Alexandre Chan

Clinical practice guidelines for the prevention and treatment of EGFR inhibitor-associated dermatologic toxicities

BackgroundEpidermal growth factor receptor inhibitors (EGFRI) produce various dermatologic side effects in the majority of patients, and guidelines are crucial for the prevention and treatment of these untoward events. The purpose of this panel was to develop evidence-based recommendations for EGFRI-associated dermatologic toxicities.MethodsA multinational, interdisciplinary panel of experts in supportive care in cancer reviewed pertinent studies using established criteria in order to develop first-generation recommendations for EGFRI-associated dermatologic toxicities.ResultsProphylactic and reactive recommendations for papulopustular (acneiform) rash, hair changes, radiation dermatitis, pruritus, mucositis, xerosis/fissures, and paronychia are presented, as well as general dermatologic recommendations when possible.ConclusionPrevention and management of EGFRI-related dermatologic toxicities is critical to maintain patients’ health-related quality of life and dose intensity of antineoplastic regimens. More rigorous investigation of these toxicities is warranted to improve preventive and treatment strategies.

Drug interactions between chemotherapeutic regimens and antiepileptics

BACKGROUND Drug-drug interactions (DDIs) are commonly seen in daily clinical practice, particularly in the treatment of patients with cancer. Seizures are often seen in patients with brain tumors and brain metastases, in whom antiepileptic drugs (AEDs) are often indicated. The risk for DDIs between anticancer drugs and AEDs is high. OBJECTIVE This review aimed to investigate the types of interactions that are observed between the AEDs and the most commonly prescribed chemotherapeutic regimens. The risk for DDIs is discussed with regard to tumor type. METHODS Data on DDIs between anticancer drugs and AEDs were compiled from the British National Formulary, Drug Information Handbook, and Micromedex Healthcare Series version 5.1. Product information of the individual drugs, as well as literature on anticancer drug-AED interactions, was searched using PubMed (years: December 1970 to January 2008; search terms: anticancer, antiepileptic, chemotherapy regimen, drug interactions, and the generic names of the individual anticancer drugs and AEDs [acetazolamide, carbamazepine, ethosuximide, felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, phenobarbital, phenytoin, primidone, tiagabine, topiramate, valproic acid, vigabatrin, and zonisamide]). RESULTS Our search identified clinically important DDIs observed with single-agent and combination regimens used for the treatment of breast cancers, colorectal cancers, lung cancers, lymphomas, and renal cell carcinomas. Carbamazepine, phenytoin, phenobarbital, and primidone were found to have prominent cytochrome P450 (CYP) enzyme-induction effects, while valproic acid had an inhibitory effect. The isozymes of major relevance to anticancer drug-AED interactions included CYP3A4, CYP2C9, and CYP2C19. Induction or inhibition of these isozymes by AEDs can cause a decrease or increase in anticancer drug concentrations. Similarly, enzyme inhibition or induction by anticancer drugs can lead to toxicity or loss of seizure control. CONCLUSIONS In this review of anticancer drug-AED DDIs, carbamazepine, phenytoin, phenobarbital, primidone, and valproic acid were found to interact the most frequently with anticancer drugs. Based on the results of this review, clinicians should be vigilant when AEDs are prescribed concurrently with anticancer drugs. DDIs can be avoided or minimized by selecting alternative AEDs that are less likely to interact. However, if potentially interacting drug combinations must be used for treatment, serum drug concentrations should be closely monitored to avoid toxicity in the patient, as well as to ensure adequate chemotherapeutic and antiepileptic coverage.

Polypharmacy in elderly patients with cancer: clinical implications and management

More and more elderly people with cancer are treated in oncology clinics worldwide every year, many of whom have comorbid disorders treated with one or more drugs. Moreover, these patients might also take self-prescribed over-the-counter drugs or complementary and alternative medicines, which they might not tell their doctor about. Initiation of chemotherapy with one or more cytotoxic or targeted agents and drugs for treatment of cancer symptoms or toxic effects related to treatment can result in polypharmacy. We examine the clinical implications of polypharmacy. Challenges for the medical teams who treat elderly patients with cancer include identification of what drugs are actually being taken by the patient, avoidance or management of any adverse effects or drug interactions, and reassessing the patients overall treatment. We address these issues and propose practical recommendations for management of treatment for elderly patients with cancer.

Clinically Significant Drug–Drug Interactions Between Oral Anticancer Agents and Nonanticancer Agents: Profiling and Comparison of Two Drug Compendia

Background: Use of oral anticancer agents is gaining wide acceptance in the treatment of cancer. However, patients receiving oral therapy are at high risk for drug–drug interactions (DDIs). Objective: To create a drug profile for each clinically significant DDI involving selected oral anticancer agents and evaluate the agreement between 2 commonly used DDI compendia: Drug Interaction Facts (DIF) 2008 and Micromedex DRUGDEX. Methods: DDI profiles were developed based on primary and tertiary literature reviews. DIF 2008 and Micromedex DRUGDEX were compared to assess the consistency of listings, severity, and scientific evidence ratings of DDIs involving the oral anticancer agents that were selected. The Spearman correlation test was used to assess the correlation of the severity ratings between the 2 compendia. Results: A total of 184 DDIs were identified. A DDI profile was created for 40 of these that met the predetermined criteria for clinically significant interactions. The comparative assessment showed inconsistency in DDI listings (15.2% of those identified were listed in DIF only and 46.7% were listed in Micromedex only), severity ratings (Spearman correlation coefficient 0.49), and scientific evidence ratings (disagreement 25.8%). Conclusions: The discrepancies in DDI listing and rating systems between the compendia evaluated here reflect the need for more studies to standardize the definitions and classifications of DDIs.

Complementary and alternative medicine (CAM) usage in Singaporean adult cancer patients

BACKGROUND In multiracial and multicultural Singapore, patients are exposed to complementary and alternative medicine (CAM) from both eastern and western cultures. Although studies have shown that CAM usage is highly prevalent among cancer patients, no study on the prevalence of CAM in Singaporean adult cancer patients had been published. PATIENTS AND METHODS 403 adult cancer patients treated at the Ambulatory Treatment Unit of National Cancer Centre Singapore completed an interviewer-administered questionnaire. RESULTS Median age of patients was 56 years old (range 22-84). Fifty-six percent of patients reported CAM usage and the most commonly used CAM include Traditional Chinese Medicine, birds nest and special diet. CAM use was found to be associated with race, education level and prior CAM use before cancer diagnosis. Fifty-four percent of respondents informed their oncologists regarding CAM usage and 66.4% of oncologists were agreeable for CAM usage. However, most patients (63%) did not verify information on CAM before usage and a majority of patients taking CAM felt it was effective. CONCLUSION Majority of adult cancer patients used CAM and it is important for health-care professionals to keep abreast of research on CAM, to actively illicit information regarding usage and to provide appropriate advice and counseling.

Risk of tyrosine kinase inhibitors-induced hepatotoxicity in cancer patients: A meta-analysis

INTRODUCTION Although existing evidence from clinical trials has demonstrated manifestation of hepatic adverse events (AEs) with the use of tyrosine kinase inhibitors (TKIs), overall risks have yet to be reported. Thus we conducted a meta-analysis to determine the risk of hepatotoxicity associated with the use of TKIs, by comparing the occurrence of hepatotoxicity of the TKI arms against that of comparison arms. METHODS A comprehensive literature search of randomized control trials involving TKIs was performed. Only randomized, double-blind and placebo-controlled phase 2 or phase 3 human trials were included. The included studies must involve the comparison of a TKI against placebo, or the comparison of TKI with chemotherapy agent against placebo with the same chemotherapy agent. RESULTS Twelve articles were included in the analysis. There was a significant overall increase in the odds of developing high-grade (grade 3 or above) hepatotoxicity with the use of TKIs compared to the control arms (Pooled OR 4.35, 95% CI 2.96-6.39). The odds of developing all-types all-grades (Pooled OR 2.42, 95% CI 1.52-3.85) and high-grade hepatotoxicity due to elevation in alanine transaminase (Pooled OR 5.22, 95% CI 2.88-9.46), aspartate transaminase (Pooled OR 6.15, 95% CI 3.09-12.25) and total bilirubin (Pooled OR 1.76, 95% CI 0.59-5.24) was higher with the use of TKI than compared to the controls. DISCUSSION This is the first meta-analysis to demonstrate a significantly increased risk of hepatic AEs associated with TKIs use. Clinicians should be aware of this risk and provide close monitoring in patients receiving these therapies.

Clinical Predictors of Chemotherapy-Induced Nausea and Vomiting in Breast Cancer Patients Receiving Adjuvant Doxorubicin and Cyclophosphamide

Background: Patients with breast cancer often receive emetogenic anthracycline–based chemotherapy as part of their treatment. Chemotherapy-induced nausea and vomiting (CINV) has been commonly reported as one of the distressing adverse effects among patients with cancer. Despite the advent of newer antiemetics and better understanding of the CINV pathophysiology, total eradication of CINV has yet to be achieved. Objective: To assess the incidence of nausea and vomiting in patients who have breast cancer and are receiving adjuvant doxorubicin and cyclophosphamide (AC) bolus chemotherapy, ascertain patients’ risk factors affecting CINV response, and study patient adherence to delayed antiemetics. Methods: This was a single-institution, prospective, observational study conducted at an outpatient cancer center in Singapore from December 2006 to December 2007. Clinical events such as CINV were collated using a standardized diary. Use of rescue antiemetics and unscheduled clinic visits due to CINV were documented. Results: Of a total of 108 participants, 16 patients were lost to follow-up and 1 provided incomplete information; thus, 91 patients were included in the analysis. Delayed antiemetics were given according to the institutions guideline and only 9 (9.9%) patients received aprepitant. Neither acute nor delayed vomiting was reported by a majority of patients and only 4 (4.4%) experienced grade 3 vomiting. The incidence of severe nausea was highest on day 3 of chemotherapy and affected 14.3% of patients. Anxiety and history of chemotherapy-induced nausea were associated with both acute and delayed nausea, and history of motion sickness was associated with delayed vomiting. Approximately 65% of patients were adherent to their prescribed delayed antiemetics. Conclusions: Most of our patients adhered to their antiemetics and tolerated AC chemotherapy reasonably well, without vomiting; yet nausea persisted. To improve CINV control, clinicians must actively communicate with patients to facilitate accurate assessment of risk factors and CINV response and to encourage adherence to delayed antiemetics.

Association of proinflammatory cytokines and chemotherapy-associated cognitive impairment in breast cancer patients: a multi-centered, prospective, cohort study

This is one of the largest multicentered, cohort studies conducted to evaluate the proinflammatory biomarkers associated with cognitive impairment in breast cancer patients. While elevated interleukin (IL)-6 and IL-1β were observed in patients with poorer response speed performance and perceived cognitive disturbances, IL-4 may be protective against chemotherapy-associated cognitive impairment.

Clinically significant drug—drug interactions between oral anticancer agents and nonanticancer agents: A delphi survey of oncology pharmacists

BACKGROUND Drug-drug interactions (DDIs) can lead to adverse clinical outcomes, particularly in oncology, because of the narrow therapeutic index of chemotherapeutic agents and because patients with cancer are at a high risk due to polypharmacy and age-related organ dysfunction. In a previously published study, drug profiles were developed based on primary and tertiary literature reviews for a list of clinically significant DDIs involving 28 oral anticancer agents (OAAs). OBJECTIVE This study was based on a Delphi survey of oncology pharmacists; the survey results were used to develop a consensus list of clinically significant DDIs involving OAAs and nonanticancer agents. METHODS In this study, the DDI profiles previously developed were updated, and the DDI pairs that were listed both in the 2009 Drug Interaction Facts (DIF) and the Thomson Micromedex DrugDex System compendia and that also met the predetermined criteria for clinical significance were selected for further evaluation. In a 2-round, electronically administered Delphi survey of oncology pharmacists, a 5-point Likert scale (1-5, where 1 = strongly agree and 5 = strongly disagree) was used to evaluate the DDI pairs based on 8 clinical aspects (clinical importance; irreversible morbidity and mortality; quality of data; quantity of data; patients organ functions; comorbid conditions; awareness of interaction; and management burden). International pharmacists who specialized in oncology pharmacy practice and had > or =5 years of practice experience were eligible to participate. RESULTS Nine of the 23 surveyed pharmacists responded, giving a response rate of 39.1%. A total of 37 DDI pairs were selected from DIF and DrugDex and evaluated by the survey respondents, resulting in the identification, via consensus, of 12 clinically significant DDI pairs. The clinical aspects with the most DDIs that reached consensus of agreement were clinical importance (82.9%) and awareness of interaction (73.2%). CONCLUSION An expert panel identified 12 clinically significant DDIs involving OAAs.

Evidence-Based Treatment Options for the Management of Skin Toxicities Associated with Epidermal Growth Factor Receptor Inhibitors

Objective: To compile evidence from randomized controlled trials, case series, and case reports to identify the effectiveness of various therapeutic agents for the treatment and prevention of dermatologie effects secondary to epidermal growth factor receptor inhibitor (EGFRI) administration. Data Sources: Literature was accessed through PubMed (2002–May 2009) and Scopus (2002–March 2009), using the terms epidermal growth factor receptor inhibitor, cetuximab, erlotinib, gefilinib, panitumumab, management, skin toxicity, and cutaneous effects. In addition, reference citations from publications identified were reviewed. Study Selection and Data Extraction: An evaluation of published clinical trials, case series, case reports, and clinical management guidelines that studied the treatment options for EGFRI-induced skin toxicities was performed. Studies that reported dosing regimens and treatment outcomes were included in this review. Data Synthesis: Management of EGFRI-induced skin toxicities has been documented in 2 randomized controlled trials, 3 case series, and 10 case reports in a total of 156 patients. There is strong evidence for the use of topical antibiotics to manage EGFRI skin toxicities. Controversy exists regarding the use of corticosteroids and retinoids for the management of EGFRI-induced rash. Several variables are noted among the number of case series and case reports, such as follow-up duration of the intervention, making any comparisons difficult. Conclusions: Overall, antibiotics are the most common treatment option and have the potential to reduce the severity of skin rash. Well-designed clinical studies with proper recording of relevant data on the management of EGFRI-induced dermatologie effects are needed to properly evaluate the use of various therapeutic agents. Apart from randomized controlled trials, comprehensive case reports are also important for clinical evaluation on a case-by-case basis.