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Original article Annals of Oncology 14: 1578–1586, 2003 DOI: 10.1093/annonc/mdg410 Phase I and pharmacokinetic study of the association of capecitabine–cisplatin in head and neck cancer patients X. Pivot1, E. Chamorey2, E. Guardiola1, N. Magné2, A. Thyss2, J. Otto2, B. Giroux3, Z. Mouri3, M. Schneider3 & G. Milano2* 1 Centre Hospitalier Jean Minjoz, Department of Medical Oncology, Besançon; 2Centre Antoine Lacassagne, Oncopharmacology Unit, Nice; 3Roche Pharmaceuticals, Neuilly sur Seine, France Received 19 December 2002; revised 25 April 2003; accepted 17 June 2003 The combination of cisplatin and 5-fluorouracil (5-FU) is considered to be the standard treatment in induction chemotherapy for patients with squamous cell carcinoma of the head and neck. Capecitabine (Xeloda®) is an oral fluoropyrimidine that is preferentially activated at the tumoral level, exploiting the higher thymidine phosphorylase activity in tumoral tissue. This phase I trial was conducted in patients with locally recurrent or metastatic head and neck carcinoma. The treatment plan included cisplatin on day 1 every 21 days, followed by capecitabine twice daily from day 2 to day 15, with a 1-week rest period. Pharmacokinetic investigations concerned plasma measurement of unchanged capecitabine, 5′-deoxy-5-fluorocytidine, 5′-doxifluridine and 5-FU using an optimized high performance liquid chromatography method, and cisplatin measurement in plasma using a limited sampling procedure. Twenty-one patients were included (mean age 61 years, range 46–76 years). Dose (mg/m2) increments for cisplatin and capecitabine (b.i.d.), respectively, were as follows: level 1, 80 and 1000 (three patients); level 2, 100 and 1000 (12 patients); and level 3, 100 and 1125 (five patients). Dose-limiting toxicities occurring during the first cycle (grade ≥3) were observed on level 2 (one patient with diarrhea, nausea, vomiting, hand–foot syndrome, one toxic death due to renal failure and neutropenia, one patient with neutropenia) and on level 3 (one patient with diarrhea, one patient with hand–foot syndrome and one patient with neutrothrombocytopenia). Due to delayed side-effects, 14 patients (67%) had repeated cycles every 28 days instead of 21 days as initially planned. Objective response was obtained in seven patients (three complete responses and four partial responses). There was no evidence of pharmacokinetic–pharmacodynamic relationships with the drugs and metabolites investigated. Combination of capecitabine and cisplatin is feasible, with a very promising response rate. The recommended doses for further phase II studies are those of level 2 with cisplatin 100 mg/m2 on day 1 and capecitabine 1000 mg/m2 b.i.d. on days 1–14, every 28 days. Key words: capecitabine, cisplatin, head and neck cancer, pharmacokinetic study, phase I clinical trial Introduction Treatment strategy for squamous cell carcinoma of the head and neck requires the use of chemotherapy at several stages [1]. The cisplatin–5-fluorouracil (5-FU) combination is particularly used as induction chemotherapy in these types of cancers. Interestingly, induction chemotherapy has led to organ preservation through a reduction of surgical indication [2]. For inoperable tumors, the concomitant chemo-radiotherapy has shown benefit over radiotherapy alone [3]. Cisplatin–5-FU has been the most commonly used regimen in this indication of chemo-radiotherapy association. In the event of relapse, salvage options such as additional surgery or radiation therapies are limited. For these patients, chemotherapy is commonly accepted as the standard therapy. A signifi- *Correspondence to: Dr G. Milano, Centre Antoine Lacassagne, Oncopharmacology Unit, 33 Avenue de Valombrose, 06189 Nice Cedex 2, France. Tel: +33-4-92-03-15-53; Fax: +33-4-93-81-71-31; E-mail: [email protected] © 2003 European Society for Medical Oncology cantly higher response rate has been obtained with cisplatin–5-FU compared with methotrexate alone, despite an absence of benefit in overall survival [3]. Thus, one can also consider the cisplatin– 5-FU combination to constitute one of the major chemotherapeutic treatments in head and neck recurrent cancer patients. Capecitabine (Xeloda®; N4-pentyloxycarbonyl-5′-deoxy-5fluorocytidine) 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 concentra- 1579 tions 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 cisplatin–capecitabine 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. Patients and methods Patients with loco-regional and/or metastatic recurrence of head and neck squamous cell carcinoma were eligible for this study. The following criteria were required for inclusion: age >18 years, performance status ≥2, life expectancy >12 weeks, no gastrointestinal disorder that might affect the gastrointestinal absorption of capecitabine, an ability to swallow for the oral administration of capecitabine, adequate hematopoietic function [white blood cell (WBC) count ≥3000/µl, absolute neutrophil count (ANC) ≥2000/µl, platelets ≥100 000/µl, hemoglobin level ≥9.0 g/dl], adequate hepatic function [total serum bilirubin level <1.5× institutional upper normal limits (UNL), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) <3× institutional UNL], adequate renal function (serum creatinine <1.5× UNL), no clinically significant cardiac disease, no history of seizures, no central nervous system or psychiatric disorder that might alter study compliance, and absence of serious uncontrolled infections. All patients gave written informed consent before inclusion. This study received the approval of the local ethical committee. 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, hand–foot 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 sideeffect 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 0–1. 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 0–1 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 3–4 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 [12–14] 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 concen- 1580 trations 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 × 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-coupledcolumn 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 0.05–10 µg/ml. The above-defined HPLC conditions led to a satisfactory separation of capecitabine and its metabolites. Areas under the plasma concentration–time 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 γ-glutamyltransferase (γGT) 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 Mann–Whitney 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), hand–foot syndrome or response and AUC values were assessed by logistic regression. Results DLT and MTD assessments Twenty-one patients were included in the present study and a total of 50 cycles of cisplatin–capecitabine were administered. Patient Table 1. Patient characteristics No. of patients 21 Median age, years (range) 58 (45–76) Gender (male/female) 20/1 Median PS (range) 1 (0–2) Primary tumor site Oropharynx 9 Oral cavity 3 Larynx 4 Pharynx 5 Local regional recurrence only 10 Metastatic recurrence only 9 Both 2 Treatment of primary tumor Surgery and radiotherapy 6 Surgery and chemo-radiotherapy 5 Induction chemotherapy and radiotherapy 6 Concomitant chemo-radiotherapy 4 Previous exposure to chemotherapy Treatment of primary tumor Treatment of recurrence Previous exposure to cisplatin–5-flurouracil regimen 16 5 9 PS, performance status. characteristics are described in Table 1. All patients had localregional recurrence and/or metastatic squamous cell carcinoma of the head and neck. All patients had received prior chemotherapy either as the treatment of the primary tumor or as a first-line chemotherapy for recurrence. Nine patients had been treated previously with cisplatin–5-FU as induction chemotherapy or as concomitant chemo-radiotherapy for the primary tumor, or as first line treatment for recurrent disease. Three patients were treated at the first dose level (dose level 1): cisplatin 80 mg/m2 and capecitabine 2000 mg/m2/day. Since no dose-limiting event was observed in any of these patients during the first course, the cisplatin dose was increased to 100 mg/m2 (dose level 2). At this new level, one patient died due to pulmonary emboli before starting capecitabine and was excluded from the analysis. The third patient treated at this dose level developed DLT, consisting of grade 3 diarrhea and grade 3 hand–foot syndrome after 6 days of capecitabine. Since one episode of DLT occurred, three additional patients were included at this dose level. The sixth patient entered at this dose level died of renal failure after cycle 1. This patient was eligible but initially had an altered general status. Therefore, three additional patients were added at this dose level. Since none of them developed significant toxicity the capecitabine dose was increased to 2250 mg/m2/day (dose level 3). One of the three patients included at this third dose level presented a limiting toxicity. This patient presented grade 3 hand– foot syndrome associated with grade 3 diarrhea after 10 days of treatment. Additional patients were then added at this dose level. 1581 Table 2. Toxicity profile Patients (n) Dose level 1a Dose level 2b Dose level 3c 3 12 5 2 2 1 Neutropenia Grade 1 Grade 2 1 Grade 3 4 1 Grade 4 1 1d 2 2 Grade 2 5 1 Grade 3 4 2 Anemia Grade 1 2 Thrombocytopenia Grade 1 2 2 Grade 2 2 4 1 Grade 3 1 1 1d Grade 4 Hand–foot syndrome Grade 1 3 1 1 1 Toxicity profile 1d 1d 1 1 1 1 The mean times for the occurrence of ANC and platelet nadirs were days 18 (range 14–22) and 20 (range 14–24), 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 nonhematological toxicity. Table 2 describes the distribution of hematological and nonhematological 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 hand–foot 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 1–2 nausea and vomiting were observed in 10 (66.7%) and seven (46.7%) patients, respectively. Four patients (26.6%) had grade 1 hand–foot syndrome, and one patient developed grade 3 hand–foot syndrome (first DLT event occurring for the third patient at the second dose level). Grade 1–2 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 Grade 2 Grade 3 Diarrhea Grade 1 Grade 2 1 d Grade 3 1 1d 1d Grade 4 Nausea Grade 1 1 5 1 4 2 2 1 1 Grade 1 1 1 2 Grade 2 1 4 1 2 1 3 Grade 2 Grade 3 Vomiting Mucositis Grade 1 Grade 2 1 Grade 3 1 Bilirubinemia Grade 1 3 Renal failure Grade 4 a 1 Cisplatin 80 mg/m2, capecitabine 2000 mg/m2/day. Cisplatin 100 mg/m2, capecitabine 2000 mg/m2/day. c Cisplatin 100 mg/m2, capecitabine 2250 mg/m2/day. d Limiting toxicity experienced at the first cycle. b A fourth patient developed a grade 3 febrile neutropenia associated with grade 4 thrombocytopenia 1 week after the completion of capecitabine administration. This patient died of a gastrointestinal hemorrhage. As limiting toxicities were different for the two previous patients, a fifth patient was included at the third dose level and grade 4 diarrhea occurred on the 10th day of treatment. Moreover, a grade 3 thrombocytopenia with grade 4 neutropenia was observed 5 days after the completion of the second cycle in the third patient treated at this dose level. For the three patients who completed the capecitabine administration, one patient died due to severe grade 4 thrombocytopenia associated with a digestive hemorrhage. The two other patients presented with grade 1–2 thrombocytopenia, neutropenia and anemia during the first cycle. Moreover, during the second course, they both developed grade 3 thrombocytopenia and grade 3 anemia. One of them had grade 4 neutropenia. Consequently, severe hematological limiting toxicity (thrombocytopenia) emerged at this dose level when the administration of the full dose of capecitabine was administered, due to the absence of severe diarrhea. As a result, the doses of cisplatin 100 mg/m2 and capecitabine 2000 mg/m2/day were taken as the MTD. Finally, with a view to confirming this observation, three additional patients were included at this dose level without any occurrence of severe toxicity. 1582 Figure 1. Pharmacokinetic profile of capecitabine and metabolites at dose level 2 for 12 patients (n = 32 cycles, mean value, error bars for 95% confidence interval of mean). Blood sampling over a 6-h period following the morning intake of the drug. patients), alopecia (three patients), paresthesias (three patients) and asthenia (11 patients). Antitumor activity Seventeen patients had measurable disease while three others had no measurable soft tissue lesions. Seven of the 17 patients (41.2%; 95% confidence interval 10.6% to 52.6%) had an objective response, including three complete responses and four partial responses. The median duration of these responses was 8.0 months (range 3–12). Seven (41.2%) and three (17.7%) patients had stable disease and progressive disease as best response, respectively. The median time to progression and survival for all 20 patients were 5.5 months (range 1.5–13) and 7.3 months (range 1–13), respectively. 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 concentration–time profile of capecitabine and its metabolites at dose level 2. The main circulating 1583 Table 3. Pharmacokinetics of capecitabine and metabolites (all patients, doses and cycles) AUC values (µg·h/ml) Dose level 1 P value Dose level 2 Dose level 3 No. of patients 2 12 5 No. of cycles 4 20 8 AUC capecitabine 3.45 ± 2.07 5.70 ± 2.65 9.00 ± 6.26 0.047a AUC 5′DFCR 3.17 ± 2.95 3.77 ± 3.29 5.43 ± 3.93 NS AUC 5′DFUR 10.26 ± 3.05 13.20 ± 6.05 11.87 ± 3.58 NS 0.36 ± 0.18 0.62 ± 0.48 0.69 ± 0.72 NS AUC 5-FU AUC values correspond to the morning intake of the drug on day 2 and on day 15, with blood sampling over a 6-h period following drug intake. Results are expressed as mean ± standard deviation. a Non-parametric comparison between dose levels 1 and 2 (same capecitabine dose), and dose level 3. AUC, area under the plasma concentration–time curve; 5′DFCR, 5′-deoxy-5-fluorocytidine; 5′DFUR, doxifluridine; 5-FU, 5-fluorouracil; NS, not significant. Table 4. Variability in AUC values (µg·h/ml) (all patients and dose levels) Capecitabine P valuea AUC day 2, cycle 1 AUC day 15, cycle 1 5.77 ± 2.50 7.56 ± 5.48 0.249 P valueb P valuec 6.95 ± 4.26 0.77 0.062 AUC day 2, cycle 2 AUC day 15, cycle 2 5.59 ± 4.63 5′DFCR 3.95 ± 2.64 4.71 ± 4.28 0.721 3.73 ± 2.61 4.05 ± 5.07 0.87 0.612 5′DFUR 11.50 ± 4.81 14.18 ± 7.05 0.039 11.13 ± 2.66 14.57 ± 4.92 0.14 0.008 0.40 ± 0.24 1.00 ± 0.69 0.005 0.36 ± 0.25 0.78 ± 0.62 0.009 0.008 5-FU AUC values correspond to the morning intake of the drug with blood sampling over a 6-h period following drug intake. Results are expressed as mean ± standard deviation. a P value: AUC day 2, cycle 1 versus AUC day 15, cycle 1 (Wilcoxon paired test). b P value: AUC day 2, cycle 2 versus AUC day 15, cycle 2 (Wilcoxon paired test). c P value: AUC day 15, cycle 1 versus AUC day 2, cycle 2 (Wilcoxon paired test). AUC, area under the plasma concentration–time curve; 5′DFCR, 5′-deoxy-5-fluorocytidine; 5′DFUR, doxifluridine; 5-FU, 5-fluorouracil. 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. Table 4 shows that there was a significant increase in AUC values (µg·h/ml) for 5′DFUR and 5-FU between days 2 (11.50 ± 4.81 and 0.41 ± 0.24, respectively) and 15 (14.18 ± 7.05 and 1.00 ± 0.68, respectively) of cycle 1; this time dependency was observed for 5-FU on cycle 1 and cycle 2 (0.36 ± 0.25 on day 2 and 0.78 ± 0.62 on day 15; P = 0.009). The statistical significance of this observation is based on intra-patient comparisons where an identical dose was taken by each patient throughout the observation period. These pharmacokinetic changes were reversible after the inter-cycle resting period and there was a significant decrease in AUC values for 5′DFUR and 5-FU between day 15 of cycle 1 and day 2 of cycle 2. For 5′DFUR and 5-FU, AUC values on day 2 of cycle 2 were comparable to the respective AUC values observed on day 2 of cycle 1. The pharmacokinetic data obtained from the 19 patients were plotted against the percentage decrease in absolute neutrophil count, hemoglobin and platelets between the corresponding nadir on day 15 and day 21 of the treatment cycle, and the pre-treatment value. On this basis, there was no evidence for pharmacokinetic–pharmacodynamic relationships with 5′DFUR and 5-FU. In addition, plasma creatinine values and liver function tests with unconjugated bilirubin, ALT, AST, AP and γGT were tested against pharmacokinetic data. Different models, based on linear, log-linear, Emax model and sigmoïdal Emax, were tested for their ability to describe the data. None of these biological parameters were significantly related to the AUC data for any of the tested compounds (5′DFUR and 5-FU), whatever the model tested. Other toxicities such as gastrointestinal disorders (diarrhea, nausea, vomiting, mucositis) or hand–foot syndrome were not significantly related to the AUC of 5′DFUR or 5-FU when using non-linear regression models. Finally, there were no relationships between the AUC values of each of these two compounds and response to capecitabine/cisplatin treatment. Free and ultrafilterable cisplatin plasma concentrations at H16 (single point procedure) are depicted in Table 5. Data were available in all the 19 investigated patients (31 cycles, median of two cycles per patient). There was no relationship between cisplatin concentrations and dose level, although a slight increase in total cisplatin concentration (µg/ml) was observable between 80 mg/m2 (2.19 ± 0.223, dose level 1) and 100 mg/m2 (2.31 ± 0.82, dose level 2 and 1584 Table 5. Pharmacokinetics of cisplatin (single point procedure cisplatin µg/ml) (concentrations at H16 values all cycle and dose levels) Dose level 1 2 3 No. of patients 2 12 5 No. of cycles 5 18 8 Ultrafilterable cisplatin 0.077 ± 0.025 0.055 ± 0.026 0.048 ± 0.015 Total cisplatin 2.19 ± 0.223 2.31 ± 0.82 2.39 ± 0.72 Results are expressed as mean ± standard deviation. 2.39 ± 0.72, dose level 3). Of note, there was a marked and significant increase (Wilcoxon paired test P = 0.007) in ultrafiltrable cisplatin concentrations between cycle 1 (0.048 ± 0.012 µg/ml) and cycle 2 (0.071 ± 0.023 µg/ml). Discussion The continuous administration of capecitabine in two, daily, divided doses for 2 weeks on an intermittent dosing schedule led to a MTD of 2510 mg/m2/day [10]. At a higher dose, capecitabine was not tolerable and the limiting toxicity included diarrhea, hand–foot syndrome, hypotension, abdominal pain and leukopenia. Three phase I trials combining capecitabine given on this intermittent schedule with other agents were recently reported. Pronk and colleagues observed that capecitabine 1650 mg/m2 plus docetaxel 100 mg/m2/day was tolerable, as was capecitabine 2500 mg/m2 plus docetaxel 75 mg/m2/day [18]. In the latter trial, the DLT appeared to be asthenia. Around one-third of patients suffered from mild nausea, vomiting, hand–foot syndrome and diarrhea. Hematological toxicity occurred in the majority of cases, grade 3–4 neutropenia was observed in 68% of all courses and grade 1–2 anemia was reported in 89% of courses. Grade 1–2 thrombocytopenia occurred in only 4% of courses, with one patient who reached grade 4. Villalona-Colera and coworkers studied the combination of paclitaxel and capecitabine. Neutropenia and hand–foot syndrome were the main DLTs; the MTD and recommended dose levels were capecitabine 1650 mg/m2/day and paclitaxel 175 mg/m2 [19]. Severe anemia and thrombocytopenia were uncommon, whereas grade 3–4 neutropenia occurred in 63% of patients. A majority of patients (58%) experienced moderate diarrhea. Overall, from these two trials, capecitabine added its own toxicity in the form of the hand–foot syndrome and diarrhea without a significant impact on the taxane toxicity profile. The hematological toxicity profile observed with paclitaxel 175 mg/m2 or docetaxel 100 mg/m2 in combination with capecitabine is similar to that resulting from the same chemotherapy given as a single agent. More recently, a phase I trial combining capecitabine with oxaliplatin was reported by Diaz-Rubio and colleagues [20]; the recommended dose schedule was capecitabine 2000 mg/m2/day (days 1–14), with i.v. oxaliplatin 130 mg/m2 (day 1) in a 21-day treatment cycle. The main DLT was diarrhea. The present study assessed the feasibility of administering a cisplatin–capecitabine 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 3–4 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, hand–foot 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 hand–foot syndrome occurred in 33% of patients. Similarly, diarrhea was observed in 33% of patients at a moderate grade 1–2 level. At the recommended dose, the rates and the severity of diarrhea and hand–foot syndrome episodes were similar to those reported from other phase I trials combining capecitabine with either paclitaxel, docetaxel or oxaliplatin [19, 21–24]. 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, 21–24]. 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 paclitaxel– capecitabine 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 14–22) and 20 (range 14–24), respectively. The recovery of blood cell counts to a level sufficient to allow the 1585 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 nonhematological toxicity in five patients: non-recovery at day 21 from grade 2 asthenia in three cases, grade 1 hand–foot syndrome in one case, and grade 1 diarrhea in one case. One 7-day delay was due to the patient’s 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 3–4 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 cisplatin–5-FU does not seem to induce irreversible resistance to further cisplatin– capecitabine treatment. 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