1 Centre Hospitalier Jean Minjoz, Department of Medical Oncology, Besançon; 2 Centre Antoine Lacassagne, Oncopharmacology Unit, Nice; 3 Roche Pharmaceuticals, Neuilly sur Seine, France
Received 19 December 2002; revised 25 April 2003; accepted 17 June 2003
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Abstract |
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Key words: capecitabine, cisplatin, head and neck cancer, pharmacokinetic study, phase I clinical trial
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Introduction |
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Capecitabine (Xeloda®; N4-pentyloxycarbonyl-5'-deoxy-5-fluorocytidine) is an oral fluoropyrimidine prodrug, with efficient gastrointestinal absorption followed by a three-step enzymatic conversion to its active metabolite [4]. At the first step, capecitabine is metabolized to 5'-deoxy-5-fluorocytidine (5'DFCR) by the hepatic carboxyl esterases. 5'DFCR is then metabolized further by cytidine deaminase to doxifluridine (5'DFUR) in hepatic and extrahepatic tissues, as well as malignant neoplasms. Finally, 5'DFUR is converted to 5-FU by the pyrimidine nucleoside phosphorylase thymidine phosphorylase (TP). TP is preferentially expressed in malignant cells and is responsible for the preferential conversion of 5'DFUR to 5-FU in neoplastic tissues [5, 6]. Capecitabine treatment induces 2.9-fold higher 5-FU concentrations in malignant compared with non-malignant tissues. This could potentially result in a higher therapeutic index for capecitabine compared with other fluoropyrimidines [7]. In addition, capecitabine given orally results in consistently higher tissue-to-plasma 5-FU concentration ratios than 5-FU administered intravenously [8]. In preclinical evaluations, the antitumor and toxicity profiles of capecitabine were consistently superior to those of 5-FU [9].
The recommended dose for phase II studies of capecitabine is 1250 mg/m2 b.i.d. for 2 weeks every 3 weeks on an intermittent dosing schedule [10]. The biological and clinically proven synergetic activity between cisplatin and 5-FU supports the rationale for a clinical evaluation of the cisplatincapecitabine combination in head and neck cancer patients.
The main objective of this phase I study was to determine the maximum tolerated dose (MTD) for the combination of cisplatin and capecitabine, and to recommend an appropriate dose for subsequent clinical trials. The other aims were to describe the main toxicities of this regimen, to characterize the pharmacokinetics of capecitabine and cisplatin in this treatment protocol, and to search for preliminary evidence of antitumor activity in patients with squamous cell carcinoma of the head and neck.
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Patients and methods |
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Administration and dose escalation
Toxicities were graded according to the National Cancer Institute Common Toxicity Criteria (NCI-CTC). The occurrence of grade 4 hematological toxicity for >3 days or severe (grade 3) non-hematological toxicity (including diarrhea, handfoot syndrome, nausea and vomiting) that did not resolve to at least grade 1 within 5 days following the institution of appropriate supportive therapy defined the dose-limiting toxicity (DLT). MTD level was defined as the highest dose level resulting in a DLT in fewer than two out of six new patients during course 1.
The starting dose combined cisplatin 80 mg/m2, administered as an intravenous infusion (1 mg/min) on day 1, with capecitabine 2000 mg/m2/day in two equally-divided oral doses every 12 h for 14 days. Treatment was planned to be repeated every 3 weeks. This capecitabine schedule was selected because higher daily doses have demonstrated better tolerability in intermittent schedules compared with continuous administration schedules [10, 11]. The starting dose of capecitabine was selected because non-overlapping principal toxicity was expected with the studied drug combination. Previous phase I trials with capecitabine reached this starting dose level of capecitabine without the occurrence of DLT. The starting dose of cisplatin was selected because the acute and/or delayed vomiting induced by cisplatin could be a major limiting side-effect for the oral administration of capecitabine. This disturbing digestive toxicity, especially when delayed, may be cisplatin exposure-related and may be reduced by a lower dose of cisplatin [12]. Cisplatin was administered by intravenous infusion at 1 mg/min. Intravenous hydration was given before and after drug administration, both based on 2 l of a 5% glucose solution containing 2.2 mM Ca2+ glucoronate, 1 g/l of Mg2+, 2 g/l of KCl and 3 g/l of NaCl. Treatment with capecitabine started on day 2, following cisplatin administration on day 1. A minimum number of three new patients was scheduled for treatment at each dose level. Intra-subject dose escalation was not permitted. Capecitabine dose levels were scheduled to be 2000, 2250, 2500 and 2750 mg/m2/day in two oral intakes every 12 h (±2 h). Cisplatin dose levels were planned to increase to 100 mg/m2 after the first three patients if no DLT occurred and if digestive toxicity appeared to be manageable.
After the total dose was calculated according to the body surface area, it was then rounded off to the closest convenient dose, based on a combination of 500 and 150 mg tablets. The precise dose of capecitabine was packed individually. Regardless of fluctuations in weight throughout the study, the dose of capecitabine remained the same unless a dose modification was required due to adverse events.
Dose modifications
Capecitabine was not administered if patients developed grade 2 non-hematological (except hyperbilirubinemia or alopecia) or grade 4 hematological toxicity. Treatment was interrupted until the toxicity recovered to grade 01. In such cases, capecitabine was resumed at the original dose level. Patients were to be withdrawn from the study if they developed any grade 4 toxicity unless clinical benefit was documented, in which case the treatment with capecitabine was given with the previous lower dose-level. Treatment was delayed for up to 2 weeks if patients had persistent toxicity of at least grade 2 on the day scheduled for the second cycle. A patient was withdrawn from the study if toxicity did not resolve to grade 01 at the end of this period.
Assessment of treatment activity and follow-up
Past medical history, physical examinations and routine laboratory studies were performed before inclusion into the study, then weekly thereafter. Routine laboratory studies included serum electrolytes, chemistry and complete blood cell count. These tests were repeated until toxicity resolved in patients with grade 34 toxicity. Treatment activity was assessed after the completion of two cycles and was maintained until progressive disease or intolerable toxicity. Responses were defined according to World Health Organization (WHO) criteria.
Pharmacokinetic study
One of the aims of this clinical trial was to examine the pharmacokinetic behavior of capecitabine and its successive metabolites (5'DFCR, 5'DFUR, 5-FU) when combined or not with cisplatin. Blood sampling for cisplatin pharmacokinetic analysis (5 ml on EDTA tubes) was based on a previously validated limited sampling procedure, with one blood sample taken 16 h after the administration of cisplatin [1214] on day 1 of the first two cycles. Ultrafilterable and total cisplatin concentrations in plasma were determined by flameless atomic absorption spectrometry according to a previously published procedure [15].
Blood samples for capecitabine and its metabolites (10 ml venopunction on EDTA tubes, immediately centrifuged at 4°C and plasma-stored at 20°C) were collected during the first two cycles (cycles 1 and 2), on days 2 and 15 of each cycle after the morning drug administration. Blood sampling for capecitabine and its metabolites (10 ml in total on EDTA tubes) was performed over a 6-h period, at t0 (just before administration of capecitabine), t15 (15 min after administration of capecitabine), t30, t60, t120, t180, t240 and t360. 5-FU concentrations were determined by high performance liquid chromotography (HPLC) according to a previously published procedure [16]. Plasma measurement of capecitabine, 5'DFCR and 5'DFUR was performed according to a HPLC method described previously by Reigner et al. [17], with several modifications. Briefly, internal standards were Ro 09-1977 for capecitabine, and tegafur for 5'DFCR and 5'DFUR. The first step comprised precipitation of plasma proteins with acetonitrile (two samples of 500 µl plasma: one sample for capecitabine, and the other for 5'DFCR and 5'DFUR). The top layer was thus transferred and evaporated to dryness under a stream of nitrogen at 37°C. For capecitabine determination, the drug residue was reconstituted with 250 µl of the HPLC mobile phase consisting of acetonitrile/Titrisol® H2SO4 pH 4.0 (Merck, Darmstadt, Germany)/water (625/50/1250 v/v/v). A Symmetry Shield RP-18 5 µm, 4.6 x 150 mm (Waters, Milford, MA) HPLC column was used for capecitabine separation and measurement (flow rate 1.0 ml/min, injection volume 80 µl) with UV detection at 310 nm. The retention times of capecitabine and internal standard were 5.0 and 8.2 min, respectively.
For 5'DFCR and 5'DFUR determination, dry samples were reconstituted with 500 µl of mobile phase consisting of methanol/Titrisol® H2SO4 pH 4.0 (Merck)/water (220/25/870 v/v/v). Samples were thus ready to be applied to a Bond-Elut® extraction cartridge (500 mg, 3.0 ml; Varian, Middelburg, The Netherlands) conditioned with 3 ml methanol, 5 ml water. The cartridges were washed with 3 ml ammonium acetate (0.2 M) and elution was performed with 2 ml methanol. Samples were evaporated to dryness under a stream of nitrogen at 37°C, and reconstituted in 250 µl of HPLC mobile phase (methanol/Titrisol®/water: 220/25/870 v/v/v). A HPLC separation was used for the determination of 5'DFCR, 5'DFUR and tegafur (internal standard) using a 2-coupled-column system consisting of two columns LiChroCART 250-4 Lichrospher 100 RP-18, 15 µm (Merck). The flow rate was 0.8/min for an injection of 80 µl, with UV detection at 267 nm. The retention times were 12.32, 14.68 and 19.89 min for 5'DFCR, 5'DFUR and tegafur (internal standard), respectively. These HPLC methods conditions permitted a lower limit of quantification at 0.05 µg/ml for both capecitabine, and 5'DFCR and 5'DFUR, and the coefficient of variation for interday accuracy <10% using a 500.0 µl plasma specimen in the calibration range 0.0510 µg/ml. The above-defined HPLC conditions led to a satisfactory separation of capecitabine and its metabolites. Areas under the plasma concentrationtime curve (AUC) were determined using the trapezoidal rule. Possible relationships between drug and metabolite pharmacokinetics and pharmacodynamics were explored using linear and non-linear sigmoid E max models fitted using MicroPHARM MPD software (The MicroPHARM Group, Paris). Parameters reflecting toxicity included the relative percentage change in hematological parameters [absolute neutrophil count, blood hemoglobin concentration and platelet count (on days 15, 21 and 28)]. In addition, whenever possible, plasma creatinine and liver function tests with unconjugated bilirubin, ALT, AST, alkaline phosphatase (AP) and -glutamyltransferase (
GT) were performed.
Statistical analysis
All statistical determinations were performed on SPSS software (SPSS, Paris, France). Paired comparisons were performed using the Wilcoxon paired test, and group comparisons were based on the MannWhitney test. Tests of significance were two-sided and considered significant at P <0.05. Relationships between the incidence of gastrointestinal toxicities (diarrhea, vomiting, nausea, mucositis), handfoot syndrome or response and AUC values were assessed by logistic regression.
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Results |
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Toxicity profile
The mean times for the occurrence of ANC and platelet nadirs were days 18 (range 1422) and 20 (range 1424), respectively. Full recovery of blood cell counts to a level allowing the administration of a second cycle was observed on day 25. Although treatment was planned with cycles to be repeated every 3 weeks, a total of nine patients had a delay of 7 days before starting the second cycle because of hematological toxicity; similarly, five patients had delayed administration related to recovery from non-hematological toxicity.
Table 2 describes the distribution of hematological and non-hematological toxicities. A detailed toxicological analysis of the 15 patients treated at capecitabine 2000 mg/m2/day (level 1 plus level 2) is given below. One needs to take into account the fact that four patients had an early interruption of capecitabine administration due to non-hematological toxicity (grade 3 diarrhea, grade
3 handfoot syndrome), whatever the dose level. Grade 3 thrombocytopenia and anemia were observed in one patient (6.7%) and four patients (26.6%), respectively. Five patients (33.3%) had grade 3 or 4 neutropenia. Grade 12 nausea and vomiting were observed in 10 (66.7%) and seven (46.7%) patients, respectively. Four patients (26.6%) had grade 1 handfoot syndrome, and one patient developed grade 3 handfoot syndrome (first DLT event occurring for the third patient at the second dose level). Grade 12 diarrhea occurred in three patients (20%), and grade 3 in one (first DLT event during the first cycle in one case). Three patients presented elevations in total serum bilirubin concentrations. These biological manifestations were generally mild to moderate. Capecitabine treatment was not interrupted due to hyperbilirubinemia. Other drug-related toxicities, not clearly dose-related, included myalgia and arthralgia (one patient), mucositis (five patients), alopecia (three patients), paresthesias (three patients) and asthenia (11 patients).
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Pharmacokinetics
Plasma capecitabine and metabolite concentrations were available in 19 patients (32 cycles, median of two cycles per patient). Figure 1 illustrates a typical example of a concentrationtime profile of capecitabine and its metabolites at dose level 2. The main circulating species was the metabolite 5'DFUR; this is confirmed by examination of the AUC values for all the species studied (Table 3). An increased dose level of capecitabine from 2000 mg/m2 (dose level 1) to 2250 mg/m2 (dose level 2) was accompanied by a significant augmentation of AUC values for capecitabine.
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Discussion |
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The present study assessed the feasibility of administering a cisplatincapecitabine regimen in heavily pre-treated head and neck cancer patients. Patients were planned to be treated with capecitabine daily for 14 days following cisplatin on day 1 every 3 weeks. Toxicity was unacceptable when the dose levels of 100 mg/m2 and 2250 mg/m2/day were reached for cisplatin and capecitabine, respectively. Diaz-Rubio and colleagues [20] found diarrhea to be the main non-hematological DLT in the present study, and this toxicity caused an early interruption of the treatment in two cases. Among the three patients who completed the capecitabine administration at this dose level, a grade 34 thrombocytopenia occurred after the first or the second course. The incidence of limiting toxicity was thus unacceptably high in patients treated at dose levels exceeding cisplatin 100 mg/m2 and capecitabine 2000 mg/m2/day, which is considered to be the dose level recommended for subsequent clinical trials.
Among patients who received the recommended dose of capecitabine, handfoot syndrome and diarrhea were the most frequent non-hematological toxicities. Commonly, these toxicities were moderate, except for one patient who combined both toxicities at grade 3 level. Overall, grade 1 handfoot syndrome occurred in 33% of patients. Similarly, diarrhea was observed in 33% of patients at a moderate grade 12 level. At the recommended dose, the rates and the severity of diarrhea and handfoot syndrome episodes were similar to those reported from other phase I trials combining capecitabine with either paclitaxel, docetaxel or oxaliplatin [19, 2124].
In the present study, the occurrence of nausea and/or vomiting induced by cisplatin had been anticipated to constitute a potentially critical issue for the administration of capecitabine. The present results indicate that on day 2, the administration of capecitabine was never delayed due to cisplatin-induced nausea and vomiting. The incidence of other non-hematological toxicities was similar to that observed in previously described phase I studies [19, 2124].
Regarding the present combination of cisplatin and capecitabine and in comparison with previously published studies, a number of specific comments need to be made. First, in the paclitaxelcapecitabine study, the mean time for ANC nadir occurrence was day 15, and recovery of blood cell counts allowed the administration of the second course at day 22 in all patients [23]. Similarly, there was no delayed second course reported in the other phase I trials combining capecitabine with other drugs [18, 20, 21, 24]. In the present study the majority of patients [14/21 (67%)] were treated every 28 days instead of 21 days as initially planned. Indeed, the mean times for the occurrence of ANC and platelets nadirs were days 18 (range 1422) and 20 (range 1424), respectively. The recovery of blood cell counts to a level sufficient to allow the administration of a second cycle was attained on day 25. Consequently, seven patients had a second cycle delayed by 7 days, and in two cases a 14-day delay was required. In addition, there was a delayed administration related to recovery from non-hematological toxicity in five patients: non-recovery at day 21 from grade 2 asthenia in three cases, grade 1 handfoot syndrome in one case, and grade 1 diarrhea in one case. One 7-day delay was due to the patients own decision. A phase II study combining cisplatin and capecitabine was recently reported in patients with advanced gastric cancer [25]. Cisplatin was administered at 60 mg/m2 on day 1, and capecitabine 1250 mg/m2 was given twice daily for 14 days followed by a 7-day rest period. There was a marked incidence of hematological toxicity, with 32% and 10% of cases experiencing grade 34 neutropenia and thrombocytopenia, respectively.
Of potential interest, the present study incorporated a pharmacokinetic investigation covering both capecitabine and cisplatin. Previous pharmacokinetic studies of capecitabine during phase I trials disagree about the predominant circulating species [10, 19, 21]. The data in the present study (Table 3) are in accordance with those reported previously by Villalona-Calero and colleagues [19] and Mackean and colleagues [10], showing that 5'DFUR is the main circulating anabolite. Previous pharmacokinetic studies [17] point out the relative stability of the AUC values for capecitabine and metabolites determined on study days 1 and 14. The conclusions of the present study differ on this point and indicate that both the 5'DFUR AUC and the 5-FU AUC increase significantly throughout the treatment course. This accumulation is, however, quantitatively moderate and reversible, with comparable AUC values of 5'DFUR and 5-FU on day 2 of cycle 1 and day 2 of cycle 2 (Table 4). The presence of cisplatin with capecitabine could be responsible for this accumulation of 5'DFUR and 5-FU during the cycle since 5'DFCR, the precursor of 5'DFUR, is excreted mainly via the kidney [17], an organ particularly sensitive to the presence of cisplatin. This accumulation of 5'DFUR and 5-FU could reflect a synergistic interaction between the two drugs in terms of pharmacokinetic behavior. Cisplatin pharmacokinetic data are consistent with previously published observations with cisplatin administered as a single agent and with a limited sampling procedure [14, 15]. In these previous studies it was reported that ultrafilterable cisplatin concentrations at H16 increased from cycle to cycle [14]. A similar observation was made in the present study. There were no relationships between pharmacokinetic data for both capecitabine and metabolites and cisplatin and pharmacodynamic observations (toxicity and treatment efficacy). This is not surprising since capecitabine undergoes activation into 5-FU at the target cellular level. Capecitabine is a typical drug for which plasma pharmacokinetics are of low potential interest in predicting pharmacodynamics. In constrast, intracellular key parameters such as thymidine phosphorylase and dihydropyrimidine dehydrogenase may be considered to provide potential modulators and predictors of capecitabine pharmacodynamics [9].
In this heavily pretreated population, the objective response rate of 31.6% is particularly encouraging. Of note, this level of antitumor activity is similar to the rate of response obtained with cisplatin 5-FU when administered as a first-line treatment for recurrent disease [3, 26]. Interestingly, previous exposure to cisplatin5-FU does not seem to induce irreversible resistance to further cisplatincapecitabine treatment. A similar observation was made regarding patients treated during the phase I trial combining capecitabine and oxaliplatin [20].
The results of the present study indicate that the administration of cisplatin and capecitabine on an intermittent schedule is feasible. The recommended dose for further evaluation is cisplatin 100 mg/m2 and capecitabine 1000 mg/m2 b.i.d. on day 114 every 4 weeks. Patient preference for oral chemotherapy at home [27] combined with the interesting and promising antitumor activity observed in the present study provides a strong clinical basis for further evaluation of this treatment regimen.
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Footnotes |
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References |
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