Comparison of renal toxicities with LY231514 600mg/m² versus 500mg/m² in the treatment of stage III or -IV cervical cancer
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Cervical cancer is the most common cancer diagnosed in females in South Africa and constitutes 16.47% of all cancers registered. LY231514, a new multi-targeted antifolate, is a potent in vitro inhibitor of thyrnidylate synthase (TS), dihydrofolate reductase (DHFR) and glycinamide ribonucleotide formyl transferase (GARFT). Anti tumour activity has also been seen in vivo and preliminary results from Phase I1 clinical trials suggest that the drug has activity against a range of solid tumours. In this thesis, data from study H3E-MC-JMAM, sponsored by Eli Lilly & Company, was analysed and conclusions made upon results obtained. Twenty-four patients with advanced carcinoma of the cervix were treated with 600mg/m2 LY231514, and eleven patients with 500mg/m2. Patients who were entered into the study had advanced squamous cell carcinoma Stage 111 or -1V disease. The patients receiving 500mg/rn2 LY231514 were also given oral folic acid (5mg) supplementation for 2 days prior to treatment, on the day of treatment and also daily thereafter for 2 days. LY231514 was given as a 10-minute infusion every 21 days. A patient's treatment could be delayed or reduced according to the Common Toxicity Criteria results from the previous cycle. Twelve patients (50%) on the 600mg/m2 regime were withdrawn from the study due to decreased creatinine clearance thus preventing further administration of the drug. In an attempt to reduce the incidence of renal toxicity, but without compromising response, the dosage of LY231514 was reduced to 500mg/m2. On this new regime, only one patient out of 11 (9%) had to be discontinued from study due to a decreased creatinine clearance. The initiative to do an analysis between the two specific patient treatment groups came to me as a result of my involvement as clinical research associate in study H3E-MC-JMAM sponsored by Eli Lilly & Company. This study was conducted to evaluate difference in response between the two treatment groups, as well as to establish a safe dosage regime. During this study I made the observation that certain patients developed a decrease in their creatinine clearance mostly during the second and third treatment cycle. I came to the conclusion that LY231514 had an influence on the renal function of the patient as observed by an extended increase in their creatinine clearance and subsequent removal from study as study drug had to be withheld for an extended period of time. Patients thus could not receive optimal treatment for their disease as 90% of LY231514 is excreted via the kidneys and decreased renal function increased the risk of toxic accumulation of the drug. I decided to investigate the possible factors responsible for the decrease in renal function while placing special emphasis on the differences seen between the 500mg/m2 and 600mg/m2 treatment groups. Another motivational factor to do this analysis was the fact that this phenomenon were not seen in other studies conducted with LY231514, definitely not in such a way that patients had to be discontinued from study due to renal toxicity. Patients enrolled into study H3E-MC-JMAM signed an Informed Consent Document (Attachment I) before any study procedures were carried out. Eli Lilly & Company gave me permission (Attachment 11) to use the patient data to perform the analysis for this thesis. The two investigator sites participating in this study included Groote Schuur Hospital in Cape Town and National Hospital in Bloemfontein. At the time of submission, the study used for the data analysis in this thesis, study H3E-MC-JMAM sponsored by Eli Lilly and Company, had ongoing patients. Eli Lilly and Company will release their final study results after all patients have been discontinued and the final statistical analysis report has been generated.
- Health Sciences