1 Cancer Research UK, Department of Medical Oncology, Beatson Oncology Centre, Western Infirmary, Glasgow; 2 Royal Marsden NHS Trust, Gastrointestinal Unit, London and Surrey; 3 Bristol-Myers Squibb Oncology, London, UK 4 University of Leeds and Tom Connors Cancer Research Centre, University of Bradford, Bradford, UK
Received 4 November 2002; revised 24 March 2003; accepted 15 April 2003
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Abstract |
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The aim of this study was to determine the maximum tolerated dose (MTD), toxicity profile and response rate of the oral 5-fluorouracil prodrug UFT (tegafur/uracil) and leucovorin (LV) in combination with irinotecan in patients with advanced or metastatic colorectal cancer.
Patients and methods:
Patients with histologically proven advanced or metastatic colorectal adenocarcinoma received first-line chemotherapy comprising UFT 250 mg/m2/day and LV 90 mg/day given on days 1 to 14, with escalating doses of irinotecan (200300 mg/m2) administered intravenously on day 1 of a three-weekly cycle. Eligibility criteria were standard. The MTD was defined as the dose at which >33% of six patients experienced a dose-limiting toxicity (DLT) during cycle 1.
Results:
A total of 32 patients were studied. Initially, six patients were treated at each of the irinotecan dose levels (200, 250 and 300 mg/m2) combined with UFT 250 mg/m2/day and LV 90 mg/day. DLTs consisting of grade 3 or 4 diarrhoea and febrile neutropenia were observed in one of 20 patients at 250 mg/m2 and three of six patients at the 300 mg/m2 irinotecan dose level. Having defined the MTD, the 250 mg/m2 dose level was established as the recommended dose (RD) and expanded to 20 patients in whom treatment was generally well tolerated. The overall response rate was 19%, with five patients having a partial response (PR) and 18 stable disease (SD) out of 32 response-evaluable patients.
Conclusion:
UFT and LV can be safely combined with irinotecan. The RDs for future studies are UFT 250 mg/m2/day and LV 90 mg/day given on days 114, with irinotecan 250 mg/m2 administered on day 1, every 3 weeks. This combination is well tolerated and active. Further investigation of UFT and LV in combination with irinotecan is warranted in patients with colorectal cancer.
Key words: chemotherapy, colorectal cancer, irinotecan, leucovorin, tegafur/uracil
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Introduction |
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The fluoropyrimidine 5-fluorouracil (5-FU) has remained the mainstay of treatment for advanced and metastatic colorectal cancer over the last 40 years, prolonging survival by 6 months [1]. 5-FU has poor oral bioavailability and its use has been limited by the need to administer it as a prolonged infusion for optimal activity [2]. The addition of leucovorin (LV) to 5-FU schedules results in prolonged inhibition of thymidylate synthase and significantly improves tumour response rates when compared with 5-FU administered alone [3].
Given the limitations of intravenous 5-FU, there has recently been a move to develop effective and well tolerated oral fluoropyrimidines. UFT is a combination of tegafur [1-(2-tetrahydrofuryl)-5-fluorouracil], an oral precursor of 5-FU, and uracil [a reversible dihydropyrimidine dehydrogenase (DPD) inhibitor] in a 1:4 molar ratio. The addition of uracil results in tumour selective, prolonged 5-FU activity by preventing its rapid breakdown [46]. Following phase I studies, a phase II trial evaluated UFT 300350 mg/m2/day in combination with LV 150 mg/m2/day given for 4 weeks with a 1 week rest, reporting an objective response rate of 42% [7]. Two large randomised phase III trials compared UFT (300 mg/m2/day)/LV with bolus 5-FU/LV. In the first trial, 816 patients received either UFT/LV or bolus 5-FU/LV administered on a 4-weekly cycle (Mayo Clinic regimen) [8]. Response rates were equivalent (11.7% and 14.5%, respectively), as was median survival (12.4 and 13.4 months, respectively). UFT/LV was, however, associated with a lower incidence of leukopenia and thrombocytopenia than the Mayo Clinic regimen, and a lower incidence of infection (P <0.05). In addition, stomatitis and mucositis were significantly less common than with the Mayo Clinic regimen (P <0.0001). The second study accrued 380 patients with metastatic colorectal cancer and compared UFT/LV with a modified Mayo Clinic regimen (bolus 5-FU/LV administered on days 15 every 5 weeks rather than every 4 weeks) [9]. The response rates, time to progression (TTP) and median survival were comparable in the two treatment arms, and the safety profile was similar to that observed in the trial described above. These studies suggest that the more convenient oral combination of UFT/LV has similar efficacy and is better tolerated than the intravenous Mayo Clinic bolus 5-FU and LV regimen in the treatment of metastatic colorectal carcinoma.
The topoisomerase I inhibitor irinotecan is active as a single agent against metastatic colorectal cancer as first-line [10, 11] or second-line treatment after failure of 5-FU [12, 13]. In randomised trials of patients with 5-FU-resistant disease, irinotecan significantly prolonged survival compared with best supportive care or infusional 5-FU [13, 14]. Furthermore, two large randomised phase III trials have demonstrated that first line treatment with irinotecan in combination with 5-FU and LV produces better tumour response rates and patient survival when compared with 5-FU and LV alone [15, 16]. Current studies are evaluating the role of 5-FU/ LV in combination with irinotecan in the adjuvant setting.
The convenient oral route of administration, antitumour activity and improved toxicity profile in comparison with intravenous 5-FU make UFT/LV an attractive option for combining with intravenous irinotecan in the treatment of advanced colorectal cancer. This current study was designed to explore the feasibility of combining UFT with oral LV and irinotecan in patients with advanced or metastatic colorectal cancer, and to determine the response rate. We selected a 3-weekly irinotecan schedule as this is widely used in single-agent regimens. We wished then to incorporate UFT/LV, avoiding the shorter schedules that are associated primarily with neutropenia and the longer schedules with which diarrhoea is common. Accordingly, we selected 2 weeks on with a 1-week rest period, and repeated both irinotecan and UFT/LV every 3 weeks.
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Patients and methods |
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All patients entered into this study had histologically or cytologically confirmed advanced or metastatic colorectal adenocarcinoma. Eligibility criteria included life expectancy 12 weeks, Eastern Cooperative Oncology Group (ECOG) performance status
2, and adequate haematological (absolute neutrophil count
2 x 109/l, platelets
100 x 109/l), hepatic (bilirubin
1.5 x upper limit of normal) and renal (serum creatinine
1.5 x upper limit of normal) function, with at least one measurable site of disease (
1 cm in at least one dimension). Patients could not have received prior chemotherapy, except adjuvant chemotherapy completed >6 months before study entry, and had disease for which treatment with fluoropyrimidines or topoisomerase I inhibitors was appropriate. Written informed consent was obtained from all patients.
Patients were excluded from the study if they had bowel obstruction, any condition that might effect absorption of UFT or LV, had received prior radiotherapy (except palliative radiotherapy for control of locally symptomatic disease and adjuvant therapy for rectal carcinoma), experienced life-threatening toxicities as result of fluoropyrimidine, required therapy with a halogenated antiviral agent or who had a history of ulcerative colitis or Crohns disease.
Treatment
Irinotecan was administered as an intravenous infusion over 90 min on day 1 of each 21-day cycle. UFT and LV were administered orally on days 114. Initially, the dose of UFT/LV was fixed at 250 mg/m2 and LV 90 mg on days 114, with irinotecan escalated from 200 to 250 then 300 mg/m2. If this proved tolerable, UFT was to be escalated further to 300 then 350 mg/m2/day.
Patients received up to a maximum of six treatment cycles. Six patients were initially entered in each cohort and the drug doses were escalated in the trial according to the schema in Table 1. The dose of UFT was calculated depending on body surface area and the total daily dose rounded to the nearest 100 mg. The daily dose of UFT and LV was divided by three and administered at 8-h intervals, either 1 h before or at least 1 h after food. Prophylactic anti-emetics were allowed according to local practice.
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Evaluation of toxicity and tumour response
Pretreatment evaluation included a complete history and clinical examination, full blood count, biochemical profile, urinalysis and electrocardiogram. In addition, a chest X-ray and/or computed tomography scan of the abdomen and other sites of disease was performed before starting chemotherapy. During therapy, patients had a weekly toxicity assessment, full blood count and biochemical profile. Physical examination and World Health Organization (WHO) performance status were recorded before each cycle (or more frequently if clinically indicated). Tumour assessments were performed after three and six cycles of therapy . Response was determined according to WHO criteria [17]. All responses were to be documented with a repeat evaluation after >4 weeks.
Dose delays and modifications
Dose delays and modifications were performed on the basis of toxicity. Dose reductions applied only to UFT and irinotecan, whereas the dose of LV was not modified. On day 1 of each cycle, treatment with all three agents was delayed for 1 week if drug-related toxicity had not resolved to grade 1 (except alopecia); if toxicity did not resolve after a delay of 2 weeks, treatment was discontinued. Following grade 3 or 4 haematological toxicity, both the irinotecan and UFT doses were reduced by 50 mg/m2/day on subsequent treatment cycles. Grade 4 neutropenia that exceeded 7 days or was associated with fever requiring hospitalisation resulted in the patient being discontinued from the study. In the event of grade 3 or 4 non-haematological toxicity (excluding alopecia, nausea and vomiting) on days 114 of any cycle, UFT/LV was withheld until the toxicity had returned to grade 1 or baseline; doses of both irinotecan and UFT were reduced by 50 mg/m2/day on subsequent cycles. In the event of grade 2 or higher diarrhoea or stomatitis on days 114, treatment was withheld until toxicities returned to baseline or grade 1 (except alopecia). If diarrhoea recurred, treatment was discontinued for that cycle.
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Results |
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Toxicity
All patients were evaluable for toxicity. The most common toxicities were nausea, fatigue, diarrhoea, leukopenia, anaemia and neutropenia. Grade 2 alopecia was reported in 20 patients and three patients experienced grade 2 stomatitis. No patients experienced grade >2 derangement in liver transaminases. Six patients had elevated bilirubin and two had elevated alkaline phosphatase (Table 3). All grade 34 toxicities are summarised in Table 3. During dose escalation, one patient in cohort 2 experienced a DLT (grade 4 diarrhoea), as did three in cohort 3 (grade 3 diarrhoea, grade 3 febrile neutropenia, and grade 4 febrile neutropenia with grade 3 thrombocytopenia and epistaxis, respectively). UFT 250 mg/m2/day, irinotecan 300 mg/m2 and LV 90 mg/day were therefore defined as the MTDs.
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There were a total of seven dose reductions at the RD, with four patients requiring one dose reduction (three grade 34 neutropenias and one grade 3 diarrhoea) and one patient requiring three dose reductions (twice for neutropenia and once for grade 3 diarrhoea). There was a total of five delayed cycles of treatment at the RD, two for 1 week due to toxicity (chest infection, weakness and diarrhoea) and one for 2 weeks (weakness). A further patient continued UFT/LV beyond day 14 without adverse events, but the physician elected to delay the subsequent cycle by 1 week. The other delays were due to public holidays.
Antitumour activity
As per the protocol, patients who received at least two cycles of treatment were evaluable for response. In addition, patients who developed rapid tumour progression or died of progressive disease before response evaluation were considered evaluable for response. The overall response rate was 19% (one complete response, five partial responses), with 18 patients (56%) having stable disease (SD) and five (15%) progressive disease on treatment (Table 4).
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Discussion |
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Current chemotherapeutic options for the treatment of patients with advanced colorectal cancer are unsatisfactory. Whilst 5-FU alone remains an important part of patient management, the addition of newer agents has resulted in improvements in response rates and overall survival. The combination of 5-FU with irinotecan leads to higher response rates, and a significant improvement in TTP and overall survival, than with either drug used alone [15, 16]. In a large multicentre randomised trial of 683 patients, weekly bolus 5-FU with LV and irinotecan for 4 out of every 6 weeks had a significantly higher objective response rate than irinotecan alone or 5-FU/LV administered according to the Mayo regimen (39%, 18% and 21%, respectively; P <0.001). Furthermore, there was a significant increase in both TTP (median 7 months; P = 0.004) and overall survival (median 14.8 months; P = 0.04) with the combination [16]. There was a higher incidence of grade 3 or 4 diarrhoea (22.7%) than with the Mayo Clinic regimen (13.2%), but this was less than with irinotecan administered alone (31%). This regimen has subsequently been adopted, but recently doubts have been raised about its safety, with an unexpectedly high toxic death rate in two separate cooperative group trials sponsored by the NCI [18, 19]. The incidence of severe or life-threatening diarrhoea and neutropenia has been reported to be lower with infused 5-FU [20]. In a randomised phase III trial comparing irinotecan with infusional 5-FU, the incidence of grade 34 diarrhoea was reported to be 22% in the irinotecan arm [21]. A second large randomised study has compared infusional 5-FU/LV and irinotecan with infusional 5 FU/LV alone [15]. Again the response rate, TTP and overall survival were significantly improved by the combination of 5-FU, LV and irinotecan. The incidence of grade 34 neutropenia was lower than that reported in the bolus study (29% and 54%, respectively), but the incidence of grade 34 diarrhoea was higher with infusional 5 FU/LV and irinotecan (44%).
Oral fluoropyrimidines such as UFT/LV offer similar efficacy to bolus 5-FU, with an improved safety profile. In addition, oral administration offers the obvious advantage of convenience for patients and is likely to be associated with pharmacoeconomic benefits [22]. Combining UFT with oral LV and intravenous irinotecan is, therefore, an attractive option, which has the potential to minimise side effects and maximise patient convenience. In this study the MTD was 300 mg/m2 of irinotecan in combination with UFT 250 mg/m2/day and LV 90 mg/day. This is consistent with toxicity studies of 3-weekly irinotecan in combination with infusional 5-FU regimens [23]. The recommended phase II dose of UFT 250 mg/m2/day and LV 90 mg/day on days 114 with irinotecan 250 mg/m2 was expanded to confirm the response rate (20%), TTP (median 6 months; 95% CI 4.16.6) and overall survival (median 16.5 months; 95% CI 11.518.2). Although the response rate is rather lower than reported with the combination of 5-FU and irinotecan, TTP and overall survival were comparable. The toxicity profile of the current regimen is also favourable. The most frequent toxicities were grade 34 diarrhoea occurring in three patients (15%), nausea in two (10%), fatigue in five (25%) and neutropenia in seven (35%) at the RD. In addition, only one patient experienced significant (grade 2) stomatitis.
This study demonstrates that UFT/LV and irinotecan can be combined safely and establishes a recommended dose for further study of UFT 250 mg/m2/day, LV 90 mg/day days 114 and irinotecan 250 mg/m2 on day 1, with treatment repeated every 3 weeks. Furthermore, the combination is active with a 20% response rate. The toxicity profile and the oral administration of UFT and LV make this regimen worthy of further investigation.
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Footnotes |
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References |
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