Post on 20-Mar-2020
Vol. 4, 2039-2045, September 1998 Clinical Cancer Research 2039
Advances in Brief
Clinical Impact of Pharmacokinetically-guided Dose Adaptation of
5-Fluorouracil: Results from a Multicentric Randomized Trial in
Patients with Locally Advanced Head and Neck Carcinomas’
R#{233}gineFety,2 Fr#{233}d#{233}ricRolland,
Muriel Barberi-Heyob, Agnes Hardouin,
LoIc Campion, Thierry Conroy,
Jean-Louis Merlin, Alain Rivi#{232}re,
Genevieve Perrocheau, Marie-Christine Etienne,
and Gerard MilanoCentre Ren#{233}Gauducheau, 44805 Nantes [R. F., F. R., L. C., G. P.J;Centre Alexis Vautrin, 54511 Vandoeuvre-L#{232}s-Nancy [M. B-H.,T. C., J-L. M.]; Centre Fran#{231}oisBaclesse, 14021 Caen [A. H., A. R.];and Centre Antoine Lacassagne, 06050 Nice [M-C. E., G. M.], France
AbstractA significant link between 5-fluorouradil (SFU) plasma
concentration and its therapeutic activity has been demon-
strated in colon and head and neck cancer patients for SFU
used as a continuous infusion. Dose adjustment based on phar-
macokinetic follow-up has been proposed to decrease hemato-
logical and digestive toxidties, but the dinical impact of thisapproach has not yet been demonstrated. A randomized mad-
ticentric study was conducted to evaluate the dinical Interest of
SFU dose adaptation guided by pharmacokineties. One hun-
dred twenty-two head and neck cancer patients were randomly
assigned to receive induction chemotherapy with cisplatin (100
� thy 1) and SFU (96-h continuous infusion), either at
standard dose (St-arm; 4 g/m2) or at a dose adjusted according
to the SFU area under the curve (AUC0�; PK-arm). In total,106 patients were evaluable for tOXiCity and response. hi the
PK-arm (n = 49), SFU doses and area under the curve were
significanfly reduced during cycle 2 and cycle 3 (P < 0.001) as
compared with the St-arm (n = 57). Grade 3-4 neutropenia
and thrombopenia were significantly more frequent in theSt-arm as compared with the PK-arm (17.5% versus 7.6%,
respectively; P = 0.013). No grade 3-4 mucositis occurred in
the PK-arm, whereas 5.1% was observed in the St-arm (P <
0.01). The objective response rate was comparable in the two
treatment arms: 77.2% in the St-arm versus 81.7% in the
Received 3/13/98; revised 5/27/98; accepted 6/8/98.The costs of publication of this article were defrayed in part by thepayment of page charges. This article must therefore be hereby markedadvertisement in accordance with 18 U.S.C. Section 1734 solely toindicate this fact.I Supported by Produits Roche, the French “F#{233}d#{233}rationNationale desCentres de Lutte Contre Ic Cancer,” and the “Ligue Nationale contre IcCancer, comit#{233}de la Meurthe et Moselle.” These data were presented inpart at the 1997 meeting of the American Society of Clinical Oncology.
2 To whom requests for reprints should be addressed, at Centre Ren#{233}Gauducheau, Boulevard Jacques Monod, 44805 Saint Herblain Cedex-France. Phone: 33-2-40-67-99-60. Fax: 33-2-40-67-97-05. Email:r-fety@gauducheau-nantes.fnclcc.fr.
PK-arm. The present study is the first to demonstrate, in a
randomized design, the dinical interest of an individual SFU
dose adaptation based on pharmacokinetic survey, in terms of
therapeutic index improvement.
IntroductionDespite being one of the oldest anticancer drugs, 5FU� is
still increasingly used in cancer chemotherapy. SFU is consid-
ered not only as the standard drug for the treatment of advanced
colorectal cancer, but also as one of the major drugs for the
treatment of breast and head and neck carcinomas (1-3). Al-
though 5FU is a prodrug, significant relationships have been
evidenced between SRi plasma concentrations, drug pharma-
codynamics, side effects, and antitumor activity (4, 5). !n this
context, critical thresholds for 5FU plasma concentrations at risk
for toxicity have been demonstrated. Indeed, Au et a!. (6) noted
that, during a 5-day continuous infusion, steady-state SRi
plasma concentrations above 1 .5 p�M were significantly associ-
ated with leukopenia. Most data were obtained from studies
conducted in head and neck cancer patients treated by SRi-
based chemotherapy as induction treatment. Thyss et al. (7)
showed a significant relationship between elevated SRi AUC
(over 30,000 ng.h/ml) and the frequency of cycles with toxicity
(myelosuppression, mucositis, and diarrhea). More recently,
Vokes et a!. (8) confirmed these observations. The next logical
step was to use these pharmacokinetic data to propose individ-
ualized SRi dose adjustment. Santini et a!. (9) adopted such a
strategy in head and neck cancer patients. They proved that the
incidence of SRi-related side effects could be reduced by mdi-
vidually controlling SFU AUC at mid-cycle during the 5-day
continuous infusion, and, if required, by modifying the SRi
dose using a simple diagram. These data were further confirmed
by other authors (10). However, these last studies (9, 10) pre-
sented methodological limitations because they were based on
historical controls as comparators to SRi dose-adapted patients.
For this reason, it was decided to conduct a multicentric study in
which the clinical interest of SF0 dose adaptation guided by
pharmacokinetics could be evaluated on the basis of a random-
ized trial. Patients with locally advanced head and neck cancer
from three different institutions were enrolled in this study and
were randomly assigned to induction chemotherapy by cisplatin
and SRi at St-arm or at PK-arm.
Patients and Methods
This prospective study involved 122 patients (1 14 men and
8 women), with a median age of 55 years (range, 29-72). All
3 The abbreviations used are: SRi, 5-fluorouracil; St-arm, standard 5FUdose; PK-arm, adjusted SRi dose; AUC, area under the curve; CR,complete response; PR, partial response; ST. stabilization.
Research. on March 26, 2020. © 1998 American Association for Cancerclincancerres.aacrjournals.org Downloaded from
St-arm
(n 61)
57
525
54(29-72)
1634
7
216
1410
60
83116
13112211
PK-arm(n 61)
49
48
55 (36-69)
1135
3
203
17
53
02
4070
169
1410
2040 Clinical Response after SFU Monitoring
Table 1 Pretreatment characteristics of patients randomly assigned toSt-arm or PK-arm
Characteristic
No. of evaluable patientsGender
MaleFemale
Median age, yr (range)Performance status (PS)
0
Primary siteOropharynxOral cavityHypopharynxLarynxDouble localizationUnknown
Stage of primary tumorT,T2T3T4Not determined
Node stageN0N1N2N3
patients had received no previous treatment and had histologi-
cally proven locally advanced squamous cell carcinoma of the
head and neck. Patients’ characteristics are listed in Table 1. The
eligibility criteria included age between 18 and 75 years; per-
formance status grade 0, 1, or 2; measurable disease, life cx-
pectancy of at least 3 months; adequate bone marrow function
(WBC >4.0 x l0�/l, neutrophil count >2.0 X iO�fl, and
platelet count >100 X l0�Il); adequate liver function (< twice
normal); and renal function (serum creatinine level <130 p�M).
Ethical committee approval was obtained and all patients gave
written informed consent.
Treatment Regimens. The treatment consisted of three
cycles of 5FIJ-cisplatin delivered every 2 weeks (11), followed
by response assessment and subsequent surgery and/or radiation
therapy. All patients were treated with curative intent. Patients
were randomly assigned to receive 5FU-cisplatin induction
chemotherapy with either SRi at St-arm or 5FU at PK-arm. In
both arms, and at day 1 of each cycle, the treatment consisted of
a 6-h prehydratation with 2 1 of 5% dextrose containing 6 g/l of
NaCl, 2 g/l of KC1, followed by cisplatin at a dose of 100 mg/m2
diluted in 500 ml of 10% mannitol and administered on a 2-h
infusion. Therapy with SRi started immediately after comple-
tion of cisplatin. SRi was infused i.v. during 96 h at a constant
rate with a volumethc pump.
In St-arm, SRi was delivered at a fixed dose of 4 g/m2/
cycle. Doses were modified according to pretreatment blood cell
counts and other toxicities. Patients with a WBC count �4.0 X
l0�Il, a neutrophil count �2.0 X i0911, or a platelet count�l00 x iO�/i received 100% of the dose. Patients with a WBC
count of 3.0-3.9 X i0911, a neutrophil count of 1.5-1.9 X iO�/l,
or a platelet count of 75-99 X i0�/l were given a total dose of
4 g/cycle. Patients with a WBC count �2.9 X l0�Il, a neutrophil
count �l.4 X !0�Il, or a platelet count �74 X l0�/l had
treatment course delayed for 1 week.
In PK-arm, patients received SRi at a dose defmed by the
AUC measured individually during treatment (12). During the
first cycle, the AUC was calculated from 0-48 h (AUCO_48h)
and during the 96-h infusion (AUCO�h) to identify patients
who accumulate SRi. For patients with an AUC0� lower than
3 X AUCO_�h, the SRi dose was adapted for cycles 2 and 3
according to diagram 1 (Fig. 1). For patients with an AUCO_�h
higher than 3 X AUCO_48h, the dose was adapted for cycles 2
and 3 according to diagram 2 (Fig. 1). During this first cycle,
SRi doses were not adapted, except when AUCO_�h was
greater than 20,000 ng.h/ml, because this value has been previ-
ously reported to be highly predictive for toxicity (12). In this
case, SRi infusion was stopped at mid-cycle. The SRi dose
administered at the beginning of cycle 2 was determined by
using diagrams 1 or 2 according to the AUCO_48h calculated at
cycle 1. The 5FU dose delivered at the beginning of cycle 3 was
the dose administered during cycle 2. During cycle 2 and cycle
3, AUCO_�h was controlled at mid-cycle and modified when
necessary. The initial dose was decreased from 15-50% when
AUCO_48b values ranged from 15,600-20,000 ng.h/ml for dia-
gram 1 and from 8,640-16,000 ng.h/ml for diagram 2. The dose
was increased (0-50%) when the AUCO.48h value was low
(below 10,400 ng.h/ml for diagram 1 and below 5,760 ng.h/ml
for diagram 2). An increase in SRi dose was possible only if the
changes in the WBC count, neutrophil count, or platelet count
were lower than 25% as compared with the previous cycle.
Without a dose reduction predicted by pharmacokinetics, and in
case of a WBC count at 3.0-3.9 X i0�/l, a neutrophil count at
1.5-1.9 X !0�/l, or a platelet count of 75-99 X i0�/l, the SRi
dose administered was a 4 g total dose/cycle. In case of a WBC
count �2.9 X iO�/l, a neutrophil count �1 .4 X iO�/l, or a
platelet count �74 X l0�Il, treatment was delayed for 1 week.
In the both arms, in case ofmucositis grade 1, the full dose
of SRi was reduced to a 4 g total dose/cycle, and in case of
grade higher than 1, treatment was delayed for 1 week. In case
of other toxicities and a serum creatiine level greater than 130
ELM, treatment was delayed for 1 week.Response and Toxicity Assessments. Assessments of
response and toxicity were performed every 2 weeks during
chemotherapy and 2 weeks after the completion of treatment. At
each visit, a physical examination was performed, with blood
cell counts and measurement of the serum creatiine level.
Response was evaluated by the product of the two perpendicular
lesion diameters, based on clinical, fibroscopic, ultrasound
and/dr computed tomography scan examination. CR was de-
fined as the disappearance of all lesions. PR was defined as a
tumor regression exceeding 50% without occurence of new
lesions. ST was defined as any tumor regression less than 50%.
Progression was defined as a tumor increase of more than 25%,
or as the occurence of any new lesion. Hematological and
nonhematological toxicities were evaluated 10 days and 14 days
after each cycle using the WHO criteria. Nonhematological
toxicities included mucositis and digestive tract toxicity (includ-
ing nausea, vomiting, and diarrhea).
Research. on March 26, 2020. © 1998 American Association for Cancerclincancerres.aacrjournals.org Downloaded from
150
50
0 10,4os 15,650 20,000 h/mi
AUCO-48h5,160 8,640
AUCO-48h
Clinical Cancer Research 2041
DIAGRAM I
% of initial 5FU dose
DIAGRAM 2
% of init�aI 5FU dose
1�,OOOng him
Fig. 1 Diagram for SRI dose delivery in patients having AUCO_%h lower than 3 X AUCo_�h (Diagram 1) or higher than 3 X AUCO_�h (Diagram2). The SRi doses were modified when AUCo_�h were above or below target AUCs at 13,000 ng.h/ml and 7,200 ng.h/ml for Diagram 1 and 2,
respectively. At the beginning of cycle 2, the SRi dose delivered was defmed according to AUCo_�h calculated at cycle 1. The initial dose wasdecreased by 15-50% when AUCO48h values ranged from 15,600-20,000 ng.h/ml for Diagram 1 and from 8,640-16,000 ng.h/ml for Diagram 2.The dose was increased (0-50%) when the AUCO_48h value was below 10,400 ng.h/ml for Diagram 1 and below 5,760 ng.h/ml for Diagram 2. Thedose delivered at the beginning of cycle 3 was the total dose administered during cycle 2. During cycle 2 and cycle 3, AUCO_48h was controlled atmid-cycle and the SRi dose was modified when necessary.
Pharmacokinetic Investigations. Plasma SRi levels
were measured in all patients included in the study. Two blood
samples/day were collected from days 1-4. Blood sampling on
day 1 was performed before 5FU administration (control prior
chemotherapy) and 2 h after SF0 infusion; on the following
days, blood sampling was done as follows: on days 2 and 3, at
8 a.m. and 5 p.m.; on day 4, at 8 a.m., and just before the end
of SRi infusion. Venous blood (5 ml) was collected into hep-
arinized tubes. The tubes were immediately centrifuged at 3000
rpm for 10 mm at 4#{176}C.Resulting plasma supernatants were
transferred to individual 3-mi polypropylene tubes and stored
frozen in the hospitalization ward. The frozen tubes were trans-
ferred to the laboratory once a day and stored at -20#{176}C.SRi
plasma concentrations were analyzed by high-performance liq-
aid chromatography (13) using UV detection (X = 262 nm). The
limit of sensitivity was 25 ng/ml. Intra- and interassay variations
were lower than 10%. The AUC was determined according to
the trapezoIdal rule. The AUC was calculated over the first part
of the cycle (AUCO48h) and during the whole pharmacokinetic
follow-up (AUCO_96h). For each patient, the pharmacokinetic
parameters representative of SFU exposure during the treatment
were the average AUCO_%h (sum of AUCO_%h for each cycle
divided by the number of cycles) and the AUCO_96h intensity
(sum of AUCO_�h for each cycle divided by the number of
weeks of treatment). Likewise, the average SFU dose/cycle
(sum of SRi dose for each cycle divided by the number of
cycles) and the 5FU dose intensity (sum of 5FU dose for each
cycle divided by the number of weeks of treatment) were
calculated for each patient.
Statistical Considerations and Analysis. The primary
end point of the study was the incidence of hematological
toxicity. The procedure tested a null hypothesis (HO) that the
occurrence of grade 3-4 hematological toxicity was similar in
both treatment groups versus the alternative hypothesis (Hi)
that occurrences were different between patients in the St-arm
and the PK-arm. A sample size of 61 patients/arm afforded
approximately 80% power to detect a 20% difference in grade
3-4 hematological toxicity between the two arms. Randomiza-
tion was stratified by center (3 centers). Categorical data were
analyzed using the x2 test. Continuous data were analyzed using
Student’s t or Mann-Whitney U two-sided tests.
The secondary end point was the equivalence of tumoral
response. The second procedure tested a null hypothesis (KO)
that the occurrence of objective response rate was different in
the two treatment arms (difference higher than 10%), versus the
alternative hypothesis (Ki) that the occurrence was identical in
the St-arm and the PK-arm. Objective response rates were
compared with the Dunnett and Gent one-sided test (14).
The statistical significance was considered at P < 0.05.
Results
Patient Characteristics. Among the 122 patients ran-
domly assigned to one of the two treatment arms, 16 patients
(13%) were subsequently found inevaluable for response and
toxicity (4 patients in the St-arm, and 12 patients in the PK-
arm). One patient had concomitant treatment with an alkylating
agent due to altered blood marrow function (polyglobulia), and
15 patients had major protocol violations: 3 patients had con-
comitant cisplatin dose reduction; 1 patient was adapted using
the diagram 1 instead of the diagram 2; 4 patients had an
incorrect dose reduction; S patients had an incorrect dose in-
crease; and 2 patients had both incorrect SRi dose increase and
dose reduction. Incorrect dose was considered as a percentage of
deviation from the recommended protocol dose higher than
20%. Of the remaining 106 evaluable patients, 57 were random-
ized to the St-arm, and 49 were randomized to the PK-arm. The
gender and age distribution between the two arms was not
significantly different. The distribution of patients within each
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2042 Clinical Response after SRi Monitoring
Table 2 Doses and mean percentage of initial planned dose received/cycle for patients with St- arm or PK-arm
Cycle 1 Cycle 2 Cycle 3
n Dose (mg) ± SD (%) n Dose (mg) ± SD (%)n Dose (mg) ± SD (%)
CisplatinSt-arm 57 171 ± 17(100) 52 170± 18(100) 49 170±18(100)
49 174 ± 17 (99.8) 45 174 ± 16 (99.8) 41 175 ± 16(99.8)P NSb NS NS
SRiSt-arm 57 6798 ± 801 (99.1) 52 6692 ± 994 (98.1) 49 6230 ± 1242 (91.6)
PK-arm 49 6683 ± 1219 (96.0) 45 51 18 ± 670 (72.6) 41 4855 ± 1670 (68.9)P NS P<0.00l P<0.001
a The percentage of cisplatin dose was 99.8% for the three cycles because one obese patient received at each cycle 95% of the initial dose.b NS, not significant.
Table 3 5FU AUCO_%h (ng . Wmi) received/cycle
Cycle 1 Cycle 2 Cycle 3
St-arn� 31,220 ± 12,414 (n 53) 33,389 ± 1 1,476 (n 50) 31,081 ± 12,551 (n 42)PK-��” 29,525 ± 10,673 (n = 45) 24,909 ± 8,491 (n 42) 23,539 ± 7,492 (n 40)
P NS P<0.OOl P<0.0l
a Due to analytical problem, AUC0_�,.J, was not evaluable for all patients.b NS, not significant.
stratification variable (performance status, tumor site, tumor
stage, and node stage) was also comparable (Table 1).
Cisplatin and SFU Doses. The initial cisplatin dosereceived/cycle was not significanfly different between the
two treatment arms (Table 2).
Considering SRi, the percentage of the SRi initial planned
dose was sigmficanfly different in the two groups of treatment
during cycle 2 and cycle 3 (P < 0.001). In PK-arm, the changes
were more pronounced (72.6% for cycle 2 and 68.9% for cycle
3) as compared with the St-arm (98.1% for cycle 2 and 9 1.6%
for cycle 3). In the St-arm, changes corresponded to reductions
in SRi delivered dose according to pretreatment toxicity (3.9%
and 20.9% of the cycles had SRi dose reductions during cycle
2 and cycle 3, respectively). In PK-arm, changes were due either
to a decrease or to an increase in SRi doses according to the
pharmacokinetic protocol for dose adaptation, or to reductions
in SRi-delivered doses according to pretreatment toxicity. Dur-
ing cycle 2, SRi dose reductions occurred in 66.6% of the
cycles and dose increases occurred in 8.8% of the cycles. During
cycle 3, the changes occurred in 78.0% of the cycles (dose
reduction) and in 4.8% of the cycles (dose increase).
When dose modifications were performed, reductions
ranged from -40% to -50% in the St-arm and from -40 to
-48% in the PK-arm. The percentages of dose increases in the
PK-arm were low: 6% and 7% for cycle 2 and cycle 3, respec-
tively.
SRi AUC/Cycle. SRi AUCO_�h were available for pa-
tients in the St-arm and the PK-arm (Table 3). During cycle 1�
there was no significant difference between the two treatment
arms (AUCO_96h 31,220 ± 12,414 ng.h/ml and 29,525 ±
10,673 ng.h/ml for the St-arm and the PK-arm, respectively).
During cycle 2 and cycle 3, AUCO_%h were significantly lower
in the PK- arm as compared with the St-arm (P < 0.01). There
was less interpatient variability for AUC values in the PK-
guided arm in comparison with the ST-arm (coefficient of
variation: 31% versus 40%, P < 0.001, cycle 3).
Toxicity. Hematological and mucosal toxicities attribut-
able to SRi were significantly reduced in the PK-arm as com-
pared with the St-arm (Fig. 2). Grade 3-4 neutropenia and
thrombocytopenia were observed in 17.5% of the cycles in the
St-arm as compared with only 7.6% in the PK-arm (P = 0.013).
A complete absence of mucositis was observed in the PK-arm,
whereas 5.1% ofthe cycles in the St-arm experienced grade 3-4
toxicity (P < 0.01). There was no significant difference in
digestive tract toxicity between the two treatment arms.
Due to SRi-related toxicity, three patients (5.2%) in the
St-arm left the study before completing chemotherapy: two
patients after cycle 1 and one patient after cycle 2. In the
PK-arm, three patients (6,1%) left the study before completing
chemotherapy: one patient after cycle 1 and two patients after
cycle 2. As for cycle delay, the incidence was lower in the
PK-arm (14.9% of cycles, corresponding to 165 days) as com-
pared with the St-arm (21.2% of cycles, corresponding to 213
days), but the difference was not significant (P = 0.269).
Response. Patients (77.2%) in the St-arm (19 of 57 or
33.3% CR; 25 of 57 or 43.9% PR) and 81.7% of patients in the
PK-arm (14 of 49 or 28.6% CR; 26 of 49 or 53.0% PR)
responded to treatment. The objective response rates were sig-
nificantly equivalent (Dunnett and Gent, P = 0.03), with upper
90% confidence limit equal to 8.7% (Fig. 3).
Link between Clinical Events and Pharmacological
Data. Table 4 illustrates the link between hematological tox-
icities and mucositis with average AUC0�,/cycle and SFU
doses. The analysis was performed on the whole study group
(n 106 patients). All patients received one, two, or three
cycles. The mean value for the average AUCO�h was signifi-
cantly related to the severity of hematological toxicity (grade
3-4; P = 0.035). No significant relationship was found with
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20� 17.5%
1�
10.
5’
(I)Ui-a
0U.0
5.1%
0
thrombocyto�-3.4
. St-arm
EIPK.aml
R
E1
8.1%
D�ttvs Toxicitygrad. 3-4
Fig. 3 Response rate 2 weeks after completionof 5FU-cisplatin chemotherapy for patients with
St-arm (0) and for patients with PK-arm (El).Test for equivalence significant: P = 0.03 (Dun-nett and Gent test).
77.2% 81.7%
53.0%
Coniplet. PMIaI
Rssponss RsponsObjectiveResponse(CR + PR)
Clinical Cancer Research 2043
Fig. 2 Grade 3-4 toxicity for patients with St-arm (EJ) and for patients with PK-arm (El). P0.013 for neutropenia and/or thrombocytopenia;P < 0.01 for mucositis; P not significant fordigestive toxicity (including nausea, vomiting,
and diarrhea).
100.
Cl) 70.I-.zUi
� 30�
20�
10.
0-
SRi dose. For mucositis, average AUCO_96h was higher in
patients with severe toxicities (grade 3-4), but the difference
was not significant as compared with patients with no or mod-
crate toxicity (grade 0-2).
Regarding objective response (Table 5), no significant as-
sociation was observed with available pharmacokinetic param-
eters (average, AUCO96h and AUCO_96h intensity) and SRi
doses (average dose/cycle and dose intensity).
DiscussionThe current role of chemotherapy in head and neck carci-
nomas is presently focused on the treatment of locally advanced
stages, for which continuous infusion SRi and cisplatin chem-
otherapy is considered as a reference protocol (15). This proto-
col has demonstrated a high response rate (80%), but severe
toxicities have been reported. Several investigators have shown
that interindividual variability in SRi clearance and AUC are
linked to the risk of severe toxicities (7, 16-18). These phar-
macokinetic parameters have also been reported to be correlated
with response and survival in patients receiving 5FU-cisplatin
induction chemotherapy (8, 19). In the present study, it was
Table 4 Analysis of clinical toxicity as a function of 5FU
pharmacological parameters (all patients)”
Average AUC�%h/
cycle (ng . h/ml)
Average dose/cycle
(mg)
Hematologic ToxicityGrade 0-2 27,622 ± 7,752 (65)” 6,104 ± 1,339 (75)Grade 3-4 3 1,45 1 ± 6,924 (26)”
P - 0.035
6,070 ± 980 (31)
NSC
Mucositis
Grade 0-2 28,866 ± 8,066 (86)” 6,098 � 1,248 (100)Grade 3-4 34,285 ± 6,814 (5)”
NS
6,225 ± 962 (6)
NS
a Values are given as mean ± SD (number of patients).b Average AUC#{216}_��/cyc1e in I 5 patients was not evaluable.
C NS, not significant.
possible to confirm the relationship between SFU pharmacoki-
netics and pharmacodynamics. Cycles with grade 3-4 hemato-
logical toxicity had significantly higher SRi systemic exposure
than cycles with grade 0-2 hematological toxicity. This obser-
vation is consistent with a study by Vokes et al. (8) who noted
Research. on March 26, 2020. © 1998 American Association for Cancerclincancerres.aacrjournals.org Downloaded from
2044 Clinical Response after SRi Monitoring
4 M. C. Etienne, E. Chatelut, M. Lavit, A. Pujol, P. Canal, and 0.
Milano, unpublished data.
Table 5 Analysis of clinical response as a function of SRi pharmacological parameters”
Average AUC�,�,/cycle (ng ‘ h/mi)
AUC�.%h intensity(ng ‘ h/mlJw)
Average dose/cycle (mg)
Dose intensity(mg/w)
Responders”NonrespondersP
29,065 ± 8,174 (75)C
28,180 ± 5,636 (l6)CNS”
15,766 ± 4,774 (75)C
16,401 ± 3,348 (l6)’�NS
6,133 ± 1,138 (87)5,887 ± 1,651 (19)
NS
3,378 ± 860 (87)3,425 ± 1,049 (19)
NSa Values are given as mean ± SD (number of patients).b Responders, patients with complete or partial responses; nonresponders, patients with stable or progressive disease.C Average AUC#{216}_%,,/cycle and AUC0_�F.J, intensity in 15 patients were not evaluable.d NS, not significant.
a significant inverse correlation between neutrophil nadir values
and SRi plasma concentration, and only a poor correlation
between SRi pharmacokinetics and mucositis. In the present
study, no link was found between SRI pharmacokinetics and
mucositis. As for tumoral response, no difference in average
AUCO_96h and AUCO_%h intensity was observed between pa-
tients who achieved a CR or PR and patients who had stable
disease or progression. This result is not consistent with previ-
ous studies (8, 19) that demonstrated that response and survival
were significantly related to high SRi plasma concentrations in
patients with head and neck cancer. This discrepancy can be
explained by the fact that in these previous studies, the patient-
to-patient variability may have been larger than in the present
one. Therefore, a closer relationship between tumor response
and SRi systemic exposure could be evidenced.
SRi therapeutic monitoring with SRi dose adjustment was
previously performed, and comparisons with historical groups
suggested that the SRi therapeutic index could be improved
with SRi dose adaptation based on pharmacokinetics (9). To
our knowledge, the present study is the first randomized trial to
investigate the clinical impact of pharmacokinetically-guided
dose adaptation. This work was centered on SRi clinical phar-
macology only, despite the potential role played by cisplatin in
the pharmacodynamics data analyzed herein. In fact, cisplatin
exhibits antitumor activity against head and neck tumors (17%
response rate; Ref. 20), and experimental data strongly suggest
that cisplatin enhances SRi cytotoxicity by indirecfly increasing
the intracellular levels of reduced folates (21, 22). In the present
study, the impact of individual SRi dose adaptation based on
pharmacokinetics on clinical outcome is striking. The present
randomized trial clearly demonstrates that patients with individ-
ually adapted SRi dose rate develop significanfly lesser toxic
manifestations than patients receiving a fixed SRi dose. In the
PK-arm, grade 3-4 neutropenia and thrombocytopenia were
reduced by more than 50%, and no grade 3-4 mucositis was
observed. These results reflect the dose reduction applied in the
PK-arm and the subsequent reduction in AUC values (Table 3).
SRi dose modifications were mainly dose reductions (66% and
78% of cycles 2 and cycles 3, respectively) and with few dose
increases (8.8% of cycles 2 and 4.8% of cycles 3), thus indicat-
ing that the target AUC in this protocol is very close to the
maximal tolerated dose.
The overall response rate remained within the range of
those usually observed in these tumors (iS). It should be noticed
that the SRi dose modifications performed did not alter the
response rate. In a retrospective study, Santim et a!. (1989)
reported similar results in monitored patients (9).
Previous work (9) shows that for the S-day continuous
infusion of SRi combined with cisplatin, the AUC predictive
for toxicity is 30 000 ng.h/ml. Our results (Table 4) for the 4-day
SRi infusion confirm that high-grade hematological toxicity is
associated to SRi AUC higher than 30,000 ng.h/ml (average
AUCO�h 31,451 ± 6,954 ng.h/ml). Taken together, these
data demonstrate that for 5- and/or 4-day continuous infusion of
SRi, the target SRi AUC for an optimal dose is 30,000 ng.b/ml.
An alternative approach based on pretreatment determination of
biological parameters instead of pharmacokinetics should be
investigated to anticipate individual SRi clearance and SRi
AUC. Such a strategy has already been applied successfully to
carboplatin with individual dosage calculation based on pre-
treatment glomerular clearance determined directly (23) or in-
directly (24). As for SRi clearance, correlations have been
demonstrated between this parameter and pretreatment hepatic
function test (serum alkaline phosphatase level), age, and the ac-
tivity of dihydropyrimidine dehydrogenase (25, 26, 27), the main
enzyme involved in the catabolism of SRi. However, these corre-
lations were too weak for a reliable prediction of SRi clearance.4
Interestingly, the development of new dihydropyrinildine dehydro-
genase inhibitors (such as ethinyluradil), when combined with SRi,
lead to the elimination of SRi mainly by kidney route and to a
decrease of the interindividual variability in SRi clearance. In this
case, it would be possible to predict SRi clearance based on
creatinine clearance and thus to evaluate the optimal individual
SRi dose before starting treatment (28).
For other drugs than anticancer agents like aminoglyco-
sides, the cost-saving benefit of therapeutic drug monitoring has
been demonstrated (29). In the present study, a pharmaco-
economic analysis was undertaken in a subgroup of 82 patients
(41 patients in each arm; data not shown). The medical cost
included three management groups. The first group included
hospitalization and patient care required to manage toxic events.
The second group included costs linked to SRi plasma concen-
tration monitoring. The third group included cost linked to
calculation of SRi dose adjustment. Overall, our analysis dem-
onstrated a reduction of 14.6% in the medical cost in the
PK-arm. More precisely, the respective costs (U. S. dollars) for
the ST-arm and the PK-arm were, $21,758 and $6,803 for
toxicity management; $0 and $13,798 for SRi monitoring; and
$16,835 and $12,325 for SRi dose adjustment. This information
Research. on March 26, 2020. © 1998 American Association for Cancerclincancerres.aacrjournals.org Downloaded from
Clinical Cancer Research 2045
indicates that economic approach should be included as an end
point in clinical pharmacokinetic studies.
In conclusion, this prospective study strongly suggests that
the exploitation of SRi pharmacokinetic-pharmacodynamic re-
lationships could improve cancer chemotherapy of locally ad-
vanced head and neck carcinomas. We hope that the present
study would show the interest, for other anticancer drugs, of
prospective studies conducted on the basis of randomized trials,
to establish the clinical value of individual drug dosage based on
real time pharmacokinetic follow-up.
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1998;4:2039-2045. Clin Cancer Res R Fety, F Rolland, M Barberi-Heyob, et al. patients with locally advanced head and neck carcinomas.of 5-fluorouracil: results from a multicentric randomized trial in Clinical impact of pharmacokinetically-guided dose adaptation
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