1 Department of Medical Oncology, Guys Hospital, London; 2 Glaxo Wellcome Research and Development, Greenford, Middlesex, UK,
Received 19 August 2002; revised 8 January 2003; accepted 22 January 2003
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Abstract |
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Oral eniluracil/5-fluorouracil (5-FU) was shown in early clinical studies to have promising activity against gastrointestinal malignancies. Oxaliplatin in combination with 5-FU also has activity against these tumour types. The primary objective of this study was to determine a tolerable dose for oral eniluracil/5-FU in combination with oxaliplatin.
Patients and methods:
Twenty-three patients with advanced gastrointestinal malignancies were recruited into this open-label study. Patients received a fixed dose of oxaliplatin (130 mg/m2 on the first day of a 21-day cycle), and the dose intensity of oral eniluracil/5-FU was gradually increased by escalating the number of days of treatment per course.
Results:
The maximum tolerated dose intensity was eniluracil/5-FU 10.0/1.0 mg/m2 twice daily for 16 days in combination with oxaliplatin 130 mg/m2 on the first day of a 21-day cycle. Dose-limiting toxicities included vomiting and diarrhoea. The objective tumour response rate was 26% with a median duration of response of 15.3 weeks (95% confidence interval 8.522.1). Twenty-two patients (96%) experienced neurotoxicity (sensory neuropathy or cold-related dysaesthesia), although only two events were severe (grade 3).
Conclusions:
The recommended dose for future study in patients with advanced gastrointestinal cancer is 10.0/1.0 mg/m2 oral eniluracil/5-FU twice daily for 14 days in combination with oxaliplatin 130 mg/m2 on the first day of each treatment cycle.
Key words: eniluracil, 5-fluorouracil, gastrointestinal cancer, maximum tolerated dose intensity, oxaliplatin
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Introduction |
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Eniluracil is an effective inactivator of dihydropyrimidine dehydrogenase, the first enzyme in the catabolism of 5-fluorouracil (5-FU) [2]. Eniluracil enables low oral doses of 5-FU to be administered, resulting in predictable plasma concentrations comparable with those reported for continuous intravenous infusion of 5-FU [3, 4]. Oral eniluracil/5-FU was shown in early clinical studies to have encouraging efficacy against colorectal and pancreatic cancer [5, 6]. Oxaliplatin is a third-generation cisplatin analogue with demonstrated activity in a wide variety of tumour types. Oxaliplatin in combination with 5-FU has significant activity against advanced colorectal cancer [7] as well as in metastatic gastric cancer [8]. Cisplatin in combination with infusional 5-FU has demonstrated efficacy against pancreatic cancer [9, 10]. Therefore, it was hypothesised that a combination of oral eniluracil/5-FU and oxaliplatin would have activity in the treatment of patients with advanced gastrointestinal cancer.
The primary objective of this study was to determine a tolerable dose for oral eniluracil/5-FU in a 21-day cycle in combination with oxaliplatin in patients with advanced gastrointestinal cancer. Secondary objectives were to estimate the objective tumour response rate, the durations of response and of progression-free survival, and to evaluate the toxicity profile of this regimen.
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Patients and methods |
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Study design
The study protocol was approved by the Guys Hospital Ethics Committee and the study was conducted according to the Declaration of Helsinki. This was an open-label, cohort-design, single-centre study of escalating doses of oral eniluracil/5-FU in combination with a fixed dose and regimen of oxaliplatin (130 mg/m2 on the first day of every 21 days) (supplied by Sanofi Synthelabo). The dose intensity of eniluracil/5-FU was gradually increased by cohort depending on the toxicities observed. Each treatment course was repeated every 21 days. Treatment continued up to a maximum of eight cycles, or until disease progression or unmanageable toxicity. Patients were recruited in cohorts of three. A cohort was expanded to six if dose-limiting toxicity was observed. If no dose-limiting toxicity was observed when three patients had completed two courses, enrolment into the next cohort was started. The maximum tolerated dose intensity (MTDI) was defined as the highest daily dose (given for two courses) at which at least two out of six patients experienced dose-limiting toxicity. Patients who did not complete the first two cycles of treatment were not evaluable for the determination of MTDI.
Dose-limiting toxicity was defined as any of the following: grade ≥3 mucositis; grade 3 palmarplantar erythrodysaesthesia; grade 3/4 other non-haematological toxicity; grade 4 haematological toxicity; unresolved non-haematological toxicity that resulted in a delay of the subsequent course of chemotherapy >7 days; haematological toxicity that resulted in a delay of the subsequent course of chemotherapy >7 days. Toxicity was graded using criteria adapted from the South West Oncology Group (SWOG) [11].
Patients were assessed at regular intervals by clinical, laboratory and radiological methods to determine their tumour response, as well as the durations of response, survival, and progression-free survival. The tumour response criteria and definitions of measurable, evaluable and non-evaluable disease were adapted from those established by the SWOG [11]. Patients who had a complete response or a partial response had a confirmatory disease assessment at least 4 weeks later. Time-to-event parameters were analysed using KaplanMeier product limit estimates. Safety assessments included monitoring adverse events, clinical chemistry and haematology parameters.
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Results |
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The dose-limiting toxicities seen in each cohort of patients are shown in Table 1. Based on early toxicity from the first cohort (eniluracil/5-FU 11.5/1.15 mg/m2 twice daily), the dose of eniluracil/5-FU was reduced to 10.0/1.0 mg/m2 twice daily. The highest dose intensity studied was eniluracil/5-FU 10.0/1.0 mg/m2 for 16 days in a 21-day cycle. One patient in this cohort died of disease progression after only one cycle, and another was considered non-compliant as he took only 50% of his tablets (not due to toxicity). Consequently, there was only one evaluable patient in this cohort. This patient experienced such severe gastrointestinal toxicity that it was not considered justified to expand the cohort to replace the two unevaluable patients. Therefore, the MTDI for this study was eniluracil/5-FU 10.0/1.0 mg/m2 twice daily for 16 days in combination with oxaliplatin 130 mg/m2 on the first day of a 21-day cycle.
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Discussion |
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Eniluracil/5-FU has been studied in two large randomised phase III studies for the first-line treatment of patients with advanced colorectal cancer, comparing eniluracil/5-FU (11.5 mg/m2/1.15 mg/m2 twice daily for 28 days every 35 days) with intravenous 5-FU/leucovorin [14, 15]. In the European study [14], response rates were similar across both treatment arms, although the 5-FU/leucovorin arm was associated with an improved survival benefit. However, compliance with the oral eniluracil/5-FU regimen and the unusually high median survival associated with the intravenous 5-FU/leucovorin control arm may have been confounding factors. In the USA study [15], both treatment arms were similar in terms of response rates and overall survival. These results limit the opportunity to develop eniluracil/5-FU in patients with advanced colorectal cancer.
In the current study we showed that the MTDI was eniluracil/5-FU 10.0/1.0 mg/m2 twice daily for 16 days in combination with oxaliplatin 130 mg/m2 on the first day of a 21-day cycle. The recommended dose of eniluracil/5-FU with oxaliplatin in patients with advanced gastrointestinal malignancy is therefore 14 days at the same doses.
The regimen of oral eniluracil/5-FU used in this study in combination with a recommended dose of oxaliplatin demonstrated anti-tumour activity in a heavily pre-treated group of patients with colorectal and gastro-oesophageal malignancy.
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Acknowledgements |
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Footnotes |
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References |
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