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In!. J. Cancer: 68,452-456 (1996)
C 1996 Wiley-Liss, Inc.
-'s;-:
Publication ofthe International Union Against Cancer
Publication de I'Union InternationaleConrre le Cancer
TUMORAL PLATINUM CONCENTRATIONS IN PATIENTS TREATED
WITH REPEATED LOW-DOSE CISPLATIN AS A RADIOSENSITIZER
Jean-Leon LAG RANG^:^, Pierre-Yves BONDIAU',
Eric TESSIER',
Pierre CHACVEL', Nicole RENEE',
and Gerard MII.ANO~.~
Marie-Christine ETIEN!W*
Departments of 'Radiation Oncology and *OncopharmacoIogy, Centre Antoine-Lacassape,Nice, France.
The aim of the present study was to check whether platinum
(Pt) concentrations achieved in tumors with a daily low-dose
schedule were close to those promoting radiosensitization.
Fifteen previously untreated patients with histologically proven
advanced uterine cervix tumors were studied. They received a
daily irradiation30 min after a short infusion of 5 mg cisplatin for
5 consecutive days every week. A biopsy was taken from the
accessible tumor mass, 4 to 6 hr after the daily injection. Blood
samples were obtained once a week, just before the daily
injection (HO) and 30 min after (H30). Quantificative analysis of
Pt concentrationswas performedby atomic absorption spectrophotometty. Plasma and tumoral Pt concentrations exhibited a
marked intersubject variability. The median tumoral Pt concentration was 1,710 mg/g. Median total and ultrafiltrable Pt
concentrations in plasmataken at HO and H30 were 23 I and 360
ng/ml. and 7 and 90 ng/ml respectively. Tumoral and total
plasma Pt concentrations significantly increased during the
course of treatment. Present data show that tumoral Pt
concentrations achieved with this CDDP schedule are in the
range of tumoral Pt concentrations previously shown to promote radiosensitization(2,000 ng/g). These results suggest that
this CDDP radiosensitization regimen might be started with
higher CDDP doses in order to reach earlier radiosensitizing Pt
tumoral concentrations.
01996 Wiley-Liss, Inc.
Cisplatin (CDDP) is one of the most active chemotherapeutic agents presently available. Apart from its direct anti-tumor
effect, CDDP exhibits interesting and apparently complex
interactions with radiation (Kallman, 1994). Experimental
data are scanty and have suggested that platinum (Pt) concentrations around 2,000 ng/ml (i.e., 10 pM) are necessary to
induce radiosensitization and inhibition of DNA repair processes (Douple and Richmond, 1978; Fu et al., 1988). Additional work by Douple et al. (1991) pointed to a threshold for
tissular Pt concentration allowing radiosensitization; according to these authors, this threshold value should be located
around 2,000 ng/g. There is currently no general consensus for
the optimal CDDP dose and optimal timing in the sequence of
administration of the drug and irradiation. However, data
obtained both in vitro (Lagrange et al., 1993) and in vivo
(Kallman, 1994) have suggested that CDDP is more effective
when given a short time before irradiation. Van Harskamp
et al. (1987) have previously reported interesting therapeutic
efficacy obtained with a combination of daily low-dose CDDP
quickly followed by radiotherapy for inoperable, non-smallcell lung cancer. In our institute, a pilot study was previously
initiated based on the same principle of daily, low-dose CDDP
plus radiotherapy in patients with inoperable cervical cancer.
According to this protocol, the daily CDDP dose ( 5 mg) is
given 30 min before irradiation (1.8-2 Gy) for 2-5 weeks,
depending on the patient's disease stage. In order to better
understand this treatment strategy, we initially investigated
both plasma and tumor pharmacokinetics in these patients
(Milano et al., 1990). The present study concerns the analysis
of tumoral Pt concentrations during the course of treatment
aiming specificallyto check whether Pt concentrations achieved
in tumors with this daily low-dose protocol were close to those
known to promote radiosensitization. The data presented
herein are complementary to those which we published prcviously (Milanoet al., 1990).
PATIENTS AND METHODS
Fifteen previously untreated women (mean age 58 years,
range 46-76) with histologically proven advanced uterine
cervix tumors were entered into this study. All patients were
treated with daily irradiation (1.8-2 Gy) 30 rnin after a short
infusion ( 5 min) of CDDP ( 5 mg in 50 ml 0.9% NaCI) for 5
consecutive days every week. This treatment was applied for 2
weeks to patients with stage-I1 diseasc (cumulative dose: 50 mg
CDDP, 20 Gy) and for 4 to 6 weeks to patients with stage
111-IV disease (cumulative dose: 100-150 mg CDDP, 40-60
Gy). Before starting treatment, all patients had normal renal
function (blood creatinine value below 150 +mol/l), a Karnofsky performance status of at least 60% and a life expectancy of
at least 12 weeks. Renal function (blood electrolytes, urea and
creatinine) and hematological function (RBC, WBC, platelet
count) were evaluated every week during treatment. Response
to treatment was evaluated at the end of the treatment period.
Complete response (CR) Corresponded to the disappearance
of all clinically visible or palpable lesions; partial response
(PR) was defined as tumor regression of >50% and was
stratified between major PR ( > 75%) and minor PR (> 50%
and <75%); no response (NR) corresponded to tumor regression of s50'%,stable disease, or progressive disease.
Pharmacokinetic investigations
Tiirnors
Every week, a clinical examination was planned to check on
changes in the tumor. At this time and whenever possible a
biopsy was taken from the accessible tumor mass 4 to 6 hr after
the daily injection once a week on the first or second day of
treatment. In total, 27 tumor biopsies were performed during
the treatment: 7 in the 1st week, 6 in the 2nd week, 7 in the 3rd
week. 4 in the 4th week, 2 in the 5th week and one in the 6th
week. Repeated tumor sampling (2 to 4) was performed for 6
patients. In addition, for 4 patients, biopsies were performed
at a certain distance after the end of treatment.
Blood samples
In addition to tumor biopsies, blood samples were obtained
once a week on the first or second day of treatment, just before
a daily injection (HO) and 30 min after the end of the injection
(H30). HO and H30 samples were taken whenever possible on
the same day and from the same patients. In case of practical
difficulties (patient's status), only the HO sample was taken.
A total of 57 blood samples were thus analyzed. Only these 2
blood samples per patient and per week were requested in
order to limit the weight of pharmacological investigations for
patients.
3T0whom correspondence and reprint requests should be addressed, at
the Centre Antoine-Lacassagne, Oncopharmaculogy Laboratory, 33
avenuc Valombrose, 06050 Nice, France. Pax:33 04 93 81 71 31.
Received: April 25,1996 and in revised form August 12, 1996.
'TUMORAL PLATINUM CONCENTRATIONS IN LOW-DOSE CISPI.ATIN TREATMENT
For 8 patients it was possible to obtain both a tumoral biopsy
and blood samples on the same day.
453
RESULTS
Considering all available data, tumoral and plasma Pt
concentrations exhibited a marked variability between subjects. Tumoral Pt concentrations were comprised between 0
Treatment of samples
and 12,600 ng/g (median 1,710, mean 2,200). At HO, total Pt
varied between 0 and 507 ng/ml (median 231, mean 227,
Blood
n = 34) and U F Pt varied between 0 and 80 ng/ml (mcdian 0,
Blood samples (3 ml) obtained in ethylenediaminetetraace- mean 7.1, n = 34). At H30, total Pt varied between 120 and 579
tic acid (EDTA) tubes were immediately placed in a water ng/ml (median 360, mcan 346, n = 23) and U F Pt varied
bath containing ice for transport to the laboratory (within between 10 and 160 ng/ml (mcdian 90, mean 85, n = 21).
10-15 min) and were then centrifuged at 4°C. A 500-pIaliquot Table I illustrates the variations in tumoral and plasma Pt
of the resulting plasma was centrifugcd for 30 min at 2,000 g concentrations according to duration of treatment course.
(4°C) in a Centrifree micropartition unit (Amicon, Denvers, Interestingly, tumoral Pt concentrations significantly increased
MA). The resulting ultrafiltrate fraction was used to determine during the course of treatment and this pattern was particuultrafilterable (UF) Pt. Total Pt was measured in the whole larly pronounced between the 1st and 4th weeks of therapy.
plasma fraction. Samples were stored at -20°C until analysis. Also, total Pt concentrations in plasma significantly increased
during the treatment course. The accumulation in total Pt
concentration was observed in plasma samples taken both at
Biopsies
Biopsies (10-15 mg) were taken from the accessible tumor HO and at H30 min. In contrast, U F Pt concentrations
mass. Excess blood was removed and the tissue sample was mcasurcd in plasma at HO and H30 did not reveal any
accumulation pattern during treatmcnt course.
placed in a screw-top plastic tube that was stored at -20°C
until analysis. Biopsies were then weighed (wet weight) and
Tumor biopsies were obtained from 8 patients on the same
digested overnight with 500 FI 50% nitric acid, then homog- day as blood samples (H30). These 8 paired samples showed
enized in a glass-glass potter. The homogenate was dried no correlation (Spearman rank correlation) between tumoral
under a nitrogen strcam (50°C) and the dried residue was Pt Concentration and either plasma total Pt concentration at
dissolved in 200 pI H 2 0 .
H30 (p = 0.23) or plasma U F Pt concentration at H30
( p = 0.17).
In 6 patients, serial tumoral biopsies were obtained. Figure 1
Pt assay
Quantificative analysis of Pt in samples was performed by illustrates the intra-patient accumulation of tumoral Pt concenatomic absorption spectrophotometry (AAS) using a Pcrkin- tration during the treatment course for these 6 patients. For 4
Elmer model 3030 atomic absorption spcctrophotometer with patients, biopsies were performed at distance, between 7 and
background correction by the Zeeman effect for trace analysis. 21 days after the end of treatment. Figure 2 shows the decrease
Ultrafiltrates and biopsy extracts were measured without in Pt tumoral concentrations for these 4 patients.
In the limited set of 8 patients available for both tumoral
dilution. Before analysis, plasma was diluted 1:2 in a 0.2%
H N 0 3 solution containing 0.01% Triton X-100. The injected pharmacokinetics and clinical response, tumoral Pt concentravolume was 20 ~ 1 A. standard curve (0, 162,325,650 ng/ml of tions were not significantly different between patients with NR
Pt) was automatically performed with an auto-sampler using a (<SO%) or P R <75% and those with P R > 7 5 % or C R
standard Pt solution. Analysis included the following steps: (Mann-Whitney test).
drying at 110°C for 40 sec; ashing at 1,400"C for 20 scc and
atomization at 2,650"C with a 3-scc stop flow and tube cleaning
at 2,650"C for 4 scc. The limit of sensitivity (2 times the noise)
DISCUSSION
was 5 ng/ml for plasma and 2.5 ng/ml for U F and biopsies.
A
review
of
published
data
concerning Pt tumoral concentraIntcr-assay reproducibility calculated from 25 successive series
of analyses was 12.2%, 9.6% and 5.5% for Pt concentrations of tions is presented in Table 11. A feature common to all studies
is the marked interpatient variability in Pt tumoral levels for a
30,300 and 900 ng/ml, respectively.
TABLE I - DESCRIPTION OF TUMOHAL 1'1, PLASMA TOTAI. Pt AND PIASMA U F Pt CON('ESTRATlONS ACCORDING TO TREATMENT COURSE (WEEKS)
.
1
2
230 (0-3100)
n=7
1830 (20-2500)
n=6
3
4
5
6
Link between increase in Pt concentrations (blood, tumor)
and the duration of treatment
(Spearman rank correlation)
HO?
~
~~
1710 (350-5500)
n=7
5525 (920-12600)
n=4
2005(410-3600)
n=2
600
n=l
r = 0.41
p = 0.034
UF Pt concentration in
plasma' (ng/ml)
Total Pt concentration in
plasma' (ngiml)
Tumoral PI
concentrationi
(ntYg)
Week
~.
106 (0-210)
n=9
289 (134-410)
n = 11
270 (224-507)
n=6
252 (10-434)
n=S
311 (304-363)
n=3
n=O
r = 0.59
p = 0.0007
1?3IS
197 (12M18)
n=7
384 (190-520)
n=6
400 (321493)
n=4
360 (210-579)
n=3
378(363-392)
n=2
45 1
n=l
r = 0.49
p = 0.021
.~
tIW
H302
0 (0-9)
n=9
90 (10-110)
n=7
85 (20-160)
n=6
112 (105-140)
n=3
80 (54-100)
n=3
58
n = l
90
10 (0-30)
n = 11
0 (0-80)
n=6
0 (0-11)
n=5
12(6-13)
n=3
n=O
NS
n = l
NS
'Median and extreme values, n = number of patients.-?HO means just before the daily CDDP injection; H30 means 30 min after the
end of the injection.
LAGKANGE ETAL.
454
I
I
8
I
I
8
I
I
I
I
I
I
0
7
14
21
26
35
100000
c
w
\
-m
C
10000
E
2
L
.r(
U
m
1000
I+
a.
I+
m
L
0
100
E
3
F
I0
42
Days o f t h e r a p y
RGURE
1 - Plot of the evolution of tumoral Pt concentrations for 6 patients undergoing serial tumoral biopsies (each symbol depicts a
different patient).
10000
I
I
I
1
I
I
8
I
0
7
14
21
-I5
\
m
c
Y
E
1
1000
c
.d
I+
m
100
L
0
E
3
I-
10
Days a f t e r c e s s a t i o n o f t h e r a p y
F~GURE
2 - Plot of decrease in tumoral Pt concentrations for 4 patients undergoing a biopsy on the last day of treatment along with a
biopsy at distance after cessation of treatment (each symbol depicts a different patient).
given dose, for instance at 100 mg/m2. When differcnccs
between mean values are considered, it appears that data are
quite well grouped, with values varying between 1,000 and
4,000 ng/ml when determined within 48 hr after drug adminis&ration,an exception being [he study of Pujol el al. (1990)
where concentrations 10 timcs higher were reported. The fact
that, in this later study, tumor samples were obtained shortly
after the end of cisplatin administration is not sufficient to
explain this markcd difference in Pt concentration as compared to other studics. Our data concerning low daily CDDP
doses concur well with those published by Stewart et al. (1995)
at a dose of 10 mg/m2. Furthermore, our results obtained after
3 and 4 wceks of rcpeated daily low-dose cisplatin, giving a
cumulated dose of 75-100 mg, are within thc range of
TUMORAI. PLATINUM CONCENTRATIONS I N LOW-DOSE CISPI.ATIN TREATMENT
455
TABLE I1 - PLATINUM COSCENTRAIIONS I N TUMORS-A KEVIEW OF THE LITERATURE
,r;:zs
Author (reference)
time after
Tumor localization
Cisplatin dose (protocol)'
cisplatin injection
-.
'Troger et al. (1991)
Hecquet et al. (1985)
Pujol et al. (1990)
Hecquet et al. (1986)
Gouyette er af. (1986)
14
22
8
8
9
Esophagus
Cervix (9)
Head and neck (10)
Breast (3)
.,
Lung
Cervix
24
Head and neck
Mattox et a/. (1983)
5
Head and neck
Vennin et al. (1985)
10
Cervix
Holdinget al. (1991)
27
Head and neck
Stewart et al. (1995)
Los et al. (1995)
Lagrange et al. (present
study)
20
23
Different tumors
Head and neck
Cervix
15
24-36 hr
48 hr
48 hr
48 hr
30 min
30 min
100 me/m2
hr (i.v.)
- (i.v.
. + i.a.) 24
24 hr (La.)
day 21 (i.v.)
day 3 (72 hr) i.a. 1 hr
50 mg/m2day 1
i.a. 6 hr
50 mg/m2day 2
(i.v. + i.a.)
i.v. 1 hr
i.v. 6 hr
100 rng/m?,4 patients (i.v.) 2 hr
50 mg/m', 1 patient (i.v.) 6 hr
24 hr
50 mg, 2 patients (i.v.)
2 hr
100 mg, 8 patients (i.v.) 4 hr
24 hr
48 hr
100 mgim? (i.v.)
0 hr
24 hr
41-64 hr
500 hr
700 hr
10 mg/m2 (i.v.)
1.25 hr ( 5 min to 6 hr)
150 mg/m? (La.)
24 hr
5 mg/day (i.v.)
4-6 hr week 1
week 2
week 3
week 4
Platinum concentrations
mean t SD and/or
range W g )
3,750 ? 2,300
1,800 f 1,000
1,600 f 800
4,200 f 1,400
51,130 f 65,500
22,490 f 53,900
1.OOO-5.Y00
'900-5;YOO
200-500
2.760 f 2.590
1;930 -t 11250
1.270 k 350
11320 f 410
1,800 1,100-2,800)
2,700 6004,400)
1,300 1,200-1,300)
500-7,250
4,970 f 8,750
2,610 f 1,930
1.830 f 1.060
3;800 l;500
3,700 ? 1,500
2,800 (8004,300)
300
15.000
380 f 140
60040,700
680 k 1,120
1,720 k 880
2.160 f 1.800
6,140 f $230
i
*
'I.V., intravenous administration; i.a., intra-arterial administration.
concentrations found after a single dose of cisplatin at 100
mg/m2. The constant accumulation of tumoral Pt we found
during the treatment period is in agreement with experimental
data showing that cisplatin uptake is not saturable (Gately and
Howell, 1993). After treatment cessation, a diminution in
tumoral Pt levels was obscrvcd in samples obtained 6 to 21
days after the end of the treatment period. This is consistent
with the data reported by Holding et al. (1991) and Hecquet
et al. (1986, 1987). There arc few data which describe CDDP
efflux from cells. We recently undertook an in v i m study to
analyze more thoroughly relative influx and efflux of CDDP
from human cancer cells in culture (Troger et af., 1992). We
observed that C D D P can leave the cells following a 2-slope
kinetic pattern with an a half-life of 1.29 hr and a p half-life of
94.4 hr. The slow release of platinum from tissues has recently
been emphasized by Schicrl et al. (1995). These authors
examined urinary platinum concentrations in 23 men at
150-3,022 days after C D D P treatment for testicular neoplasm.
Regression analysis showed 2 phases of long-term renal
platinum excretion, one occurring between 150 and 900 days of
follow-up and the other beginning at 900 days after cisplatin
administration. Onc can spcculate on the possible cytotoxicity
exhibited by the long-term circulating Pt species. We recently
reported data concerning the in vitro cytotoxic effects of a
serum aliquot taken 3 weeks after cisplatin administration in a
patient with renal insufficiency (Lagrange et a/., 1994). Interestingly, this serum sample induced marked in vitro cytotoxic
effects on cancer cells in culture which were much greater that
those which could have been anticipated considering the Pt
concentration of this serum sample. Thus, the release of Pt from
tissues, as stressed in the present study, may lead to Pt
circulating species which can play a role in the pharmacological effects of the drug.
Troger et al. (1992) have shown that the cytotoxicity of
C D D P in vitro is directly related to intracellular concentrations
of the drug. O n the other hand, decreased Pt accumulation
develops early during the selection of resistant cclls both in
vitro and in vivo (Gately and Howell, 1993). Our knowledgc
concerning the hypothetical link between tumoral Pt concentrations and clinical response is limited. So far, both Bielack et al.
(1989) and ourselves (Troger et al., 1991) have failed to
demonstrate any relationship between tumor Pt concentration
and treatment efficacy. Here again, based on a small number of
cases, we reached the same conclusions. Pujol et al. (1990)
found a weak correlation between simultaneous plasma and
tumoral Pt concentrations. In the present study, based on a
limited number of paired samples, we failed to find a relationship between these 2 parameters. Thus, the variability in
plasma pharmacokinetics does not seem to account for the
differences in tumor Pt concentrations. It must be emphasized
that, according t o the work of Fu et al. (1988), low-dose-rate
irradiation probably had no influence on the pharmacokinetics
of plasma and tumor Pt. Stewart et al. (1995) recently reported
on factors affecting Pt concentrations in human tumor specimens. They found, by multiple stepwise regression analysis,
that the patient characteristics most closely associated with
tumor Pt concentrations were tumor type, serum calcium and
chloride and bilirubin levels.
Some studies indicate that the radiosensitizing capability of
C D D P is highly time-dependent (Lagrange et a/., 1993; Kallman, 1994). C D D P would be more effective when given a short
time before irradiation. This suggests that C D D P in tissues
does not remain in a radiosensitizing form (not identified) for
more than a limited period of time. However, some authors
have reported the attainment of tumoral Pt concentrations
around 2,000 ng/g which induced radiosensitization (Carde
456
LAGRANGE E T A L
and Laval, 1981; Douple et a/., 1991). Table I shows that, on
average, these optimal concentrations were obtained by the
2nd week of treatment. In addition to enhancing our understanding of Pt concentrations in tumors, the present results, in
the light of the pharmacokinetic data, point to several practical
consequences. The main one could involve shortening the total
duration of the cycle and starting the protocol with higher daily
doses in order to reach potentially radiosensitizing Pt tumor
concentrations carlier in the treatment course. This approach
was recently used by Los et al. (1995) who demonstrated that
intra-arterial administration of high-dose CDDP led to high
tumor Pt concentrations and CDDP-DNA adducts, which
resulted in high rcsponse rates when combined with daily
irradiation.
REFERENCES
BIELACK,
S.S., EKTAMNN,
R. and Loon, G., Platinum disposition after haemodialysis in clcaring them. Europ. J. Cancer, 14, 2057-2060
intratumoral and intravenous infusion of cisplatin for osteosarcoma. (1994).
Cancer Cheniother. Pharmacol., 24,376-380 ( 1989).
LAG RANG^, J.L., FISCHEL,
J.L., GALLIANI,
S., FORMENTO,
P., GUILLOT.
M. and MILASO,G., Importance of the irradiation timing
CARDE,P. and LAVAI.,F., Effect of cis-dichlorodiamine platinum I1 T., BAKDON,
and X rays and mammalian cell survival. Inr. J. Radial. Oncol., 7, within a chemotherapy sequence including cisplatin and 5FU folinic
acid. Experimental results. Europ. J. Cancer, 29,1531-1535 (1993).
929-933 (1981).
F.A., BARTON,
R., HEAI'H.D.D., DES ENGELSE,
DOUPLE,
E.B. and RICHMOND,
D.R.C., Platinum complexes a s radio- Los, G . , BLOMMAERT,
L., I~ASCHFIT,
C., VICARIO,
D., WEISMAN,R., ROBBINS,
K.T., and
sensitizers of hypoxic mammalian cells. Brit. J. Cancer, 37, 98-102
HowIi.~.,S.B., Selective intra-arterial infusion of high-dose cis latin in
(1978).
with advanced head-and-neck cancer results in hi& tumor
DOUPLE.E.B., WILLS,M.L. and JONES,E.L., Radiopotentiation in a patients
platinum concentrations and cisplatin-DNA adduct formation. Cancer
murine tumor (MTG-B) by continuous infusion platinum. In: M. Cheniother.
Pharmacol., 37,150-154 (1995).
Rotman and J.C. Rosenthal (eds.), Concomitant continuous infusion
chemotherapy and radiation, pp. 191-196. Springer, New York (1991). MAITOX, D.E., STEKSSON,L.A., VANHOFF, D.D., KUHN,J.G. and
REPI'A, A.J., Tumor concentrations of latinum in patients with
Fu. K.K., DE GKEOOKIO,
M.W. and PHILLIPS.
J.W., Plasma and tumor head-and-neck cancer. Otolatyngol. H e a l Neck Surg., 91, 271-275
concentrations of cisplatin following intraperitoneal infusion o r bolus (1983).
injection with or without continuous low-dose rate irradiation. Nat.
MILANO,
G., TROGER,
V., COURDI,
A.. FON~ANA,
X.. CHAUVEL,
P. and
Cancer Inst. Monogr., 6, 123-127 (1988).
LAGRANGE,
J.L., Pharmacokinetics of cisplatin given at a daily low
GATELY,D.P. and HOWELL,S.B., Cellular accumulation of the dose as a radiosensitizer. Cancer Chernother. fhannacol., 27, 55-59
anticancer agent cisplatin. A review. Brit. J. Cancer, 67, 1171-1176
( 1990).
(1993).
PUJOL,J.L., Curissoi., D., GESTIS-BOYER,
C., BRES,J. and MICHEL,
GOUYETTE,
A,, Apaiis, A., FOKA,
M. and RICHARD,
J.M., Pharmaco- F.B., Tumor-tissue and plasma concentration of platinum during
kinetics of intra-arterial and intravenous cisplatin in head-and-neck chemotherapy of non-small-cell lung canccr patients. Cancer Checancer patients. Europ. J. Cancerrlin. Oncol., 22,257-263 (1986).
mother. Pharmacol., 27,72-75 (1990).
HECOUET,
B., LEROY,A.. LEFEBVRE,
J.L., PEYRA'~,
J.P. and ADENIS, S C H I ~ KR.,
I . , ROHKER,B. and HOHNLOSER,
J., Long-term platinum
L., Uptake of platinum corn ounds in human tumors: in vitro study. excretion in patients treated with cisplatin. Cancer Chrmother.fharmaBrill. Cancer, 73,535-541 (1916).
Col., 36,75-78 (1995).
HECOUET,
B., VENNIN,
P., FOIJRNIER,
C., LEFEBVRI,
J L , C A n , A., STEWAKT.D.J., MOI.EPO,J.M., GREEN,R.M., MONTPETIT,
V.A.J.,
BONNETERKE,
J., ADENIS,
L. and DEMAILLE,
A,, Platinum concentra- HUGENHOLTZ,
M.D.,
H., LAMOTHE,
A., MIKHAEI.,N.Z., REDMOND,
tion in human tumors of head and neck. uterine cervix and breast
GADIA,M. and GOEL,R., Factors affecting platinum concentrations in
following treatment with cisplatin. Cancer Chettiother. fhannacol., 15, human surgical tumor specimens after cisplatin. Brit. J. Cancer, 71,
310-312 (1985).
598-604 (1995).
HECOUET,
B., VENNIN,
P., FOURNIEK,
C. and POISSOSXIER,
B., Eval- TROGEK,
V., FISCHEL,
J.L., FORMENTO,
P., GIOANSI,
J. and MILANO,
uation of the pharmacological benefit and determination of the G.. Effects of prolonged exposure to cisplatin on cytotoxicity and
influencing factors of intra-arterial cis-diamminedichloroplatinum ad- intra-cellular drug concentration. Europ. J. Cancer, 28,82-86 (1992).
ministration in atients with uterine cervical cancer. Cancer Res., 47, TROGER,
V., FRANCOIS,
E., FRENAY,
M., NAMEK,
M. and MILAKO,G.,
6134-6137 (1987).
Analysis of tissue platinum distribution in atients with cancer of the
HOLDING,
J.D., LININJP,
W.E., BOWDLER,
D.A., SIODLAK,M.Z. and oesophagus. Europ. J. Cancer, 27,256-259 8991).
STELI..P.M., Disposition and tumor concentrations of latinum in VAN€IAKSKAMP,
G., BOVEN,E., VERMORKEN,
J.B., VANDEUTEKOM,
hypoalbuminaemic patients after treatment with cisplatin E r cancer of
E , GOLDING,
H., STAM,J., NJO, K.H., KAKIM,A.B.D.M.F., T I ~ R I AH..
the head and neck. Brir. J. din. fharnicrcol., 32, 173-179 (1991).
R.P. and PINEDO.
H.M., P h a s e 4 trial of combined radiotherapy and
KALLMAN,R.F., The importance of schedule and drug dose intensity in daily low-dose cisplatin for inoperable locally advanced non-small-cell
combination modalities. Int. 1. Radiat. Oncol., 28,761-771 (1994).
lung cancer. lnt. J. Radiut. Oncol.. 13, 1735-1738 (1987).
c . , DEMAILLE,
M.C. and ADENIS,
LAGRANGE,
J.L., CASSUTO-VIGUIER,
E., BARBE,V., FISCHEL.
J.L., VENNIN, L., lIECOUET, B., FOURNIER,
MOSDAIN,
J.R.,EIIE , M.C., FERRERO.
J.M., CREISSON-DUCRAY,
L., Sequential mcasurement of intratumoral platinum concentrations
P. and MILASO,G . , Cytotoxic effects of long-term in cervix uterine tumors after cisdichlorodiammineplatinum (CDDP)
A., FORW.NTO.
circulating ultrafilterable platinum species and limited efficacy of
administration. Anticancer Res., 5,369-370 (1985).
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