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Antineoplastic Agents↗
Biomedical subjects
Jim Cassidy
Publications and source records attributed to Jim Cassidy.
Effect of renal impairment on the pharmacokinetics and tolerability of capecitabine (Xeloda) in cancer patients.
PURPOSE: The primary objective of this study was to investigate the influence of renal impairment on the pharmacokinetics of capecitabine and its metabolites in cancer patients. Capecitabine (Xeloda) is an orally administered precursor of 5'-deoxy-5-fluorouridine (5'-DFUR), which is preferentially activated to 5-fluorouracil (5-FU) in tumors. METHODS: A total of 27 patients were enrolled, of whom 24 were evaluable for pharmacokinetics (6 with normal renal function, 8 with mild, 6 with moderate, and 4 with severe renal impairment at baseline). Patients received capecitabine orally at the standard dosing regimen (1250 mg/m(2) capecitabine twice daily for 2 weeks followed by a 1-week rest period). On study days 1 and 14, blood samples were collected to evaluate the pharmacokinetics of capecitabine and its metabolites. The relationship between the area under the plasma concentration-time curve (AUC) and creatinine clearance (CL(CR)) was assessed by log-linear regression analysis. RESULTS: The primary pharmacokinetic parameter with respect to the effect of renal dysfunction was systemic exposure to 5'-DFUR, 5-FU and FBAL determined on study day 14. Renal impairment led to an increase in the systemic exposure to 5'-DFUR and FBAL (23% and 109% increase in AUC, respectively) for a 50% reduction in CL(CR). By contrast, renal impairment may lead to decreased exposure to 5'-DFCR. There was no evidence for an effect of renal impairment on systemic exposure to 5-FU or capecitabine. Renal impairment did not have a major effect on peak concentration (C(max)) or elimination half-life (t(1/2)) of capecitabine, 5'-DFCR, 5'-DFUR, and 5-FU. However, in the case of FBAL, moderate or severe renal impairment caused up to a twofold increase in C(max) and prolongation of t(1/2). All patients with severe renal impairment (four patients) had drug-related grade 3 or 4 adverse-events (AEs) and serious AEs. Patients with moderate renal impairment experienced a similar number of grade 3 or 4 AEs (six of nine patients) but had a higher incidence of serious AEs (three of nine patients) when compared with those with normal renal function (four of six patients and one of six patients, respectively). A similar effect was seen in patients with mild renal dysfunction (grade 3 or 4 AEs in four of eight patients; serious AEs in three of eight patients). The relationship between systemic exposure to capecitabine or its metabolites and safety was investigated using logistic regression. This exploratory analysis showed a strong positive relationship between AUC of 5'-DFUR and treatment-related grade 3 or 4 AEs, whereas there was no relationship with exposure to capecitabine, 5'-DFCR, 5-FU or FBAL. CONCLUSIONS: Renal impairment has no effect on the pharmacokinetics of capecitabine or 5-FU, but leads to an increase in the systemic exposure to 5'-DFUR and FBAL. However, only the AUC of 5'-DFUR is correlated with safety. Based on the safety results in patients with severe renal impairment, a dose modification cannot be recommended for these patients and they should not be treated with capecitabine. Additional data from the clinical safety database and pharmacokinetic results from the present study support the recommendation that patients with moderate renal impairment should be treated with 75% of the recommended standard starting dose to achieve systemic exposure comparable to that in patients with normal renal function.
Antimetabolites, Antineoplastic↗
Analysis of key cell-cycle checkpoint proteins in colorectal tumours.
Aberrations in the components of cell-cycle checkpoints are a common feature of many tumours and several have been shown to have prognostic significance in colorectal cancer. In this study, seven components of cell-cycle control [cyclin D1, retinoblastoma (pRb), p21, p27, p16, p53, and proliferating cell nuclear antigen (PCNA)] were examined in a large series of well-characterized colorectal adenocarcinomas using immunohistochemistry to ascertain co-regulation and influence on survival. The majority (92%) of the tumours had abnormal staining of > or =2 cell-cycle control factors. Expression of cyclin D1 protein was correlated with both p21 (p<0.001) and p27 (p=0.033), suggesting co-regulation of these proteins in colorectal tumours. Only cyclin D1 (p=0.048) and p53 (p=0.025) were directly associated with PCNA levels, suggesting a more important role in the proliferative capacity of tumour cells. Significant associations between cell cycle-related proteins and clinicopathological data were observed: cyclin D1 and p53 proteins were correlated with patient age (p=0.042 and p<0.001, respectively) and p53 (p=0.01) and p21 (p=0.024) proteins were associated with tumour site. Expression of cyclin D1 protein was the only protein examined that was related to improved outcome in these patients (p=0.0266), but it was not an independent predictor of survival. These results suggest that loss of control of cell-cycle checkpoints is a common occurrence in colorectal tumours and may be an important therapeutic target.
Adenocarcinoma↗
Oxaliplatin-related side effects: characteristics and management.
Oxaliplatin is the only third-generation platinum derivative to have found a place in routine cancer therapy. It is particularly useful therapy for advanced colorectal cancer and has shown scheduling flexibility in combination with 5-fluorouracil/folinic acid. Oxaliplatin has a unique pattern of side effects unrelated to those observed with other therapeutic platinum derivatives. During the course of oxaliplatin clinical trials, the adverse events most often cited were hematologic toxicity, gastrointestinal tract toxicity, and a neurolopathy unlike that observed with other platinum derivatives. Grade 3/4 neutropenia occurred in 41.7% of patients in the phase III clinical trial that used the FOLFOX-4 regimen, and thrombocytopenia is a rare event sometimes observed after multiple cycles of therapy. Nausea and vomiting is usually mild to moderate and readily controlled with standard antiemetics. Grade 1/2 diarrhea may occur but studies have shown that 5-fluorouracil contributes significantly more to gastrointestinal toxicity than does single-agent oxaliplatin. Nephrotoxicity has not been reported in any of the oxaliplatin trials, allowing administration of oxaliplatin without hydration. Oxaliplatin-induced neurotoxicity consists of a rapid-onset acute sensory neuropathy and a late-onset cumulative sensory neuropathy that occurs after several cycles of therapy. In about three fourths of patients, neurotoxicity is reversible with a median time to recovery of 13 weeks after treatment discontinuation. To date, oxaliplatin has proven to be a safe and effective therapy for colorectal cancer and side effects have been easy to manage with appropriate awareness from patients and care providers.
Antineoplastic Agents↗
Striking the right balance in colorectal cancer care--a qualitative study of rural and urban patients.
BACKGROUND: Colorectal cancer is the second most common cause of cancer-related death in Scotland. For patients, the journey from diagnosis through treatment is complex and there are inequalities in survival rates. OBJECTIVES: The aim of the present study was to explore how patients with colorectal cancer perceive their care. METHODS: This was a qualitative study involving 95 patients and relatives of patients with colorectal cancer in the North, Northeast and Northern Isles, Scotland. Focus groups (32 participants) were conducted in hospital, and interviews (63 participants) in patients' own homes in order to explore their experiences of health services for cancer-what was good, what was bad and what was needed. Analysis was inductive, with exploration of similar and divergent perspectives within themes. RESULTS: Patients wanted rapid diagnosis, specialist treatment and good communication, but their experiences of and perspectives on these areas were often divergent. Delays in diagnosis could stem from late presentation by patients, but also from early presentation when the cancer could go undetected. GP continuity was desirable, but sometimes implicated in delays. Patients preferred their GPs to be advocates, not gatekeepers. The context, however, was one where some patients pursued their care tenaciously while others did not. For some, speed of progress through the system was everything, but others found this could be impersonal. Outlying patients had to balance transport difficulties with the benefits of distant specialist treatment. Some patients wanted full information to be provided directly, but others could not cope with this. CONCLUSIONS: From patients' perspectives, ideal cancer care cannot be achieved in a uniform way. For some of the key goals of cancer treatment to be met, including rapid access to specialist treatment for all and good communication of bad news and test results, a balance must be struck which tailors care to individuals.
Adult↗