Download Phase I and pharmacokinetic study of the association of

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-
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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.
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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.
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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
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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
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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. 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 1–14 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.
References
1. Vokes EE, Weichselbaum RR, Lippman SM, Hong WK. Head and neck
cancer. N Engl J Med 1993; 328: 184–194.
2. Forastiere AA, Metch B, Schuller DE et al. Randomized comparison of
cisplatin plus fluorouracil and carboplatin plus fluorouracil versus methotrexate in advanced squamous-cell carcinoma of the head and neck: a
Southwest Oncology Group study. J Clin Oncol 1992; 10: 1245–1251.
3. Pignon JP, Bourhis J, Domenge C, Designe L. Chemotherapy added to
locoregional treatment for head and neck squamous-cell carcinoma: three
meta-analyses of updated individual data. MACH-NC Collaborative
Group. Meta-Analysis of Chemotherapy on Head and Neck Cancer.
Lancet 2000; 355: 949–955.
4. Miwa M, Ura M, Nishida M et al. Design of a novel oral fluoropyrimidine
carbamate, capecitabine, which generates 5-fluorouracil selectively in
tumours by enzymes concentrated in human liver and cancer tissue. Eur J
Cancer 1998; 34: 1274–1281.
5. Kono A, Hara Y, Sugata S et al. Activation of 5′-deoxy-5-fluorouridine by
thymidine phosphorylase in human tumors. Chem Pharm Bull (Tokyo)
1983; 31: 175–178.
6. Takebayashi Y, Yamada K, Miyadera K et al. The activity and expression
of thymidine phosphorylase in human solid tumours. Eur J Cancer 1996;
32: 1227–1232.
7. Schuller J, Cassidy J, Dumont E et al. Preferential activation of capecitabine
in tumor following oral administration to colorectal cancer patients.
Cancer Chemother Pharmacol 2000; 45: 291–297.
8. Ishikawa T, Utoh M, Sawada N et al. Tumor selective delivery of
5-fluorouracil by capecitabine, a new oral fluoropyrimidine carbamate, in
human cancer xenografts. Biochem Pharmacol 1998; 55: 1091–1097.
9. Ishikawa T, Sekiguchi F, Fukase Y et al. Positive correlation between the
efficacy of capecitabine and doxifluridine and the ratio of thymidine
phosphorylase to dihydropyrimidine dehydrogenase activities in tumors
in human cancer xenografts. Cancer Res 1998; 58: 685–690.
10. Mackean M, Planting A, Twelves C et al. Phase I and pharmacologic
study of intermittent twice-daily oral therapy with capecitabine in patients
with advanced and/or metastatic cancer. J Clin Oncol 1998; 16: 2977–
2985.
11. Budman DR, Meropol NJ, Reigner B et al. Preliminary studies of a novel
oral fluoropyrimidine carbamate: capecitabine. J Clin Oncol 1998; 16:
1795–1802.
12. Pivot X, Marghali N, Etienne MC et al. A multivariate analysis for predicting cisplatin-induced delayed emesis. Oncol Rep 2000; 7: 515–519.
13. Pivot X, Guardiola E, Etienne M et al. An analysis of potential factors
allowing an individual prediction of cisplatin-induced anaemia. Eur J
Cancer 2000; 36: 852–857.
1586
14. Lagrange JL, Medecin B, Etienne MC et al. Cisplatin nephrotoxicity: a
multivariate analysis of potential predisposing factors. Pharmacotherapy
1997; 17: 1246–1253.
15. Lagrange JL, Cassuto-Viguier E, Barbe V et al. Cytotoxic effects of longterm circulating ultrafiltrable platinum species and limited efficacy of
haemodialysis in clearing them. Eur J Cancer 1994; 30: 2057–2060.
16. Santini J, Milano G, Thyss A et al. 5-FU therapeutic monitoring with dose
adjustment leads to an improved therapeutic index in head and neck
cancer. Br J Cancer 1989; 59: 287–290.
17. Reigner B, Blesh K, Weidekamm E. Clinical pharmacokinetics of
capecitabine. Clin Pharmacokinet 2001; 40: 85–104.
18. Pronk LC, Vasey P, Sparreboom A et al. A phase I and pharmacokinetic
study of the combination of capecitabine and docetaxel in patients with
advanced solid tumours. Br J Cancer 2000; 83: 22–29.
19. Villalona-Calero MA, Weiss GR, Burris HA et al. Phase I and pharmacokinetic study of the oral fluoropyrimidynine capecitabine in combination
with paclitaxel in patients with advanced solid malignancies. J Clin Oncol
1999; 17: 1915–1925.
20. Diaz-Rubio E, Evans TRJ, Tabernero J et al. Capecitabine (Xeloda®) in
combination with oxaliplatin: a phase I dose-escalation study in patients
with advanced or metastatic solid tumors. Ann Oncol 2002; 13: 558–565.
21. Cassidy J, Dirix L, Bissett D et al. A phase I study of capecitabine in
combination with oral leucovorin in patients with intractable solid tumors.
Clin Cancer Res 1998; 4: 2755–2761.
22. Van Cutsem E, Findlay M, Osterwalder B et al. Capecitabine, an oral
fluoropyrimidine carbamate with substantial activity in advanced colorectal
cancer: results of a randomized phase II study. J Clin Oncol 2000; 18:
1337–1345.
23. Villalona-Calero MA, Blum JL, Jones SE et al. A phase I and pharmacology study of capecitabine and paclitaxel in breast cancer patients. Ann
Oncol 2001; 12: 605–614.
24. Venturini M, Del Mastro L, Garrone O et al. Phase I, dose-finding study of
capecitabine in combination with docetaxel and epirubicin as first-line
chemotherapy for advanced breast cancer. Ann Oncol 2002; 13: 546–552.
25. Kim TW, Kang YK, Ahn JH et al. Phase II study of capecitabine plus cisplatin as first-line chemotherapy in advanced gastric cancer. Ann Oncol
2002; 13: 1893–1898.
26. Jacobs C, Meyers F, Hendrickson C et al. A randomized phase III study of
cisplatin with or without methotrexate for recurrent squamous cell carcinoma of the head and neck. A Northern California Oncology Group study.
Cancer 1993; 52: 1563–1569.
27. Liu G, Franssen E, Fitch MI, Warner E. Patient preferences for oral versus
intravenous palliative chemotherapy. J Clin Oncol 1997; 15: 110–115.