1Abteilung für Onkologie, Hämatologie, Immunologie und Rheumatologie, Universitätsklinikum Tübingen, Tübingen; 2Asklepios Fachkliniken München-Gauting, Gauting; 3Johannes Gutenberg Universität Mainz, Mainz; 4St Johannes Hospital, Duisburg, Germany
Received 6 August 2001; revised 13 November 2001; accepted 5 December 2001.
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Abstract |
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Ftorafur is an orally available prodrug of 5-fluorouracil (5-FU). Its combination with uracil in a molar ratio of 1:4 (UFT) increases the 5-FU concentration in tumor cells compared with ftorafur alone. Paclitaxel has a broad spectrum of activity against solid tumors and synergic effects with UFT have been demonstrated in vitro. A phase I study was performed to determine the maximum tolerated dose of the combination of UFT and paclitaxel in patients with advanced solid tumors.
Study design
UFT and folinic acid were applied at 300 mg/m2/day and 90 mg/day, respectively, on days 128, repeated on day 36. Paclitaxel was applied on days 1, 8, 15 and 22 of each cycle. The starting dose of paclitaxel was 50 mg/m2 and escalation in 10 mg/m2 steps was performed up to 100 mg/m2 weekly.
Results
Forty-seven consecutive patients with various solid tumors have been included in six different dose levels. One hundred and thirty cycles have been applied. The treatment was well tolerated overall. Most frequently encountered adverse effects were gastrointestinal and hematological toxicity (diarrhea CTC 3/4 in 6% of patients, anemia in 11%, leukocytopenia in 9%, polyneuropathy in 9%, fatigue in 11%, other in 6%). Partial remissions were observed in 28% of patients.
Conclusion
Owing to the lack of overlapping toxicities, UFT/folinic acid plus paclitaxel can be combined at doses of proven single agent activity. Side effects are mainly attributable to the gastrointestinal toxicity of UFT and to the neuro- and hematotoxicity of paclitaxel. The recommended doses for phase II studies are 300 mg/m2 of UFT plus 90 mg of folinic acid on days 128, and 90 mg/m2 of paclitaxel weekly.
Key words: dose escalation, paclitaxel, phase I/II, phase I study, solid tumors, UFT
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Introduction |
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Paclitaxel functions as a microtubule stabilizer and has a broad spectrum of activity against different solid tumors [2022]. Studies have documented that paclitaxel can be safely applied as a 1-h infusion [23]. This weekly schedule is associated with very limited hematological toxicity but an increased incidence of peripheral neuropathy [24]. In addition to a potential synergic effect when combining paclitaxel and UFT, the toxicity profiles of both drugs hardly overlap. We therefore initiated a phase I study combining UFT at a fixed dose with escalating doses of paclitaxel given weekly.
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Patients and methods |
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Pre-treatment evaluation included a complete medical history and physical examination, basic laboratory evaluation, and staging of the underlying malignancy with either ultrasound, chest radiograph or computed tomography (CT) scan. Both cytostatic agents were supplied by Bristol-Myers-Squibb, Munich, Germany.
The paclitaxel dose was escalated in 10 mg/m2 steps, starting with a dose of 50 mg/m2 at dose level 1. No intra-individual dose escalation was performed. Paclitaxel was applied as a 1-h infusion after adequate pre-medication with dexamethasone and anti-histamines weekly for 4 weeks. Both, UFT and folinic acid were given at fixed doses of 300 mg/m2/day and 90 mg/day, respectively. UFT and folinic acid were orally given on days 128, divided into three doses per day. Patients were asked not to take food for 1 h before and after each dose. The 28 days of treatment were followed by a 1 week rest. In case of CTC grade 3 granulocytopenia or thrombocytopenia, treatment was interrupted until recovery of the hematological parameters. In case of grade 2 diarrhea or mucositis, treatment was interrupted. On recovery, UFT was restarted with a dose reduced by 50 mg/m2. Depending on the observed non-hematological toxicities, dose reductions of either UFT, paclitaxel or both were recommended for the subsequent courses. Response was evaluated after every second cycle. Patients with progressive disease or intolerable toxicities were taken off protocol. Patients were considered evaluable for response if they received at least one complete cycle of therapy, unless treatment was stopped due to early progression. WHO criteria were used to assess response to treatment.
Three patients per dose level were planned to be included. In case of one DLT, three further patients were treated at that level. After determining the MTD, six additional patients were to be treated at this dose level. MTD was defined as at least two out of three or three out of six patients with DLT at a given dose level. Non-hematological toxicities grade 3/4, febrile neutropenia, granulocytopenia grade 3 and thrombocytopenia grade 4, inability to take at least 75% of the planned dose or necessity to hold therapy for >12 days were all considered dose limiting.
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Results |
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DLT were encountered at dose levels 14 and 6. These consisted of diarrhea (three), mucositis (two), anemia CTC grade 3 (one) and drug-related fatigue syndrome (one). However, with two DLT per dose level at most, the MTD as defined in the protocol was not reached up to the highest dose level of paclitaxel 100 mg/m2. Overall, diarrhea was the most common toxicity, observed in 26 of 47 (55%) patients during 47 of 130 cycles (36%). However, this side-effect remained mild except in two patients with grade 3 and one patient with grade 4 toxicity. The incidence of this side-effect was equally distributed among patients at all dose levels. Myelosuppression of the regimen was moderate, the white blood cell count dropped below 2000/µl (corresponding to CTC grade 3 leukocytopenia) during six of 130 (5%) cycles; all events were observed in patients treated at the upper three dose levels of paclitaxel (80100 mg/m2 weekly). After eight cycles of UFT/paclitaxel, anemia grade 3 was noted in five patients, red blood cell transfusions were given during nine of the 130 cycles. Four of 47 patients (9%) presented with symptoms of grade 3 polyneuropathy occurring during the third cycle. All cases of polyneuropathy have been observed at dose levels 46. Table 2 summarizes the observed adverse effects of CTC grades 3 and 4 that were considered possibly or probably related to treatment. Dose reductions of UFT were necessary in 11 cycles, mainly due to diarrhea. In 32 of 130 cycles (25%) the UFT dose was not applied on at least 1 day. The dose of paclitaxel was reduced in a single patient during nine cycles; one dose of paclitaxel was missed. Nine cycles of the combination treatment started with a delay due to persisting leukocytopenia or thrombocytopenia.
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To summarize, the observed side-effects are, in terms of frequency and intensity, in line with those reported previously when both drugs were given as single agents. UFT-induced diarrhea was dose-limiting. No over-additive toxicity of this combination has been observed. With repetitive applications of paclitaxel, polyneuropathy was encountered more frequently.
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Discussion |
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The response rate of 28% for a heavily pre-treated group of patients is encouraging. However, the study design and the heterogeneity of patients with different underlying malignancies precludes definitive statements concerning the efficacy of this combination.
A recent phase II study has combined another oral fluoropyrimidine, capecitabine, with paclitaxel [26]. In this study, which included 17 patients with solid tumors, paclitaxel had been given every 3 weeks at a dose of 135175 mg/m2 as a 3-h infusion, and capecitabine was given continuously in doses escalated to 1675 mg/m2/day, divided in to two daily doses. The toxicity profile of the capecitabinepaclitaxel combination differed substantially from that of the present study. Myelosuppression was found to be the principle DLT, with grade 3 or 4 neutropenia occurring during 18 of 66 courses (27%). Otherwise, the side-effects of the capecitabinepaclitaxel combination were considered acceptable. No tumor responses to treatment were noted. The increased hematological toxicity might be explained by the use of the 3-weekly schedule of paclitaxel in this study. In contrast, the weekly paclitaxel schedule used in the current study has allowed a high dose intensity of paclitaxel to be given with low hematological toxicity.
In summary, the combination of UFT and paclitaxel is a well tolerated regimen that can easily be applied on an outpatient basis. The preliminary data on efficacy warrant further investigation. The recommended dose for subsequent phase II studies is paclitaxel given weekly at 90 mg/m2 on days 1, 8, 15 and 22, together with UFT 300 mg/m2 divided into three doses on days 128 plus folinic acid 90 mg/day p.o. This combination seems to be attractive for the treatment of patients with breast cancer, adenocarcinoma of the lung, head and neck squamous cell cancer and bladder cancer.
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Footnotes |
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