Oral Anticancer Therapy: Management of Drug Interactions.

Oral anticancer therapy is increasingly integrated into the care of patients with cancer. Recognition and management of drug-drug interactions (DDIs) is critical to providing efficacious and safe anticancer treatment. DDIs with QTc-prolonging agents, anticoagulants, enzyme inducers and inhibitors, antidepressants, and acid suppressants are commonly encountered with anticancer therapies. Here, we review frequently observed DDIs and outline literature-supported suggestions for their management.

Regulation of carboxylesterase-2 expression by p53 family proteins and enhanced anti-cancer activities among 5-fluorouracil, irinotecan and doxazolidine prodrug.

BACKGROUND AND PURPOSE: For four decades, 5-fluorouracil (5-FU) has been a major anti-cancer medicine. This drug is increasingly used with other anti-cancer agents such as irinotecan. Irinotecan and many others such as PPD (pentyl carbamate of p-aminobenzyl carbamate of doxazolidine) require activation by carboxylesterase-2 (CES2). 5-FU, on the other hand, reportedly induces CES2 in colorectal tumour lines. The aims of this study were to determine the molecular basis for the induction and to ascertain interactive cell-killing activity between 5-FU and ester prodrugs. EXPERIMENTAL APPROACH: Colorectal and non-colorectal lines and xenografts were treated with 5-FU and the expression of CES2 was determined. Cell-killing activity of irinotecan and PPD were determined in the presence or absence of CES2 inhibitor. Several molecular experiments were used to determine the molecular basis for the induction. KEY RESULTS: Without exceptions, robust induction was detected in cell lines expressing functional p53. High-level induction was also detected in xenografts. 5-FU pretreatment significantly increased cell-killing activity of irinotecan and PPD. Molecular experiments established that the induction was achieved by both transactivation and increased mRNA stability through p53. Either p63 or p73, functionally related to p53, did not support the transactivation. CONCLUSIONS AND IMPLICATIONS: The results in this study suggest that FOLFIRI, a common regimen combining irinotecan and 5-FU, should switch the dosing sequence, namely from 5-FU to irinotecan, to enhance hydrolytic activation of irinotecan. This modified order likely reduces the dose of anti-cancer agents, thus minimizing overall toxicity. The results also conclude that p53 family members act differently in regulating gene expression.

Improving pharmacist knowledge of oral chemotherapy in the community.

BACKGROUND: Approximately 10% of chemotherapy agents are administered orally, with anticipated annual growth of this practice. In the future, community pharmacy practitioners will potentially serve a larger role in the management of patients with cancer. OBJECTIVE: To improve pharmacist confidence, knowledge of oral chemotherapy agents, and dispensing behaviors through live continuing pharmacy education (CPE) programs. METHODS: A prospective cohort study of pharmacists attending live CPE programs in Rhode Island and Maine was conducted between March and May 2010. A survey was administered before and after the educational program; primary outcome measures included change in level of pharmacist confidence in oral chemotherapy knowledge, overall knowledge, and willingness to adjust behavior when dispensing oral chemotherapy agents in community pharmacy. RESULTS: Two hundred fifty-seven of the 410 pharmacists in attendance participated in the survey. Pharmacists significantly improved in confidence level, from no confidence to some confidence (p < 0.001). Counseling the family on the safe handling of oral chemotherapy increased from 37.1% pre-CPE program to 100% post-CPE program. Following the CPE program, behaviors such as (1) using a separate counting tray, (2) wearing gloves, and (3) requiring a double-check improved from 22.5%, 31.5%, and 29.4% baseline to 92.0%, 81.3%, and 81.8%, respectively. All responses to knowledge-based questions improved significantly. CONCLUSIONS: A live CPE program on oral chemotherapy designed to improve pharmacist confidence and knowledge, as well as inform about behaviors, is an effective method. Additional education to improve the knowledge of community-based practitioners to safely dispense and properly counsel patients receiving oral chemotherapy is required.

Fanconi's syndrome and nephrogenic diabetes insipidus in an adult treated with ifosfamide.

Fanconi's syndrome is a serious condition characterized by type II proximal renal tubular dysfunction, with urinary loss of glucose, amino acids, phosphate, bicarbonate, and potassium. Ifosfamide-induced Fanconi's syndrome is reported in about 1.4-5% of children being treated for solid tumors, yet only a few cases have been reported in adults. We describe a 54-year-old man who came to the hospital with symptoms of neutropenic fever 4 days after his fourth cycle of ifosfamide and doxorubicin treatment for recurrent sarcoma with metastases to the lung. During admission, he was noted to have severe renal tubular dysfunction; ifosfamide-induced nephrogenic diabetes insipidus and Fanconi's syndrome were suspected. He received supportive therapy that resulted in incomplete resolution of signs and symptoms. The patient was discharged after a 5-day hospital stay when his white blood cell count increased from 0.1-2.5 × 10(3) /mm(3) and his fever had resolved. Use of the Naranjo adverse drug reaction probability scale indicated a probable relationship (score of 7) between the patient's development of diabetes insipidus and Fanconi's syndrome and his use of ifosfamide. This dual diagnosis of diabetes insipidus and Fanconi's syndrome in an adult makes this case unusual, as well as therapeutically challenging. We conducted a review of the existing literature regarding ifosfamide-induced Fanconi's syndrome and describe the proposed mechanisms and therapeutic options. This case suggests that patients treated with ifosfamide should be monitored closely for renal function to identify, and perhaps prevent, these rare adverse events. Preliminary animal models show promise for adding N-acetylcysteine to ifosfamide treatment, but more research is necessary before using this drug as a therapeutic option.

Treating hypertension in the very elderly.

OBJECTIVE: To review the evidence for strict blood pressure (BP) management in the very elderly, defined as patients aged 80 years and older. DATA SOURCES: A literature search was performed using PubMed (1950 through November 2010) for the MeSH terms hypertension and elderly; subterms of identified MeSH terms (ie, explosion) for the elderly were also searched. A broader search was conducted of PubMed articles published in the past 4 years. Searches were conducted for additional primary literature referenced in identified articles; an updated Cochrane Database review was also performed. STUDY SELECTION AND DATA EXTRACTION: All identified studies that specifically included very elderly patients and BP were reviewed. DATA SYNTHESIS: The BP goal established in the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) is less than 140/90 mm Hg, regardless of age, unless a compelling indication exists. Although evidence suggests that lowering BP will lower the risk of stroke, lower BP in the very elderly may result in higher mortality. Many physicians are reluctant to treat BP in accordance with the JNC 7 goal in very elderly patients for a variety of reasons, including concerns about fall risk, lack of benefit in mortality reduction, and concerns about drug interactions and adverse effects. Results from a randomized controlled trial and meta-analysis have demonstrated reductions in stroke, heart failure, and cardiovascular events in the very elderly. The American College of Cardiology Foundation/American Heart Association recently published guidelines for elderly patients that suggest treating the very elderly carefully and with different BP goals than previously recommended. CONCLUSIONS: Optimal management of hypertension in the very elderly remains a concern. Few studies have evaluated hypertension in this population, and studies that included patients over 80 enrolled too few to draw conclusions. Although the HYVET (Hypertension in the Very Elderly Trial) study did have adequate power to evaluate the very elderly, because this study was stopped early because of significant findings in mortality, unanswered questions remain regarding optimal BP targets.

Efaproxiral: a radiation enhancer used in brain metastases from breast cancer.

OBJECTIVE: To review the mechanism of action and clinical data of efaproxiral use in brain metastases of breast cancer. DATA SOURCES: Articles were identified through MEDLINE (1966-June 2005) and EMBASE (1980-May 2005) searches using the key words efaproxiral and RSR13. Published abstracts over the previous 10 years from various scientific meetings, including American Society of Clinical Oncology and San Antonio Breast Cancer Symposium, were also searched for investigations of efaproxiral. Data on efaproxiral were also provided by Allos Therapeutics. STUDY SELECTION AND DATA EXTRACTION: All published clinical data in humans regarding efaproxiral use in brain metastases from breast cancer were selected for this review. In addition, published studies in humans that discussed the pharmacokinetics, pharmacodynamics, and safety of efaproxiral were evaluated. DATA SYNTHESIS: Efaproxiral is a synthetic allosteric modifier of hemoglobin that results in a shift of the hemoglobin oxygen dissociation curve to the right. Therefore, oxygen is more readily released from hemoglobin into tissues. Efaproxiral demonstrated a significant survival benefit when used as a radiation enhancer in patients with brain metastases originating from breast cancer. The safety profile of efaproxiral and improved survival rates make this agent advantageous over radiation alone. Further investigation and results from the ongoing clinical trials will help to define the role of efaproxiral in clinical practice. CONCLUSIONS: Efaproxiral is the first synthetic allosteric modifier to demonstrate significant improvement in survival in patients undergoing radiation therapy for brain metastases of breast cancer. Validation of this effect in ongoing clinical trials will be important in determining the role of efaproxiral in brain metastases from breast cancer.