Clinical and pharmacokinetics study of oxaliplatin in colon cancer patients.
ABSTRACT to evaluate the therapeutic efficacy of oxaliplatin and to analyze the pharmacokinetics of both ultrafiltrable (free) and protein-bound platinum in patients with metastatic colon cancer.
60 patients with stage IV colon carcinoma received 4-6 (mean 4.5) cycles of oxaliplatin based combination chemotherapy. Response rate, progression-free survival (PFS) and toxicity were evaluated. The pharmacokinetics of oxaliplatin was evaluated in 8 patients who were given 85 mg/sqm or 130 mg/sqm using an infusion time of 2-4 h. Pharmacokinetic analysis was performed on blood, plasma and plasma ultrafiltrable by ICP-MS (Inductively Coupled Plasma Mass Spectrometry).
Overall response rate (complete and partial) occurred in 33 (55%) patients. The median time of progression was 9.3 months. Cumulative neurotoxicity, vomiting and diarrhea, myelosuppression appeared in 32.3%, 21.3%, and 39.4% patients, respectively. The mean Cmax and AUC 0-24 of oxaliplatin increased in a dose-related manner. The pharmacokinetics of platinum after oxaliplatin administration was triphasic characterized by a short initial distribution phase and a long terminal elimination phase.The clearance of ultrafiltrable platinum was relatively high and the clearance of platinum from plasma and blood cells was relatively low, which is probably a reflection of the covalent binding of platinum to these matrices.
Oxaliplatin is active and well tolerated in patients with advanced colon cancer. With a relatively low interpatient variability, it is eliminated triphasically and the mean Cmax and AUC 0-24 increases in a dose-related manner. These results provide a scientific basis for the safe and effective use of oxaliplatin in the clinic.
[show abstract] [hide abstract]
ABSTRACT: Of the new generation platinum compounds that have been evaluated, those with the 1,2-diaminocyclohexane carrier ligand-including oxaliplatin--have been focused upon in recent years. Molecular biology studies and the National Cancer Institute in vitro cytotoxic screening showed that diaminocyclohexane platinums such as oxaliplatin belong to a distinct cytotoxic family, differing from cisplatin and carboplatin, with specific intracellular target(s), mechanism(s) of action and/or mechanism(s) of resistance. In phase I trials, the dose-limiting toxicity of oxaliplatin was characterized by transient acute dysesthesias and cumulative distal neurotoxicity, which was reversible within a few months after treatment discontinuation. Moreover, oxaliplatin did not display any, auditory, renal and hematologic dose-limiting toxicity at the recommended dose of 130 mg/m2 q three weeks or 85 mg/m2 q two weeks given as a two-hour i.v. infusion. Clinical phase II experiences on the antitumoral activity of oxaliplatin have been conducted in hundreds of patients with advanced colorectal cancers (ACRC). Single agent activity reported as objective response rate in ACRC patients is 10% and 20% overall in ACRC patients with 5-fluorouracil (5-FU) pretreated/refractory and previously untreated ACRC, respectively. Synergistic cytotoxic effects in preclinical studies with thymidylate synthase inhibitors, cisplatin/carboplatin and topoisomerase I inhibitors, and the absence of hematologic dose-limiting toxicity have made oxaliplatin an attractive compound for combinations. Phase II trials combining oxaliplatin with 5-FU and folinic acid ACRC patients previously treated/refractory to 5-FU showed overall response rates ranging from 21% to 58%, and survivals ranging from 12 to 17 months. In patients with previously untreated ACRC, combinations of oxaliplatin with 5-FU and folinic acid showed response rates ranging from 34% to 67% and median survivals ranging from 15 to 19 months. Two randomized trials totaling 620 previously untreated patients with ACRC, comparing 5-FU and folinic acid to the same regimen with oxaliplatin, have shown a 34% overall response rate in the oxaliplatin group versus 12% in the 5-FU/folinic acid group for the first trial; and 51.2% vs. 22.6% in the second one. These statistically significant differences were confirmed in time to progression advantage for the oxaliplatin arm (8.7 vs. 6.1 months, and 8.7 vs. 6.1 months, respectively). A small but consistent number of histological complete responses have been reported in patients with advanced colorectal cancer treated with the combination of oxaliplatin with 5-FU/folinic acid, and secondary metastasectomy is increasingly done by oncologists familiar with the combination. Based on preclinical and clinical reports showing additive or synergistic effects between oxaliplatin and several anticancer drugs including cisplatin, irinotecan, topotecan, and paclitaxel, clinical trials of combinations with other compounds have been performed or are still ongoing in tumor types in which oxaliplatin alone showed antitumoral activity such as ovarian, non-small-cell lung, breast cancer and non-Hodgkin lymphoma. Its single agent and combination therapy data in ovarian cancer confirm its non-cross resistance with cisplatin/carboplatin. While the role of oxaliplatin in medical oncology is yet to be fully defined, it appears to be an important new anticancer agent.Annals of Oncology 11/1998; 9(10):1053-71. · 6.43 Impact Factor
[show abstract] [hide abstract]
ABSTRACT: Oxaliplatin, a diaminocyclohexane-containing platinum, has a spectrum of activity and mechanisms of action and resistance that appear to be different from those of other platinum-containing compounds, notably cisplatin. The first part of this review describes the differences between oxaliplatin and cisplatin in terms of their spectrum of activity and adduct formation and then goes on to discuss molecular and cellular experimental data that potentially explain them. Particular emphasis is placed on the differential role of DNA repair mechanisms. In addition, the anticancer effects of oxaliplatin are optimized when it is administered in combination with other anticancer agents, such as 5-fluorouracil, gemcitabine, cisplatin, or carboplatin; topoisomerase I inhibitors; and taxanes. In vitro and preclinical combination data that could optimize oxaliplatin-based chemotherapy are also reviewed.Molecular Cancer Therapeutics 02/2002; 1(3):227-35. · 5.23 Impact Factor
[show abstract] [hide abstract]
ABSTRACT: Oxaliplatin (cis-[(1R,2R)-1,2-cyclohexanediamine-N,N'] oxalato(2-)-O,O'] platinum; Eloxatine) is a novel platinum coordination complex used for the treatment of metastatic colorectal carcinoma in combination with fluoropyrimidines. The objective of this review is to integrate the key data from multiple studies into a single, comprehensive overview of oxaliplatin disposition in cancer patients. The pharmacokinetics (PKs) of unbound platinum in plasma ultrafiltrate after oxaliplatin administration was triphasic, characterized by a short initial distribution phase and a long terminal elimination phase (t1/2, 252-273 h). No accumulation was observed in plasma ultrafiltrate after 130 mg/m2 every 3 weeks or 85 mg/m2 every 2 weeks. Interpatient and intrapatient variability in platinum exposure (area under the curve(0-48)) is moderate to low (33 and 5% respectively). In the blood, platinum binds irreversibly to plasma proteins (predominantly serum albumin) and erythrocytes. Accumulation of platinum in blood cells is not considered to be clinically significant. Platinum is rapidly cleared from plasma by covalent binding to tissues and renal elimination. Urinary excretion (53.8 +/- 9.1%) was the predominant route of platinum elimination, with fecal excretion accounting for only 2.1 +/- 1.9% of the administered dose 5 days postadministration. Tissue binding and renal elimination contribute equally to the clearance of ultrafilterable platinum from plasma. Renal clearance of platinum significantly correlated with glomerular filtration rate, indicating that glomerular filtration is the principal mechanism of platinum elimination by the kidneys. Clearance of ultrafilterable platinum is lower in patients with moderate renal impairment; however, no marked increase in drug toxicity was reported. The effect of severe renal impairment on platinum clearance and toxicity is currently unknown. Covariates such as age, sex, and hepatic impairment had no significant effect on the clearance of ultrafilterable platinum, and dose adjustment due to these variables is not required. Oxaliplatin undergoes rapid and extensive nonenzymatic biotransformation and is not subjected to CYP450-mediated metabolism. Up to 17 platinum-containing products have been observed in plasma ultrafiltrate samples from patients. These include several proximate cytotoxic species, including the monochloro-, dichloro-, and diaquo-diaminocyclohexane platinum complexes, along with several other noncytotoxic products. Oxaliplatin does not inhibit CYP450 isoenzymes in vitro. Platinum was not displaced from plasma proteins by a variety of concomitant medications tested in vitro, and no marked PK interactions between oxaliplatin, 5-fluorouracil, and irinothecan have been observed. These results indicate that the additive/synergistic antitumor activity observed with these agents is not due to major alterations in drug exposure, and the enhanced efficacy is likely to be mechanistically based. Together, these PK, biotransformation, drug-drug interaction analyses and studies in special patient populations provide a firm scientific basis for the safe and effective use of oxaliplatin in the clinic. These analyses also reveal that the pharmacological activity of oxaliplatin may be attributable, at least in part, to the unique pattern of platinum disposition observed in patients.Clinical Cancer Research 05/2000; 6(4):1205-18. · 7.74 Impact Factor
Received: 21.08.2008 Accepted: 18.12.2008
J Gastrointestin Liver Dis
March 2009 Vol.18 No 1, 39-43
Address for correspondence:
Rapsodiei Str, 7
Clinical and Pharmacokinetics Study of Oxaliplatin
in Colon Cancer Patients
Claudia Burz1, Ioana Berindan-Neagoe1,3 , Ovidiu Balacescu3, Claudiu Tanaselia2, Monica Ursu2, Adriana Gog2,
Laurian Vlase4 , Mircea Chintoanu2, Loredana Balacescu3, Sorin E Leucuta4, Alexandru Irimie5, Victor Cristea1
1) Department of Immunology, University of Medicine and Pharmacy “Iuliu Hatieganu”; 2) INCDO-INOE 2000,
Research Institute for Analytical Instrumentation; 3) Functional Genomics and Experimental Pathology Department,
Cancer Institute “I Chiricuta”; 4) Department of Pharmaceutical Technology and Biopharmaceutics, University of
Medicine and Pharmacy “Iuliu Hatieganu”; 5) Cancer Surgery Department, University of Medicine and Pharmacy “I.
Hatieganu”, Cluj-Napoca, Romania.
Aim: to evaluate the therapeutic efficacy of oxaliplatin
and to analyze the pharmacokinetics of both ultrafiltrable
(free) and protein–bound platinum in patients with
metastatic colon cancer. Method: 60 patients with stage
IV colon carcinoma received 4-6 (mean 4.5) cycles of
oxaliplatin based combination chemotherapy. Response
rate, progression-free survival (PFS) and toxicity were
evaluated. The pharmacokinetics of oxaliplatin was
evaluated in 8 patients who were given 85 mg/m2 or 130
mg/m2 using an infusion time of 2-4 h. Pharmacokinetic
analysis was performed on blood, plasma and plasma
ultrafiltrable by ICP-MS (Inductively Coupled Plasma Mass
Spectrometry). Results: Overall response rate (complete
and partial) occurred in 33 (55%) patients. The median time
of progression was 9.3 months. Cumulative neurotoxicity,
vomiting and diarrhea, myelosuppression appeared in 32.3%,
21.3%, and 39.4% patients, respectively. The mean Cmax
and AUC 0-24 of oxaliplatin increased in a dose-related
manner. The pharmacokinetics of platinum after oxaliplatin
administration was triphasic characterized by a short initial
distribution phase and a long terminal elimination phase.
The clearance of ultrafiltrable platinum was relatively high
and the clearance of platinum from plasma and blood cells
was relatively low, which is probably a reflection of the
covalent binding of platinum to these matrices. Conclusion:
Oxaliplatin is active and well tolerated in patients with
advanced colon cancer. With a relatively low interpatient
variability, it is eliminated triphasically and the mean Cmax
and AUC 0-24 increases in a dose-related manner. These
results provide a scientific basis for the safe and effective
use of oxaliplatin in the clinic.
Colon cancer – oxaliplatin – pharmacokinetics –
Colorectal cancer is the second leading cause of cancer-
related death in the Western world. Platinum compounds are
widely used in the treatment of many cancers. Cisplatin [cis-
diamine-dichloroplatinum (II), CDDP], the first compound
of this group represents the first-line therapeutic agent for
several solid tumors. Its nephrotoxicity and ototoxicity are the
two factors limiting its clinical use. To increase anti-cancer
efficacy and to minimize the side effects, second and third
generation platinum compounds have been developed.
Oxaliplatin is a third generation platinum analog with
1,2-diaminocyclohexane (DACH) substituting the amine
groups of cisplatin. It is more potent than cisplatin in vitro,
requiring fewer inter and intra DNA strands adducts to
achieve the same cytotocixity and has demonstrated activity
in preclinical studies against a broad variety of cellular
lines, some of them cisplatin resistant [1-3]. Oxaliplatin is
widely used in the treatment of colorectal carcinoma and in
combination with 5-fluoro-uracil plus leucovorin represents
the first-line treatment for metastatic colorectal cancer [4,
5]. Neurotoxicity is its main side effect .
The response and the toxicity to therapy depend on many
complex factors including drug pharmacokinetic parameters.
Oxaliplatin undergoes biotransformation into aquated
forms in the blood, where three species can be found: total
platinum, ultrafiltrable or “free” platinum and erythrocyte
platinum [7, 8].
This study evaluated the benefits and side effects of
oxaliplatin chemotherapy in 60 patients with stage IV colon
Patients and methods
Phase II study design
This is a phase II study which involved patients with
metastatic colon cancer in treatment at the Cancer Institute
40 Burz et al
“Ion Chiricuta” Cluj-Napoca, Romania from January 2003
to November 2007. The primary end point was the overall
response rate. Secondary end points included TTP (time to
progression) and safety. The pharmacokinetics parameters of
oxaliplatin were determined in two groups of patients who
received different schemes of oxaliplatin-based combination
chemotherapy. The number of patients included in the
study was chosen according to the scientific research data
Patients aged 30 to 70 years with histologically
proven colorectal cancer and measurable metastatic or
locally advanced colorectal cancer were eligible for the
study. Pleural effusion and ascites were not accepted as
measurable criteria. Other inclusion criteria were adequate
haematological, hepatic and renal functions. Exclusion
criteria included prior therapy with oxaliplatin and history
of previous malignancy within 5 years. Tumor response was
assessed according to the WHO criteria.
Each patient received a combination of chemotherapy
containing oxaliplatin 85 mg/m2 by continuous intravenous
infusion for 2 h on day 1, and bolus FU 400 mg/m2 plus
leucovorin 200 mg/m2 , followed by FU 600 mg/m2 as 22-
hour infusion on days 1 and 2 every 2 weeks (FOLFOX4).
The toxic effects were evaluated using the National
Cancer Institute common toxicity criteria. Neurosensory
toxicity was graded as follows: grade 0 - no symptoms;
grade 1 - paresthesias or dysesthesias of short duration
with complete resolution before the next cycle; grade 2,
paresthesias or dysesthesias persisting between two cycles
without functional impairment; grade 3 - paresthesias or
dysesthesias with functional impairment.
The pharmacokinetics of oxaliplatin was evaluated
in 8 patients given 85 mg/m2 oxaliplatin (FOLFOX4, 4
patients) or 130 mg/m2 (XELOX in 3- week treatment cycles
- oxaliplatin day 1 followed by oral capecitabine 1000 mg/m2
twice daily day 1 to day 15, 4 patients) using an infusion
time of 2 and 4 h respectively. Blood samples were collected
into NH4-heparinized tubes during the infusion every 30
min for 2h, and every hour until up to 4h after the end of
infusion and at three time-points after the end of infusion
(12, 15, 24 h). The plasma was separated immediately and an
aliquot was ultrafiltrated using Amicon ultrafiltration filters,
Millipore, at 3000 rot/min for 30 min. The ultrafiltrate and
total plasma samples were immediately stored at -2000C for
a maximum of 2 weeks. Fractionated urine was collected in
glass containers before infusion and up to 24 h after drug
Determination of platinum levels
Pharmacokinetic analysis was performed on blood,
plasma and plasma ultrafiltrable. Platinum content of
biological samples was analyzed using a quadrupole mass
spectrometer (Perkin Elmer SCIEX, Elan DRC II, Toronto,
Canada). Samples were diluted 10 times. High purity
platinum monoelement standard solution was used for
calibrating the system prior to any analysis and the resulted
calibration curve had 5 points: blanks, 0.1ppb, 1 ppb, 5 ppb
and 10 pbb. Pulse mode was used during determination for
best detector sensitivity and the whole system was checked
daily for optimum running parameters, being the whole time
within producer’s specification. After each day of analysis,
to avoid any clogging of the cones and the plasma injector,
the system was cleaned. All reagents used were purchased
The pharmacokinetic analysis of oxaliplatin during
a constant rate infusion was performed by analysing the
platinum [Pt+] concentrations in plasma, plasma ultrafiltrate
[UFT], whole blood using Inductively Coupled Plasma
Mass Spectrometry (ICP-MS) in patients with metastatic
The plasma concentration-time data following the
administration was analyzed by a noncompartmental method
using the computer software Winnonlin, Pharsight, USA.
The peak plasma concentration, Cmax, and the time to reach
the peak concentration, Tmax, were obtained directly from
the experimental observation. The area under the plasma
concentration - time curve (AUC) from time 0 to T, AUCO-T
where T is the time of the last measurable concentration,
was calculated by the trapezoidal method.
The statistical analysis for the pharmacokinetic
evaluation was made according to the number of patients
chosen using the Statistical Package for Social Sciences
(SPSS), with Mann-Whitney test. P < 0.05 was considered
Prior to therapy all patients gave their informed consent
to participate in the study after having been informed about
the purpose of this evaluation.
A total of 60 patients (age 30 to 66; 27 males and
33 females) with metastatic colorectal cancer were
included into the study. Of 60 patients, 30 had well
differentiated adenocarcinoma, 16 had poorly differentiated
adenocarcinoma, and 14 had signet ring cell carcinoma.
Patients characteristics are shown in Table I.
The overall response rate (complete and partial) occurred
in 33 (55%) patients including 10 complete responses and
23 partial responses.
Time to progression was 9.3 months.
Concerning the toxicity, cumulative neurotoxicity,
vomiting and diarrhea, myelosuppression appeared in 32.2%,
21.3%, and 39.4% patients, respectively (Table II).
Most cases were grades 1 or 2. Hepatotoxicity was
observed in 10 patients (5.46%). One patient died possibly
of renal failure. The platinum concentration was high and
the renal clearance low.
Pharmacokinetic analysis of oxaliplatin
In eight patients, the pharmacokinetic analysis was
Oxaliplatin in colon cancer patients 41
Table I. Patients characteristics
No. of patients
Age (years)30-45 13
Primary cancerrectal 18
Prior treatment surgery 33
no treatment 27
ECOG : Eastern Cooperative Oncology Group; RT/CT adj.:
Radiotherapy/Chemotherapy post-surgery (5FU+leucovorin:FUFOL).
Table II. The main side effects of chemotherapy
Side effectsAnemia Neutropenia Thpenia Digestive Allergical NeurotoxHepatic
Gr.I2818 918 1 362
Gr.II76417 118 6
incidence %19.2% 13.11% 7.10%21.31% 1.63%32.25%5.46%
Tabel III. Comparison of mean (SD) pharmacokinetic parameters of platinum in blood, plasma and
ultrafilterable plasma (UFT)
T1/2 (h)Cl (liters/h)Vss (liters)
blood1.89 (0.19)54.2 (3.27)23.5 (3.47)2.71 (0.84) 94.87 (30.1)
85mg/mpplasma1.61 (0.21) 51.4 (6.32) 26.1 (7.60)2.77 (0.61) 108 (38.5)
UFT0.38 (0.17)4.8 (0.72)12.1 (1.83)30.17 (7.75) 567 (20)
130mg/mpblood3.39 (1.89)53.43 (5.4)16.9 (3.22)3.87 (0.168)96.34 (16.1)
plasma 2.35 (0.75)54.81 (6.68)24.2 (3.65)3.81 (0.554)132.6 (4.51)
UFT0.86 (0.63)5.87 (0.25)9.32 (2.17)35.24 (3.18) 469.25 (17.71)
Fig 2. The pharmacokinetics of platinum [Pt+] in
plasma at 85 mg/m2 and 130 mg/m2.
performed during the first cycles of oxaliplatin, whereas in
two of them, two cycles were analyzed. The pharmacokinetic
parameters are summarized in Table III.
After a dose of 130 mg/m2, mean platinum Cmax values
were 3.39μg/ml in blood, 2.35 μg/ml in plasma and 0.86
μg/ml in plasma ultrafiltrate. Mean AUC0-24 values were
53.43 μg/ml٠h in blood, 54.8 μg/ml٠h in plasma and 5.87
μg/ml٠h in plasma ultrafiltrate. For a 85 mg/m2 dose, the
mean platinum Cmax and AUC values were lower than these
for 130 mg/m2 dose.
The clearance of ultrafiltrable platinum was relatively
high, ranging from 30.17l/h at 85 mg/m2 to 35.24 l/h at
130 mg/m2. Clearance of platinum from plasma and blood
cells was relatively low, from 2.71 to 3.87 both in plasma
Concerning the volume of distribution (Vss), platinum
had a high volume of distribution from plasma ultrafiltrate
Fig 1. The rate of response to chemotherapy. CR:
complete response; PR: partial response; SD: stable
disease; ED: evolutive disease.
42 Burz et al
Fig 3. The pharmacokinetics of platinum [Pt+] in
plasma ultrafiltrate at 85 mg/m2 and 130 mg/m2
ranging from 469.25 to 567 liters. In plasma and blood, the
volume of distribution was lower.
The platinum half-times in the ultrafiltrate were
triexponential, characterized by short initial α and β
distribution phases followed by a long terminal γ phase
No accumulation was observed in plasma ultrafiltrate or
plasma after 130 mg/m2 every 3 weeks or 85 mg/m2 every
Colon cancer is one of the major causes of cancer
morbidity and mortality in the Western world. Approximately
half of the patients are diagnosed with local stages and
undergo potentially curative surgery. The remaining patients
present metastatic disease and only systemic chemotherapy
Table IV. Pharmacokinetic evaluation for blood, plasma and ultrafiltrate plasma for different doses of oxaliplatin.
Plasma Plasma ultrafiltrate
z Exact Sig.
z Exact Sig.
-2.309.029*-2.021 .057-1.732 .114
-2.309 .029*-2.309 .029*-2.309 .029*
-1.155.343 -.866.486.000 1.000
.000 1.000-.866.486 -1.155 .343
*p<0.05; Vss = volume of distribution
with palliative intention is available. Chemotherapy has been
shown to have a favorable impact on survival and quality of
life of patients with colorectal cancer. Oxaliplatin represents
one of the most active drugs for the treatment of colorectal
cancer and, in particular, the FOLFOX regimen of oxaliplatin
and infusional fluorouracil plus leucovorin is the standard
therapy for patients with metastatic colorectal cancer .
Combination chemotherapy studies using oxaliplatin
and 5FU showed a response rate of 40-55% with a median
survival of approximately 18 months, therefore oxaliplatin
is indicated as a first line therapy for metastatic colorectal
cancer [11-13]. Dose-limiting toxicities include a cumulative
peripheral sensory neuropathy that is reversible following
withdrawal of oxaliplatin but at high doses can become
irreversible and with an impact on the quality of life of these
patients. Typical symptoms include paresthesias (presenting
as cold related dysesthesia), and laryngopharyngeal
dysesthesia [14, 15].
Our results demonstrate that oxaliplatin is effective and
well tolerated in treating colorectal cancer. Overall response
rate (complete and partial) occurred in 33 (55%) patients
including 10 complete response and 23 partial response. The
median time of progression was 9.3 months. These results
do not differ much from those of other phase II studies.
Using the same chemotherapy, Goldberg et al  obtained
a median time to progression of 8.7 months, a response rate
of 45% and a median survival of 19.5 months.
Concerning the pharmacokinetics of oxaliplatin, our
results have showed that the mean Cmax and AUC0-24
increased in a dose related manner. For a 85 mg/m2 dose, the
mean platinum Cmax and AUC values were lower than those
for 130 mg/m2 dose. Our results are concordant with those of
other phase II studies of oxaliplatin in human colon cancer
regarding the pharmacokinetic evaluation [16, 17].
The platinum half-time in ultrafiltrate was triexponential
characterized by short initial α and β distribution phases
followed by a long terminal γ phase. The short initial half-
life of platinum may represent the rapid clearance of intact
oxaliplatin and its metabolites into tissue and removal
from the systemic circulation via glomerular filtration.
Oxaliplatin in colon cancer patients 43
The long terminal half-time of unbound platinum in
plasma ultrafiltrate may represent the slow release of low
molecular weight platinum aminoacid conjugates after the
degradation of cellular macromolecules, such as proteins.
This pharmacokinetic behaviour was also reported .
Concerning the volume of distribution (Vss), platinum
has a high Vss from plasma ultrafiltrate ranging from 268 to
750 liters. It may be due to the lipophilic nature of DACH
platinum complexes and the irreversible binding of platinum
to proteins, DNA, and other cellular macromolecules .
The clearance of ultrafiltrable platinum was relatively
high and the clearance of platinum from plasma and blood
cells was relatively low. An explanation for these values is
the covalent binding of platinum to these matrices.
No accumulation was observed in the plasma ultrafiltrate
or plasma after 130 mg/m2 every three weeks or 85 mg/m2
every two weeks.
To summarize, this study shows that FOLFOX4 is an
effective therapy for patients with metastatic colon cancer
and our results are congruent with others studies regarding
the overall response rate, the time to progression and toxicity.
Concerning the oxaliplatin pharmacokinetics, our results
have shown that the mean Cmax and AUC 0-24 increased
in a dose related manner.
In conclusion, these results, in line with those of other
phase II oxaliplatin studies in human colon cancer with
regard to pharmacokinetics and safety, provide a scientific
basis for the effective use of oxaliplatin in clinical therapy.
Conflicts of interest
The authors have no conflict of interest in relation to
1. Raymond E, Chaney SG,Taamma A, Cvitkovic E. Oxaliplatin: a
review of preclinical and clinical studies. Ann Oncol 1998; 9: 1053-
2. Luo FR, Wyrick SD, Chaney SG. Cytotoxicity, cellular uptake and
cellular biotransformation of oxaliplatin in human colon carcinoma
cell lines. Oncol Res 1998; 10: 595-603.
3. Raymond E, Faivre S, Chaney S, Woynarowski JM, Cvitkovic E.
Cellular and molecular pharmacology of oxaliplatin. Mol Cancer
Ther 2002; 1: 227-235.
4. Goldberg RM, Sargent DJ, Morton RF, et al. A randomized controlled
trial of fluorouracil plus leucovorin, irinotecan and oxaliplatin
combinations in patients with previously untreated metastatic
colorectal cancer. J Clin Oncol 2004; 22: 23-30.
5. Bing Han1, Ruihua Xu1, Yanxia Shi1, et al. Oxaliplatin, fluorouracil
and leucovorin (FOLFOX) as first-line chemotherapy for metastatic
or recurrent colorectal cancer patients. Chinese J Clin Oncol 2007;
6. Donzelli E, Carfi M, Miloso M, et al. Neurotoxicity of platinum
compounds: comparison of the effects of cisplatin and oxaliplatin on
the human neuroblastoma cell line SH-SY5Y. J Neurooncol 2004;
7. Graham MA, Lockwood GF, Greenslade D, Brienza S, Bayssas
M, Gamelin E. Clinical pharmacokinetics of oxaliplatin: a critical
review. Clin Cancer Res 2000; 6: 1205-1218.
8. Extra JM, Marty M, Brienza S, Misset JL. Pharmacokinetics and
safety profile of oxaliplatin. Semin Oncol 1998; 25 (2 suppl 5): 13-
9. Xu N, Fang WJ, Zhang XC, et al. A phase II trial of oxaliplatin, folinic
acid, and 5-fluorouracil (FOLFOX4) as first-line chemotherapy
in advanced colorectal cancer: A China single-xenter experience.
Cancer Invest 2007; 25: 599-605.
10. Makatsoris T, Kalofonos HP, Aravantinos G, et al; Hellenic
Cooperative Oncology Group. A phase II study of capecitabine plus
oxaliplatin (XELOX): a new first-line option in metastatic colorectal
cancer. Int J Gastrointest Cancer 2005; 35: 103-109.
11. De Gramont A, Figer A, Seymour M, et al. Leucovorin and
fluorouracil with or without oxaliplatin as first-line treatment in
advanced colorectal cancer. J Clin Oncol 2000; 18: 2938-2947.
12. Giacchetti S, Perpoint B, Zidani R, et al. Phase III multicenter
randomized trial of oxaliplatin added to chronomodulated
fluorouracil-leucovorin as first-line treatment of metastatic colorectal
cancer. J Clin Oncol 2000; 18: 136-147.
13 Grothey A, Deschler B, Kroening H, et al. Phase III study of bolus
5-fluorouracil/ folinic acid (Mayo) vs weekly high-dose 24 h 5 FU-
infusion/ FA + Oxaliplatin for advanced colorectal cancer. Proc Am
Soc Clin Oncol 2002;21:129a.
14. Lehky TJ, Leonard GD, Wilson RH, Grem JL, Floeter MK.
Oxaliplatin–induced neurotoxicity: acute hyperexcitability and
chronic neuropaty. Muscle Nerve 2004; 29: 387-392.
15. Chiara S, Nobile MT, Gozza A, et al. Phase II study of weekly
oxaliplatin and high dose infusional 5-fluorouracil plus leucovorin
in pretreated patients with metastatic colorectal cancer. Anticancer
Res 2004; 24: 355-360.
16. Graham MA, Brienza S, Misset JL,Cupissol E, Gamelin E, Allain
P. Pharmacokinetics of oxaliplatin given in repeated doses of 130
mg/m2 by 2h infusion every three weeks to cancer patients. Sanofi
Res Report VAR3149, 1998.
17. Shirao K, Matsumura Y, Yamada Y, et al. Phase I study of single-dose
oxaliplatin in Japanese patients with malignant tumors. Jpn J Clin
Oncol 2006; 36: 295-300.
18. Graham MA, Gamelin E, Misset JL, et al. Clinical pharmacokinetics
of oxaliplatin. Proc Am Assoc Cancer Res 1998; 39: 159.