is up to 34 months, with a five year survival rate of 24.5%. Similarly, reported median survival after pulmonary resection of MGC is 21 months with long term survival of greater than 5 years a possibility. Several case reports and small studies have documented evidence of long-term survival in select individuals who undergo CHPP for MGC. DESIGN: The GYMSSA trial is a prospective randomized trial for patients with MGC. It is designed to compare two therapeutic approaches: gastrectomy with metastasectomy plus systemic chemotherapy (GYMS) versus systemic chemotherapy alone (SA). Systemic therapy will be composed of the FOLFOXIRI regimen. The aim of the study is to evaluate overall survival and potential selection criteria to determine those patients who may benefit from surgery plus systemic therapy. The study will be conducted by the Surgery Branch at the National Cancer Institute (NCI), National Institutes of Health (NIH) in Bethesda, Maryland. Surgeries and followup will be done at the NCI, and chemotherapy will be given by either the local oncologist or the medical oncology branch at NCI. TRIAL REGISTRATION: ClinicalTrials.gov ID. NCT00941655.

Sorafenib and sunitinib: novel targeted therapies for renal cell cancer.

Renal cell cancer (RCC) is a relatively uncommon malignancy, with 51,190 cases expected to be diagnosed in 2007. Localized disease is curable by surgery; however, locally advanced or metastatic disease is not curable in most cases and, until recently, had a limited response to drug treatment. Historically, biologic response modifiers or immunomodulating agents were tested in clinical trials based on observations that some cases of RCC can spontaneously regress. High-dose aldesleukin is approved by the United States Food and Drug Administration as a treatment for advanced RCC; however, the drug is associated with a high frequency of severe adverse effects. Responses have been observed with low-dose aldesleukin and interferon alfa, but with little effect on overall survival. Sorafenib and sunitinib are novel therapies that target growth factor receptors known to be activated by the hypoxia-inducible factor and the Ras-Raf/MEK/ERK pathways. These pathways are important in the pathophysiology of RCC. Sorafenib and sunitinib have shown antitumor activity as first- and second-line therapy in patients with cytokine-refractory metastatic RCC who have clear-cell histology. Although complete responses are not common, both drugs promote disease stabilization and increase progression-free survival. This information suggests that disease stabilization may be an important determinant for response in RCC and possibly other cancers. Sorafenib and sunitinib are generally well tolerated and are considered first- and second-line treatment options for patients with advanced clear cell RCC. In addition, sorafenib and sunitinib have shown promising results in initial clinical trials evaluating antitumor activity in patients who are refractory to other antiangiogenic therapy. The most common toxicities with both sorafenib and sunitinib are hand-foot syndrome, rash, fatigue, hypertension, and diarrhea. Research is directed toward defining the optimal use of these new agents.

Chemotherapy dose density in early-stage breast cancer and non-Hodgkin's lymphoma.

Delivering standard-dose chemotherapy on schedule is important for survival in early-stage breast cancer and non-Hodgkin's lymphoma. Trials of dose-escalated regimens, in which higher-than-standard doses of chemotherapy are used, have produced equivocal results. In contrast, dose-dense regimens, in which standard doses are given with shorter (usually 14-day) intervals between cycles, have been more efficacious than standard 21-day regimens in trials in both early-stage breast cancer and non-Hodgkin's lymphoma. Furthermore, a shorter course of chemotherapy is likely to cause less disruption in patients' lives. Despite the evidence of the importance of maintaining chemotherapy dose intensity (the amount of drug administered/unit of time), undertreatment of patients with early-stage breast cancer and non-Hodgkin's lymphoma is common. Neutropenia is the primary dose-limiting toxicity of many chemotherapy regimens, and it is frequently managed by dose reductions and delays that decrease dose intensity. Colony-stimulating factors reduce the prevalence and severity of neutropenia and its complications, and their proactive use can improve adherence to the planned schedule of both standard-dose and dose-dense chemotherapy The promising results with dose-dense chemotherapy in early-stage breast cancer and non-Hodgkin's lymphoma indicate that it should be tested in patients with other chemosensitive tumors.