Efficacy and safety of oxaliplatin, 5-Fluorouracil, and folinic Acid combination chemotherapy as first-line treatment in metastatic or recurrent gastric cancer.

Abstract

We retrospectively determined the efficacy and safety of the combination of oxaliplatin, 5-fluorouracil (5-FU), and folinic acid (FA) as first-line chemotherapy for patients with metastatic or recurrent gastric cancer.
Between January 2006 and August 2009, 39 patients with histologically-confirmed, metastatic or recurrent gastric cancer underwent chemotherapy, and the results were retrospectively investigated. The chemotherapy regimen consisted of oxaliplatin (100 mg/m(2)) and FA (200 mg/m(2); 2-hour infusion), then 5-FU (2,400 mg/m(2); 46-hour continuous infusion) every 2 weeks.
Thirty-nine patients received a total of 210 treatment cycles. The median number of cycles was 6 (range, 1 to 16). Of the 32 evaluable patients, zero patients achieved a complete response and 11 patients achieved a partial response (response rate, 28.2%). The median time-to-progression and overall survival were 4.3 months (95% confidence interval [CI], 2.0 to 6.5 months) and 9.8 months (95% CI, 3.5 to 16.0 months), respectively. The main hematologic toxicity was anemia, which was observed in 119 cycles (56.7%). Grade 3/4 neutropenia was observed in 32 cycles (15.2%). The main non-hematologic toxicity was constipation, which was observed in 91 cycles (46.2%). Peripheral neuropathy occurred in 71 cycles (33.8%); all cases were grade 1 or 2. No treatment-related deaths were reported.
This study showed that combination chemotherapy with oxaliplatin, 5-FU, and FA is an active and well-tolerated regimen as first-line treatment in patients with metastatic or recurrent gastric cancer.

Full text

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Efficacy and Safety of Oxaliplatin, 5-Fluorouracil, and
Folinic Acid Combination Chemotherapy as First-Line
Treatment in Metastatic or Recurrent Gastric Cancer
Cancer Res Treat. 2011;43(3):154-159
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Han Jo Kim, MD1
Jun Young Eun, MD1
Young Woo Jeon, MD1
Jina Yun, MD2
Kyoung Ha Kim, MD3
Se Hyung Kim, MD2
Hyun Jung Kim, MD2
Sang-Cheol Lee, MD3
Sang Byung Bae, MD1
Chan Kyu Kim, MD2
Nam Su Lee, MD3
Kyu Taek Lee, MD1
Seong-Kyu Park, MD2
Jong-Ho Won, MD3
Dae Sik Hong, MD, PhD2
Hee Sook Park, MD3
1Division of Hematology and Oncology,
Department of Internal Medicine,
Soonchunhyang University Cheonan
Hospital, Cheonan, 2Divisions of
Hematology and Oncology, Department of
Internal Medicine, Soonchunhyang
University Bucheon Hospital, Bucheon,
3Division of Hematology and Oncology,
Department of Internal Medicine,
Soonchunhyang University Seoul Hospital,
Soonchunhyang University College of
Medicine, Seoul, Korea
Correspondence: Dae Sik Hong, MD, PhD
Division of Hematology and Oncology,
Department of Internal Medicine, Soonchunhyang
University Bucheon Hospital, Jung 1-dong,
Wonmi-gu, Bucheon 420-767, Korea
Tel: 82-32-621-5184
Fax: 82-32-621-5018
E-mail: dshong@schmc.ac.kr
Received April 5, 2011
Accepted May 24, 2011
http://dx.doi.org/10.4143/crt.2011.43.3.154
Original Article
Open Access
154 Copyright ⓒ2011 by the Korean Cancer Association
This is an Open-Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/
licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
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pISSN 1598-2998eISSN 2005-9256
Purpose
We retrospectively determined the efficacy and safety of the combination of oxaliplatin, 5-
fluorouracil (5-FU), and folinic acid (FA) as first-line chemotherapy for patients with metastatic
or recurrent gastric cancer.
Materials and Methods
Between January 2006 and August 2009, 39 patients with histologically-confirmed, me-
tastatic or recurrent gastric cancer underwent chemotherapy, and the results were re-
trospectively investigated. The chemotherapy regimen consisted of oxaliplatin (100 mg/m2)
and FA (200 mg/m2; 2-hour infusion), then 5-FU (2,400 mg/m2; 46-hour continuous infusion)
every 2 weeks.
Results
Thirty-nine patients received a total of 210 treatment cycles. The median number of cycles
was 6 (range, 1 to 16). Of the 32 evaluable patients, zero patients achieved a complete re-
sponse and 11 patients achieved a partial response (response rate, 28.2%). The median time-
to-progression and overall survival were 4.3 months (95% confidence interval [CI], 2.0 to 6.5
months) and 9.8 months (95% CI, 3.5 to 16.0 months), respectively. The main hematologic to-
xicity was anemia, which was observed in 119 cycles (56.7%). Grade 3/4 neutropenia was
observed in 32 cycles (15.2%). The main non-hematologic toxicity was constipation, which
was observed in 91 cycles (46.2%). Peripheral neuropathy occurred in 71 cycles (33.8%); all
cases were grade 1 or 2. No treatment-related deaths were reported.
Conclusion
This study showed that combination chemotherapy with oxaliplatin, 5-FU, and FA is an active
and well-tolerated regimen as first-line treatment in patients with metastatic or recurrent
gastric cancer.
Key words
Stomach neoplasms, Drug therapy, Oxaliplatin

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Han Jo Kim, et al_Oxaliplatin Combination for Advanced Gastric Cancer
VOLUME 43 NUMBER 3 SEPTEMBER 2011 155
Introduction
Despite the declining incidence of gastric cancer in Western
countries, gastric cancer is the most frequently diagnosed cancer
worldwide, and is one of the main causes of cancer deaths [1]. In pa-
tients with advanced gastric cancer with distant metastasis or re-
currence, systemic chemotherapy has been recommended as standard
treatment, and the prolongation of survival or increase in the quality of
life is well-established [2]. However, patients with advanced gastric
cancer with distant metastasis or recurrence remain incurable, and these
patients have a median survival of only 7-13 months, despite receiving
chemotherapy [3]. Also, first-line standard chemotherapy regimens
have not been defined for patients with advanced gastric cancer.
Cisplatin-based regimens have demonstrated superior efficacy com-
pared to platinum-free regiments, although cisplatin-based regimens
have significant toxicity [4,5].
Oxaliplatin is a third generation platinum compound with a lack of
cross-drug resistance with cisplatin, a synergistic effect with 5-
fluorouracil (5-FU), and a satisfactory safety profile compared to
cisplatin [6-9]. Moreover, many adducts of oxaliplatin appear to be
more effective in inhibiting DNA synthesis than adducts of cisplatin
[10-12]. Two phase III trials have directly compared oxaliplatin-based
versus cisplatin-based regimens [13,14], both of which have concluded
that oxaliplatin is at least as effective as cisplatin, and has a lower
toxicity profile, except neurotoxicity, in combination regimens for
patients with advanced gastric cancer. In several phase II studies
involving the treatment of advanced gastric cancer, various com-
binations of oxaliplatin, 5-FU, and folinic acid (FA), as first- or second-
line treatments, have shown considerable activity [15-19]. However,
the optimal dose and schedule of combination oxaliplatin, 5-FU, and
FA were not established. The aim of this retrospective study was to
report the efficacy and toxicity of a biweekly protocol of oxaliplatin
(100 mg/m2) combined with 5-FU (2,400 mg/m2; 46-hour continuous
infusion), and FA (200 mg/m2) as first-line treatment on response,
survival, and toxicity rates of metastatic and recurrent gastric cancer in
Korean patients.
Materials and Methods
1Eligibility criteria
The eligibility criteria were as follows: 1) histologically-confirmed
metastatic or recurrent adenocarcinoma of the stomach and ≥18 years
of age; 2) no previous chemotherapy, except post-operative adjuvant
chemotherapy or chemoradiation that was received ＞6 months pre-
viously; 3) an Eastern Cooperative Oncology Group (ECOG) perfor-
mance status of 0-2; 4) no serious or uncontrolled concurrent medical
illness; 5) at least one measurable lesion; and 6) adequate baseline
hematologic function (absolute neutrophil count [ANC]≥1.5×109/L,
platelet count≥100×109/L), adequate hepatic function (serum bili-
rubin≤1.25×upper normal limit [UNL], serum aspartate amino-
transferase, alanine aminotransferase≤2.5×UNL, serum alkaline
phosphatase≤5.0×UNL), and adequate renal function (serum
creatinine≤1.5 mg/dL). The exclusion criteria were as follows: 1) pre-
existing peripheral neuropathy; 2) concurrent or prior malignancy,
except curative resection of cervical carcinomain situ or squamous cell
carcinoma of the skin; 3) active infection; and 4) concurrent treatments
that interfered with the evaluation of the study.
2Treatment protocol and dose modifications
1) Chemotherapy protocol
Oxaliplatin (100 mg/m2) and FA (200 mg/m2) were given as a 2-
hour intravenous infusion followed by 5-FU (2,400 mg/m2) as a 46-
hour continuous infusion every 2 weeks. Treatment was continued
until disease progression, unacceptable toxicity, patient refusal, or at the
discretion of the physician. Anti-emetic prophylaxis was given
according to a local protocol. Granulocyte colony-stimulating factor
was not routinely used in the study.
2) Treatment delays and dose modifications
Each cycle was started if the ANC and platelet count on the day of
treatment were＞1.5×109/L and ＞100×109/L, respectively. In the
case of toxicity≥grade 3, except alopecia, chemotherapy was delayed
1 week, then restarted after full recovery. A reduction of 25% in all
drug doses was applied to grade 3/4 thrombocytopenia or febrile
neutropenia, grade 4 neutropenia, and grade 3/4 non-hematologic
toxicity in the previous cycle of chemotherapy.
3Response and toxicity assessment
The response to treatment was assessed according to the Response
Evaluation Criteria in Solid Tumors (RECIST) criteria (ver. 1.0) [20].
Computed tomography (CT) scans of the measurable lesions were
performed within 2 weeks prior to treatment. After every 4th cycle of
chemotherapy, CT scans were performed to determine the response of
the disease, or sooner if there was evidence of any clinical
deterioration. Complete blood cell counts with differentials and serum
biochemistries were repeated prior to the start of each chemotherapy
cycle, and the toxicity was graded according to the National Cancer
Institute Common Toxicity Criteria (NCI-CTC, ver.3.0).
4Statistical analysis
Overall survival (OS) was calculated from the first day of chemo-
therapy to the date of death. Time-to-progression (TTP) was calculated
from the first day of chemotherapy to the date of disease progression.
The Kaplan-Meier method was used to analyze the TTP and OS, and

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Cancer Res Treat. 2011;43(3):154-159
156
CANCER RESEARCH AND TREATMENT
the 95% confidence interval (CI) for the median time-to-event was
computed. The Cox proportional hazard method was used for
assessing independent prognostic factors. Statistical significance was
calculated at the 95% CI (p＜0.05). All the analyses were performed
using SPSS ver. 14.0 (SPSS Inc., Chicago, IL).
Results
1Patient characteristics
Between January 2006 and August 2009, 39 patients with a median
age of 62 years (range, 38 to 78 years) were retrospectively studied in
Seoul, Bucheon, and Cheonan Soonchunhyang University Hospitals.
There were 22 men and 17 women, and 2 patients (5.1%) had an
ECOG performance status of 2. Thirty-one patients (79.5%) had pri-
mary metastatic disease and 8 patients (20.5%) had recurrent disease.
Lymph nodes were the most common metastatic sites. The metastasis
involved two organs in 11 patients (28.2%) and ＞3 organs in 11
patients (28.2%). Eight patients who had previously undergone cu-
rative surgery received adjuvant 5-FU-containing chemotherapy. The
majority of the patients (71.8%) had 1 or 2 involved regions, and the
common target lesion was a lymph node or the liver. The patient
baseline characteristics are listed in Table 1.
2Tumor responses and survival
Thirty-two of the 39 patients were evaluable for response according
to the RECIST criteria (ver. 1.0). The response was not assessable in 7
patients who were lost to follow-up (n=3), voluntary refusal for further
treatment after 1 or 2 cycles (n=2), and death before the 4 cycles of
0
1.0
Cumulative probability of survival
(mo)
0.0
6
0.8
0.6
0.4
0.2
1218
Median: 4.3 mo
(95% confidence interval, 2.0 to 6.5 mo)
Fig. 1. Kaplan-Meier curve for time-to-progression.
0.0
1.0
Cumulative probability of survival
(yr)
0.0
1.0
0.8
0.6
0.4
0.2
2.0 3.0
Median: 9.8 mo
(95% confidence interval, 3.5 to 16.0 mo)
Fig. 2. Kaplan-Meier curve for overall survival.
Table 1.Patient characteristics
No. of patients (%)
Total
Median age (range, yr)
Gender
Male
Female
ECOG performance status
0-1
2
Disease status
Metastatic
Recurrent
Site of metastasis
Lymph node
Liver
Abdominal pelvic mass
Lung
Others
No. of organs involved
1
2
＞3
39
62 (38-78)
22 (56.4)
17 (43.6)
37 (94.9)
2 (5.1)
31 (79.5)
8 (20.5)
19 (48.7)
12 (30.8)
9 (23.1)
6 (15.4)
7 (18.0)
17 (43.6)
11 (28.2)
11 (28.2)
ECOG, Eastern Cooperative Oncology Group.
Table 2.Response rates of patients
No. of patients (%)
(n=39)
Complete response
Partial response
Stable disease
Progressive disease
Not assessable
Overall response rate (%)
Disease control rate (%)
0 (0)
11 (28.2)
14 (35.9)
7 (17.9)
7 (17.9)
28.2
64.1

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Han Jo Kim, et al_Oxaliplatin Combination for Advanced Gastric Cancer
VOLUME 43 NUMBER 3 SEPTEMBER 2011 157
chemotherapy (n=2). Eleven patients (28.2%) achieved a partial
response, 14 patients (35.9%) had stable disease, and 7 patients
(17.9%) had progressed during the course of treatment (Table 2). None
of the patients achieved a complete response. On intention-to-treat
analysis, the overall response rate (ORR) and disease control rates were
28.2% (95% CI, 11.7 to 44.7%) and 64.1% (95% CI, 49.9 to 78.3%),
respectively. The median duration of follow-up was 20.1 months
(range, 2.1 to 63.0 months). The TTP and OS were 4.3 months (95%
CI, 2.0 to 6.5 months) (Fig. 1) and 9.8 months (95% CI, 3.5 to 16.0
months) (Fig. 2), respectively.
3Factors affecting survival and response
An analysis of prognostic factors affecting survival was attempted.
Then, age (0-64 years vs.＞65 years), gender, a history of surgery or
chemotherapy, ECOG performance status (0-1 vs. 2), disease status
before chemotherapy (newly diagnosed vs. recurrent), and the number
of metastases (0-2 vs.＞3) were compared between the two groups.
Based on univariate analysis, the ECOG performance status (p=0.004)
and the number of metastases (p=0.033) were significantly different
between the two groups. Only the ECOG performance status was a
significant factor affecting survival based on multivariate analysis
(hazard ratio, 0.134; p=0.043). However, there were no significant
factors affecting response.
4Toxicity and dose intensity
Two hundred ten chemotherapy cycles were administered to the 39
patients. The median number of cycles was 6 (range, 1 to 16). Table 3
shows the summaries of the incidence of main toxicities. The major
grade 3 or 4 hematologic toxicities per cycle were neutropenia (15.2%)
and thrombocytopenia (7.6%). Two patients (5.1%) had febrile
neutropenia. The major non-hematologic toxicities per cycle were
constipation (46.2%) and nausea (41.9%). Peripheral neuropathy per
cycle occurred in 33.8% of the patients and all cases were grade 1-2;
there were no treatment interruptions or discontinuations due to
neuropathy. One patient (2.6%) had acute renal failure after 1 treatment
cycle, which required transient hemodialysis. The relative dose
intensities of oxaliplatin and 5-FU were 87.4% and 86.2% of the
planned doses, respectively. No treatment-related deaths occurred.
Discussion
Despite a large number of randomized trials, the best agent or
optimal regimen for the first-line treatment of advanced gastric cancer
has not been determined. A variety of different oxaliplatin combination
regimens have been studied (oxaliplatin plus 5-FU, epirubicin, or
capecitabine) in phase II trials. Also, several studies involving various
combinations of oxaliplatin/5-FU/FA for treating advanced gastric
cancer have been published; these studies have shown consistent
results regarding the activity of oxaliplatin combinations [15-19]. The
range of TTP, median OS, and ORR of these trials were 4.3-6.2 and
7.3-9.6 months, and 26-45%, respectively. Although data from ran-
domized controlled phase III trials have not been published, in practice
various combinations of oxaliplatin/5-FU/FA are used for the treatment
Patient (n=39)Cycle (n=210)
Toxicity
Grade 1/2 (%)Grade 3/4 (%)Grade 1/2 (%)Grade 3/4 (%)
Hematologic
Neutropenia
Febrile neutropenia
Thrombocytopenia
Anemia
Gastrointestinal
Nausea
Vomiting
Diarrhea
Constipation
Stomatitis
Neurosensory
Hepatic
AST/ALT
Bilirubin
Renal
Creatinine
10/39 (25.6)
-
8/39 (20.5)
20/39 (51.3)
12/39 (30.8)
2/39 (5.1)
7/39 (20.0)
5/39 (12.8)
68/210 (32.4)
-
45/210 (21.4)
110/210 (52.4)
32/210 (15.2)
2/210 (1.0)
16/210 (7.6)
9/210 (4.3)
24/39 (61.5)
14/39 (35.9)
5/39 (12.8)
21/39 (53.8)
15/39 (38.5)
20/39 (51.3)
2/39 (5.1)
2/39 (5.1)
-
-
-
-
88/210 (41.9)
53/210 (25.2)
14/210 (6.7)
91/210 (46.2)
54/210 (25.7)
71/210 (33.8)
2/210 (1.0)
2/210 (1.0)
-
-
-
-
3/39 (7.7)
1/39 (2.6)
1/39 (2.6)
-
7/210 (3.3)
1/210 (0.5)
1/210 (0.5)
-
1/39 (2.6)1/39 (2.6)2/210 (1.0)1/210 (0.5)
Table 3. Toxicities according to the National Cancer Institute Common Toxicity Criteria
AST, aspartate aminotransferase; ALT, alanine aminotransferase.

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Cancer Res Treat. 2011;43(3):154-159
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CANCER RESEARCH AND TREATMENT
of advanced gastric cancer in Korea. However, one prospective study
involving oxaliplatin/5-FU/FA as first-line chemotherapy in Korean
patients with advanced gastric cancer has been conducted [21]. In that
study, all 37 patients were elderly (＞65 years of age). The objective of
our study was to assess the efficacy and toxicity of a biweekly
combination of oxaliplatin (100 mg/m2in a 2-hour infusion), FA (200
mg/m2in a 2-hour infusion), and 5-FU (2,400 mg/m2in a 46-hour
continuous infusion) as first-line treatment for treating younger patients
with advanced gastric cancer in Korea. Although our study was
retrospective, the results showed that the chemotherapy regimen was
an effective and safe combination for advanced gastric cancer as first-
line treatment in Korea, as well as Western countries. The OS of 9.8
months was within the range of previous trials (7-12 months) using
platinum-containing and taxane- or irinotecan-based regimens.
Although survival is not a reliable point for evaluation of efficacy in a
retrospective study, the median survival of 9.8 months in the current
study compared favorably with previous studies [3]. The treatment
compliance for this regimen was good, with a dose adherence to both
oxaliplatin and 5-FU of＞85%. Owing to the patient selection bias, a
comparison of the toxicity profiles in this study with other phase II
studies that used various oxaliplatin and 5-FU administration schedules
is not relevant. Compared with previous biweekly regimens [15-17],
the biweekly protocol in the current study used higher levels of oxali-
platin (100 mg/m2vs. 85-100 mg/m2), and lower levels of FA (200
mg/m2vs. 400-500 mg/m2) and 5-FU (2.4 g/m2vs. 2.4-3.0 g/m2). In the
current study, major grade 3/4 hematologic toxicity, including
neutropenia (30.8%) and thrombocytopenia (20.0%), was encountered.
Although we infused 5-FU continuously without bolus to reduce he-
matologic toxicity, the rates of grade 3/4 neutropenia and thrombo-
cytopenia were relatively high compared with other studies [16,18,19].
It is possible that the rate of hematologic toxicity reflected the relatively
high dose of oxaliplatin; however, to make such an assumption, more
evidence should be provided, such as 85 mg/m2vs. 100 mg/m2of
oxaliplatin in Caucasian and Asian populations. Nevertheless, the toxi-
cities were manageable. Neurotoxicity is the most common side effect
in an oxaliplatin-containing protocol, but there was no grade 3/4 neuro-
toxicity encountered during the current study, which may have been
due to the relatively low cumulative dose of oxaliplatin (median, 521
mg/m2) used in this setting; indeed, neuropathy is particularly prevalent
for cumulative doses＞540 mg/m2[22]. One female patient had acute
renal failure after one treatment cycle requiring transient hemodialysis;
she had normal renal function before treatment and did not receive me-
dications with renal toxicity. Further, she declined continuation of treat-
ment for voluntary withdrawal after one cycle. Therefore, the investi-
gator considered renal toxicity a possible untoward effect related to
oxaliplatin [16]. In the current study, diarrhea occurred in 6.7% of the
cycles, but 46.2% of the cycles had associated constipation (grade 1 or
2). Compared with the other oxaliplatin/5-FU/LV regimens studied in
gastric cancer, the rate of constipation was high [16,19]. It would be
worthwhile to determine whether or not oxaliplatin would slow the in-
testinal transit time in Asians.
Conclusion
Although our study was retrospective, biweekly combination
chemotherapy with oxaliplatin, 5-FU, and FA was well-tolerated and
active as first-line treatment in patients with metastatic or recurrent
gastric cancer.
Conflicts of Interest
Conflict of interest relevant to this article was not reported.
1. Pisters PW, Kelsen DP, Powell SM, Tepper JE. Cancer of the stomach. In: De Vita VT Jr,
Hellman S, Rosenberg SA, editors. Cancer: principles and practice of oncology. 7th ed.
Philadelphia, PA: Lippincott Williams & Wilkins; 2005. p. 909-44.
2. Glimelius B, Ekström K, Hoffman K, Graf W, Sjödén PO, Haglund U, et al. Randomized
comparison between chemotherapy plus best supportive care with best supportive care
in advanced gastric cancer. Ann Oncol. 1997;8:163-8.
3. Ohtsu A. Chemotherapy for metastatic gastric cancer: past, present, and future. J
Gastroenterol. 2008;43:256-64.
4. Waters JS, Norman A, Cunningham D, Scarffe JH, Webb A, Harper P, et al. Long-term
survival after epirubicin, cisplatin and fluorouracil for gastric cancer: results of a
randomized trial. Br J Cancer. 1999;80:269-72.
5. Vanhoefer U, Rougier P, Wilke H, Ducreux MP, Lacave AJ, Van Cutsem E, et al. Final
results of a randomized phase III trial of sequential high-dose methotrexate, fluoroura-
cil, and doxorubicin versus etoposide, leucovorin, and fluorouracil versus infusional
fluorouracil and cisplatin in advanced gastric cancer: a trial of the European Organi-
zation for Research and Treatment of Cancer Gastrointestinal Tract Cancer Cooperative
Group. J Clin Oncol. 2000;18:2648-57.
6. Arnould S, Hennebelle I, Canal P, Bugat R, Guichard S. Cellular determinants of
oxaliplatin sensitivity in colon cancer cell lines. Eur J Cancer. 2003;39:112-9.
7. Marchetti P, Galla DA, Russo FP, Ricevuto E, Flati V, Porzio G, et al. Apoptosis induced
by oxaliplatin in human colon cancer HCT15 cell line. Anticancer Res. 2004;24:219-26.
8. Ravaioli A, Marangolo M, Pasquini E, Rossi A, Amadori D, Cruciani G, et al. Bolus
fluorouracil and leucovorin with oxaliplatin as first-line treatment in metastatic
colorectal cancer. J Clin Oncol. 2002;20:2545-50.
9. Extra JM, Espie M, Calvo F, Ferme C, Mignot L, Marty M. Phase I study of oxaliplatin
in patients with advanced cancer. Cancer Chemother Pharmacol. 1990;25:299-303.
10. Woynarowski JM, Faivre S, Herzig MC, Arnett B, Chapman WG, Trevino AV, et al.
Oxaliplatin-induced damage of cellular DNA. Mol Pharmacol. 2000;58:920-7.
11. Schmidt W, Chaney SG. Role of carrier ligand in platinum resistance of human
carcinoma cell lines. Cancer Res. 1993;53:799-805.
12. Mamenta EL, Poma EE, Kaufmann WK, Delmastro DA, Grady HL, Chaney SG.
Enhanced replicative bypass of platinum-DNA adducts in cisplatin-resistant human
ovarian carcinoma cell lines. Cancer Res. 1994;54:3500-5.
13. Cunningham D, Starling N, Rao S, Iveson T, Nicolson M, Coxon F, et al. Capecitabine
and oxaliplatin for advanced esophagogastric cancer. N Engl J Med. 2008;358:36-46.
14. Al-Batran SE, Hartmann JT, Probst S, Schmalenberg H, Hollerbach S, Hofheinz R, et
al. Phase III trial in metastatic gastroesophageal adenocarcinoma with fluorouracil,
leucovorin plus either oxaliplatin or cisplatin: a study of the Arbeitsgemeinschaft
References