Annals of Oncology Advance Access originally published online on September 13, 2006
Annals of Oncology 2007 18(1):88-92; doi:10.1093/annonc/mdl317
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
© 2006 European Society for Medical Oncology
gastrointestinal tumors |
Phase II trial of irinotecan plus oxaliplatin and 5-fluorouracil/leucovorin in patients with untreated metastatic gastric adenocarcinoma
Division of Hematology–Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
* Correspondence to: Dr W. K. Kang, Division of Hematology–Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Ilwon-dong Kangnam-ku, Seoul 135-710, Korea. Tel: +82-2-3410-3451; Fax: +82-2-3410-0041; E-mail: wkkang{at}smc.samsung.co.kr
 |
Abstract |
|---|
 Top Abstract introductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
|---|
Background: This nonrandomized open label phase II study evaluated the efficacy and safety of FOLFOXIRI in metastatic or recurrent gastric cancer patients.
Patients and methods: Patients with histologically proven, metastatic gastric adenocarcinoma, aged 18–70 years, performance status zero to two, no prior chemotherapy, and with signed written informed consent were eligible. Treatment consisted of irinotecan 150 mg/m2 day 1, oxaliplatin 85 mg/m2 day 1, leucovorin 100 mg/m2 day 1, and 5-fluorouracil 2000 mg/m2 as a 48-h continuous infusion starting on day 1, which was repeated every 2 weeks.
Results: From August 2004 to August 2005, 48 patients were prospectively enrolled. The median age was 54 years (24–69). In total, 386 cycles were administered with a median of nine cycles per patient (range 1–12 cycles) and 45 of 48 patients were assessable for treatment response. An independent review of tumor responses resulted in overall response rate of 66.7% (95% confidence interval = 53.4% to 80.0%) by intent-to-treat analysis with one complete response and 31 partial responses. The median survival of all patients was 14.8 months and the median time to progression was 9.6 months. Most common grade 3/4 toxic effects were neutropenia (12% of all cycles) and emesis (8% of all cycles). Grade 2 peripheral neuropathy occurred in five patients. One (2%) patient had severe tumor bleeding and five (10%) patients experienced grade 3 diarrhea.
Conclusions: The modified FOLFOXIRI combination chemotherapy showed a very promising preliminary antitumor activity and was generally well tolerated as a first-line treatment of patients with metastatic gastric cancer.
Key words: gastric cancer, irinotecan, oxaliplatin, chemotherapy
|
introduction |
|---|
|
TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
|---|
Gastric cancer is the leading cause of cancer death worldwide with the incidence of 18.9/100 000 per year and the mortality rate of 14.7/100 000 per year [1] and is the most common malignancy in Korea [2]. Metastatic gastric cancer remains a therapeutic challenge for medical oncologists due to poor prognosis. Several randomized phase III trials comparing combination chemotherapy such as 5-fluorouracil (5-FU), doxorubicin, and mitomycin or 5-FU, doxorubicin, and high-dose methotrexate with best supportive care have demonstrated significantly prolonged overall survival (OS) (8–10 months) for chemotherapy group as compared to best supportive care alone (3–5 months) [3, 4]. Since then, various combination chemotherapy regimens were tested in phase II or phase III trials in metastatic gastric cancer patients including our previous study with epirubicin, docetaxel (Taxotere Aventis), and cisplatin [5]. A recent phase III trial comparing docetaxel-cisplatin-5-FU (DCF) to the reference arm of cisplatin-5-FU (CF) showed a significant superiority of DCF in terms of survival (9.2 versus 8.6 months), time to progression (TtP) (5.6 versus 3.7 months), and response rate (RR) (37% versus 25%) than CF arm [6]. However, because DCF regimen was associated with high incidence of grade 3 or greater toxic effects, the regimen has not yet been widely accepted as the standard first-line chemotherapy for gastric cancer patients. Thus, the optimum front-line chemotherapy regimen should be extensively investigated in these patients to improve survival.
Irinotecan, a camptothecin analog, acts as an antitumor agent by inhibiting the eukaryotic enzyme DNA topoisomerase I [7, 8]. Irinotecan has demonstrated high activity as a monotherapy in gastric cancer patients with RR from 18% to 43% [9, 10]. Phase II studies with irinotecan plus 5-FU and leucovorin (FOLFIRI) showed an RR of 40% with median survival time between 10.7 and 12.6 months [11–13]. We have previously designed a phase II study of modified FOLFIRI (irinotecan 150 mg/m2, leucovorin 100 mg/m2, infusion of 5-FU 2000 mg/m2, every 2 weeks) in gastric cancer patients who had failed to taxane/cisplatin chemotherapy and reported a RR of 21% with low toxicity profile [14].
Oxaliplatin, an alkylating agent, inhibits DNA replication by forming DNA adducts between two adjacent guanines or guanine and adenine molecules. Oxaliplatin has shown a notable activity against colorectal cancer in combination with 5-FU and leucovorin, which led to several phase II trials in gastric cancer. The oxaliplatin/5-FU/leucovorin regimen yielded RRs in the range of 38% to 54% with median survival time from 8 to 11 months with tolerable toxicity [15–18].
In an attempt to develop a more active and efficacious chemotherapy regimen, two newer agents, irinotecan and oxaliplatin, were combined with or without 5-FU and leucovorin in a few phase I trials, which showed safe toxicity profile in patients with advanced solid tumors [19, 20]. Preclinical studies reported synergistic antitumor activities between irinotecan and oxaliplatin in several tumor cell lines [21–23]. A phase II study of irinotecan, oxaliplatin plus continuous infusion of 5-FU/leucovorin (FOLFOXIRI, irinotecan 165 mg/m2, oxaliplatin 85 mg/m2, leucovorin 200 mg/m2, 5-FU 3200 mg/m2, every 2 weeks) without chronomodulation in 32 colorectal cancer patients produced a very promising activity with RR of 72% [24]. Another phase II study of FOLFIRINOX (oxaliplatin 85 mg/m2, irinotecan 180 mg/m2, leuvovorin 400 mg/m2, 5-FU 500 mg/m2 i.v. bolus followed by continuous infusion of 5-FU 2400 mg/m2, every 2 weeks) in advanced pancreatic cancer patients also yielded RR of 26% with manageable toxicity [25]. On the basis of these encouraging results, we conducted a phase II study in order to assess the efficacy and safety of the modified FOLFOXIRI as a front-line chemotherapy in patients with metastatic gastric cancer.
|
patients and methods |
|---|
|
TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
|---|
patient eligibility
Eligible patients were required to have histologically confirmed metastatic adenocarcinoma of the stomach, at least one bidimensionally measurable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria, no previous chemotherapy or radiotherapy, age between 18 and 70 years, an Eastern Cooperative Oncology Group performance status of two or less, a life expectancy of at least 3 months, adequate hematologic parameters [hemoglobin
9.0 g/dl, absolute neutrophil count (ANC) 1500 per µl; platelet count 100 000 per µl], renal function (creatinine clearance by Cockroft formula 50 ml/min or creatinine 
1.5 mg/dl), and liver parameters [aspartate aminotransferase, alanine aminotransferase 3x the upper limits of normal (ULN), total bilirubin <2x ULN]. Patients, who received adjuvant chemotherapy >12 months from the date of study entry, were eligible for the study. Patients with metastasis to the central nervous system, prior history of another malignancy within 5 years of study entry except for basal cell carcinoma of the skin or carcinoma in situ of the uterine cervix, were excluded from the study. All participants provided written informed consent before they entered the study, which was approved by the institutional review board.
treatment
Patients received oxaliplatin 85 mg/m2 diluted in 500 ml 5% dextrose as a 2-h i.v. infusion followed by irinotecan 150 mg/m2 diluted in 500 ml 5% dextrose as a 90-min infusion. After leucovorin 100 mg/m2 was given in a 2-h infusion, 5-FU 2000 mg/m2 was administered as a 48-h continuous infusion. Treatment cycles were repeated every 2 weeks until evidence of disease progression, unacceptable toxicity, patient's refusal, or for a maximum of 12 cycles. For emesis prophylaxis, 5-HT3 antagonists were given before chemotherapy. Atropine 0.25 mg s.c. was administered for prophylaxis of cholinergic syndrome. No prophylactic granulocyte colony-stimulating factors (G-CSF) were recommended for neutropenia.
Application of irinotecan, oxaliplatin, or 5-FU was delayed as long as there was diarrhea or mucositis of Common Toxicity Criteria (CTC) grade 1 or greater, neutropenia <1500 per µl, or thrombocytopenia <100 000 per µl. Oxaliplatin was reduced by 25% of the previous dose in case of grade 2 peripheral neuropathy. The dose of irinotecan was reduced by 25% of the previous dose in case of CTC grade 3 or greater diarrhea. If ANC was >1000 per µl and platelet >75 000 per µl after 1-week delay, chemotherapy was administered without dose reductions. If ANC was <1000 per µl or platelet <75 000 per µl after 1-week delay, chemotherapy was delayed for one additional week. If ANC was >1000 per µl and platelet count >75 000 per µl following a 2-week delay from the planned date of chemotherapy, doses of irinotecan, oxaliplatin, and 5-FU were reduced by 25%. If patients required a delay of >2 weeks for recovery, patients went off the study protocol.
efficacy assessment
The primary objective of the study was RR and secondary objectives were toxicity, OS and TTP. Pre-treatment evaluation included history and physical examination, complete blood cell count with differentials, chemistry, chest X-ray, computed tomography (CT) scan of abdomen and pelvis, and any other diagnostic procedures as clinically indicated. During treatment, a history taking, physical examination including toxicity assessment, complete blood cell count, and chemistry were carried out every 2 weeks before each cycle. Appropriate imaging studies including abdominal and pelvis CT scan were carried out every three cycles (6 weeks) to evaluate treatment response, or sooner if needed for documentation of disease progression. Responses were to be confirmed by subsequent CT scans 4 to 6 weeks after the initial response documentation. Patients were assessed every 2 months for disease progression following the completion of the chemotherapy. Responses were classified according to RECIST criteria [26]. Tumor measurements were independently reviewed by a radiologist and an oncologist, who were blinded from the tumor assessments carried out by investigators.
Patients who received at least one cycle of treatment were considered assessable for response and toxicity. TTP was calculated from the first day of treatment to the date on which disease progression was first documented or of the last follow-up. OS was calculated from the first day of treatment to the date of death or last follow-up. Toxicity was monitored according to the National Cancer Institute (NCI) CTC scale version 3.0.
statistical considerations
According to a Simon's two-stage phase II optimal design [27], a sample size of 43 was required to accept the hypothesis that the true RR is >40% with 80% power, and to reject the hypothesis that the RR is <20% with 5% significance. At the first stage, if there were fewer than three responses out of the initial 13 patients, an early termination of the study was required. Assuming that 10% of patients were inassessable, a total of 48 patients were planned to be accrued for this study.
Descriptive statistics was reported as proportions and medians. Kaplan–Meier estimates were used in the analysis of time-to-event variable and the 95% confidence interval (CI) for the median time to event was computed. The dose intensity (DI) was calculated as the ratio of the total dose in milligrams per square meter of the patient, divided by the total treatment duration expressed in days. The relative DI was calculated as the ratio of the DI actually delivered to the DI planned by the protocol.
|
results |
|---|
|
TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
|---|
patient characteristics
From August 2004 to August 2005, 48 patients were enrolled. The baseline characteristics are listed in Table 1. The median age was 54 years (range 24–69 years). All patients had a histologically proven adenocarcinoma of the stomach and no patient had gastroesophageal junction carcinomas. Forty-five (94%) had distant lymph node metastases, 19 (40%) liver metastases, and 35 (73%) had two or more sites of metastases. Of the 13 patients with single organ involvement, nine patients had metastasis limited to lymph nodes; however, the nodal involvements occurred in left paraaortic, aortocaval, retrocaval, retropancreatic, and supraclavicular lymph nodes. All patients had metastatic disease at the time of study entry.
|
treatment and drug delivery
In total, 386 cycles were administered with a median of nine cycles per patient (range 1–13 cycles). The delivered relative dose intensities were 82% for irinotecan, 82% for oxaliplatin, and 83% for 5-FU.
response
Forty-five (93.8%) of 48 patients were assessable for response. Three patients were not assessable but were included in the intent-to-treat analysis. Three patients stopped chemotherapy after one cycle because of patients' refusals. The overall response rate (ORR) was 68.8% (95% CI 55.7% to 81.9%) by intent-to-treat analysis and 73.3% (95% CI 60.8% to 85.8%) by per-protocol analysis. There were two complete responses (CRs) and 31 partial reponses (PRs). All CRs and PRs were confirmed at least 4 weeks later. An independent review of tumor responses resulted in ORR of 66.7% (95% CI 53.4% to 80.0%) by intent-to-treat analysis with one CR and 31 PRs. The extent of disease (patients with one organ, two organs or more than two organs involvement) did not influence RRs (data not shown). Of the 12 assessable patients with single-organ metastasis, the site-specific RRs were 100% (n = 1) for intra-abdominal soft tissue mass and 78% (n = 7) for lymph nodes. Upon disease progression, 24 patients (50%) received a second-line treatment, including docetaxel/cisplatin (n = 22) and paclitaxel/cisplatin chemotherapy (n = 2). At the time of writing two patients are continuing therapy.
survival
All patients were included in the survival analysis. The median follow-up duration was 13.9 months (range 6.7–18.7 months). The median survival of all patients was 14.8 months and the median TtP was 9.6 months (Figure 1).
|
toxicity
All patients were assessable for safety. Toxic effects observed during the study are listed in Table 2. The most common toxic effects were neutropenia and anemia. Most patients experienced neutropenia during their course of therapy with 40% of patients (n = 19) for grade 3 and 13% (n = 6) for grade 4 neutropenia. Grade 1 or 2 neutropenia was detected in 77% of cycles (n = 297). However, there were only two episodes of grade 3 neutropenic fever of all cycles in two patients. There was no treatment-related death or life-threatening neutropenic fever. Nonhematologic toxic effects of grade 3–4 occurred in <10% of cycles. Grade 3 nausea and vomiting occurred in 44% of patients. Although peripheral neuropathy was commonly observed, most patients had mild (grade 1 in 48%, grade 2 in 10% of patients) symptoms, and no patients had severe peripheral neuropathy requiring treatment interruptions. Mild to moderate diarrhea, which was reversible and manageable, developed in 69% of the patients, while grade 3 diarrhea occurred in five (10%) patients. There was only one patient who was admitted in the emergency room for management of grade 3 diarrhea for 2 days. One patient, who did not have thrombocytopenia, experienced severe tumor bleeding. Fifteen (31%) patients required dose reductions of at least one drug due to grade 3 or 4 nonhematologic toxic effects; seven (15%) patients were delayed >1 week because of nonhematologic toxic effects. No patients were discontinued from the study due to toxic effects.
|
|
discussion |
|---|
|
TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
|---|
Metastatic gastric cancer remains an incurable disease with poor prognosis despite recent advances in combination chemotherapeutic drugs. Recently, the largest phase III trial, V-325 trial, compared DCF with the reference regimen of CF and demonstrated significant superiority of DCF in terms of survival (9.2 versus 8.6 months), TtP (5.6 versus 3.7 months), and RR (37% versus 25%) than CF arm [6]. Because DCF is an intensive combination with the incidence of grade 3–4 neutropenia of 82%, the benefit-to-risk ratio should be cautiously determined in incorporating the regimen in practice, especially in an elderly population. Therefore, we studied the combination of 5-FU with both irinotecan and oxaliplatin in order to develop a potentially more efficacious front-line chemotherapy of metastatic gastric cancer with acceptable toxicity.
We adopted a simplified FOLFOXIRI regimen that could be administered more easily in clinical practice, which was designed by Masi et al. [24] for colorectal cancer patients, and modified the dosage in an attempt to reduce toxic effects. They conducted a phase I/II study with the original FOLFOXIRI regimen in which 5-FU was chronomodulated and observed that 32% of cycles required G-CSF support to maintain the planned schedule [28]. In a subsequent phase II trial by the same study group, they adopted a simplified FOLFOXIRI with irinotecan 165 mg/m2, oxaliplatin 85 mg/m2, leucovorin 200 mg/m2, and a 48-h infusion of 5-FU 3200 mg/m2 without chronomodulation and reported equivalent efficacy with less toxic effects in metastatic colorectal cancer patients [24]. Besides this study, a number of other studies with triple combination have used a lower dose of each drug to further reduce toxic effects. Souglakos et al. [29] evaluated the efficacy and tolerance of triple combination with lower doses (irinotecan 150 mg/m2, oxaliplatin 65 mg/m2 with 5-FU 400 mg/m2 bolus followed by 600 mg/m2 22-h infusion for 2 days) in 31 colorecetal patients and demonstrated a RR of 58% with high toxicity profile (45% grade 3–4 neutropenia, 32% grade 3–4 diarrhea). Martinez et al. [30] assessed the feasibility of triple combination regimen with reduced dose (oxaliplatin 85 mg/m2 and irinotecan 150 mg/m2, repeated every 15 days, with 5-FU 500 mg/m2 bolus and folinic acid 20 mg/m2 on days 1, 8, and 15) in 26 colorectal cancer patients and reported more favorable toxicity profile (50% grade 3–4 neutropenia, <1% grade 3–4 diarrhea). Prior phase II studies in gastric cancer patients showed promising antitumor activity with irinotecan 150 mg/m2 every 2-week schedule [9, 10]. In addition, we showed that modified FOLFIRI (irinotecan 150 mg/m2, leucovorin 100 mg/m2, and a 48-h infusion of 1000 mg/m2 5-FU) had moderate activity with RR of 21% as a second-line therapy and with mild toxic effects (11% grade 3–4 neutropenia, 3% grade 3–4 diarrhea) in metastatic gastric cancer [14]. Therefore, we evaluated the treatment schedule of irinotecan 150 mg/m2, oxaliplatin 85 mg/m2, leucovorin 100 mg/m2, and 5-FU 2000 mg/m2 as a 48-h infusion, repeated every 2 weeks, in order to enhance the feasibility of the regimen.
In this study, the ORR was 68.8% (95% CI 55.7% to 81.9%) by intent-to-treat analysis with two CRs and 31 PRs. All responses were confirmed by a second assessment at least 4 weeks later. Tumor RRs that were obtained by an independent review were similar to the ORR assessed by the authors (66.7%). Although nine patients had metastases confined to lymph nodes only, these lymph nodes were all located in distant sites. Hence, the observed RR of 68.8% (66.7% by independent review) is among the highest RRs reported for gastric cancer. Accordingly, the median survival time (14.8 months) was longer compared with other phase II or III trials in gastric cancer (range 5.8–12.6 months), although the median follow-up time is 13.9 months at the time of the analysis [31].
The modified FOLFIXIRI regimen with reduced dosages demonstrated tolerable toxicity profile in this trial. Although the incidence of grade 3–4 neutropenia seemed to be high (53% of patients), neutropenia was usually short lasting and rarely complicated by neutropenic fever (0.5% of all cycles). The incidence of neutropenia may potentially be reduced by administration of prophylactic G-CSF; however, such prophylactic G-CSF is unlikely to benefit these patients due to rare associations with infection. The regimen, however, showed relatively high frequency of grade 3 or 4 emesis (8% of all cycles; 44% of all patients), which led to dose reductions in 10 (20.8%) patients. The relative dose intensities were 82% for irinotecan, 82% for oxaliplatin, and 83% for 5-FU in this study, which were comparable to phase II study of similar regimen in colon cancer patients [23].
In conclusion, the modified FOLFOXIRI combination is a well-tolerated treatment modality with very promising activity in untreated metastatic gastric cancer patients. The investigational combination is planning to be tested in randomized phase II to III trials versus docetaxel-based chemotherapy and in phase II trials in combination with novel molecular targeted agents in order to enhance survival in metastatic gastric cancer patients.
|
Acknowledgements |
|---|
|
TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
|---|
We acknowledge the CJ Corp. who generously donated Irinotecan (CAMPTO) for the study.
Received for publication April 10, 2006. Revision received July 24, 2006. Accepted for publication July 25, 2006.
|
References |
|---|
|
TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
|---|
1. Cunningham D, Jost LM, Purkalne G, Oliveira J. (2005) ESMO Minimum Clinical Recommendations for diagnosis, treatment and follow-up of gastric cancer. Ann Oncol 16:Suppl 1, i22–i23.
2. Bae JM and Park JG. (2002) Annual report of the Korea Central Cancer Registry Program 2000: based on registered data from 131 hospitals. Cancer Res Treat 34:77–83.
3. Murad AM, Santiago FF, Petroianu A, et al. (1993) Modified therapy with 5-fluorouracil, doxorubicin, and methotrexate in advanced gastric cancer. Cancer 72:37–41.[CrossRef][ISI][Medline]
4. Pyrhonen S, Kuitunen T, Nyandoto P, Kouri M. (1995) Randomised comparison of fluorouracil, epidoxorubicin and methotrexate (FEMTX) plus supportive care with supportive care alone in patients with non-resectable gastric cancer. Br J Cancer 71:587–591.[ISI][Medline]
5. Lee SH, Kang WK, Park J, et al. (2004) Combination chemotherapy with epirubicin, docetaxel and cisplatin (EDP) in metastatic or recurrent, unresectable gastric cancer. Br J Cancer 91:18–22.[CrossRef][ISI][Medline]
6. Moiseyenko VM, Ajani JA, Tijulandin SA, et al. (2005) Final results of a randomized controlled phase III trial (TAX325) comparing docetaxel (T) combined with cisplatin (C) and 5-fluorouracil (F) to CF in patients (pts) with metastatic gastric adenocarcinoma (MGC). J Clin Oncol 23:308s.
7. Hsiang YH, Lihou MG, Liu LF. (1989) Arrest of replication forks by drug-stabilized topoisomerase I-DNA cleavable complexes as a mechanism of cell killing by camptothecin. Cancer Res 49:5077–5082.
8. Tanizawa A, Fujimori A, Fujimori Y, Pommier Y. (1994) Comparison of topoisomerase I inhibition, DNA damage, and cytotoxicity of camptothecin derivatives presently in clinical trials. J Natl Cancer Inst 86:836–842.
9. Futatsuki K, Wakui A, Nakao I. (1994) Late phase II study of irinotecan hydrochloride (CPT-11) in advanced gastric cancer. CPT-11 Gastrointestinal Cancer Study Group. Gan To Kagaku Ryoho 21:1033–1038.[Medline]
10. Bleiberg H. (1999) CPT-11 in gastrointestinal cancer. Eur J Cancer 35:371–379.[CrossRef][ISI][Medline]
11. Pozzo C, Barone C, Szanto J, et al. (2004) Irinotecan in combination with 5-fluorouracil and folinic acid or with cisplatin in patients with advanced gastric or esophageal-gastric junction adenocarcinoma: results of a randomized phase II study. Ann Oncol 15:1773–1781.
12. Bouche O, Raoul JL, Bonnetain F, et al. (2004) Randomized multicenter phase II trial of a biweekly regimen of fluorouracil and leucovorin (LV5FU2), LV5FU2 plus cisplatin, or LV5FU2 plus irinotecan in patients with previously untreated metastatic gastric cancer: a Federation Francophone de Cancerologie Digestive Group Study—FFCD 9803. J Clin Oncol 22:4319–4328.
13. Yilmaz U, Oztop I, Alacacioglu A, Yaren A, et al. (2005) Irinotecan combined with infusional 5-fluorouracil and high dose leucovorin (FOLFIRI) for the treatment of advanced gastric carcinoma as the first line chemotherapy. J Clin Oncol 23:165 (Abstr 4164).
14. Kim ST, Kang WK, Kang JH, et al. (2005) Salvage chemotherapy with irinotecan, 5-fluorouracil and leucovorin for taxane- and cisplatin-refractory, metastatic gastric cancer. Br J Cancer 92:1850–1854.[CrossRef][ISI][Medline]
15. Louvet C, Andre T, Tigaud JM, et al. (2002) Phase II study of oxaliplatin, fluorouracil, and folinic acid in locally advanced or metastatic gastric cancer patients. J Clin Oncol 20:4543–4548.
16. De Vita F, Orditura M, Matano E, et al. (2005) A phase II study of biweekly oxaliplatin plus infusional 5-fluorouracil and folinic acid (FOLFOX-4) as first-line treatment of advanced gastric cancer patients. Br J Cancer 92:1644–1649.[CrossRef][ISI][Medline]
17. Lordick F, Lorenzen S, Stollfuss J, et al. (2005) Phase II study of weekly oxaliplatin plus infusional fluorouracil and folinic acid (FUFOX regimen) as first-line treatment in metastatic gastric cancer. Br J Cancer 93:190–194.[CrossRef][ISI][Medline]
18. Al-Batran SE, Atmaca A, Hegewisch-Becker S, et al. (2004) Phase II trial of biweekly infusional fluorouracil, folinic acid, and oxaliplatin in patients with advanced gastric cancer. J Clin Oncol 22:658–663.
19. Wasserman E, Cuvier C, Lokiec F, et al. (1999) Combination of oxaliplatin plus irinotecan in patients with gastrointestinal tumors: results of two independent phase I studies with pharmacokinetics. J Clin Oncol 17:1751–1759.
20. Ychou M, Conroy T, Seitz JF, et al. (2003) An open phase I study assessing the feasibility of the triple combination: oxaliplatin plus irinotecan plus leucovorin/5-fluorouracil every 2 weeks in patients with advanced solid tumors. Ann Oncol 14:481–489.
21. Guichard S, Arnould S, Hennebelle I, et al. (2001) Combination of oxaliplatin and irinotecan on human colon cancer cell lines: activity in vitro and in vivo. Anticancer Drugs 12:741–751.[CrossRef][Medline]
22. Zeghari-Squalli N, Raymond E, Cvitkovic E, Goldwasser F. (1999) Cellular pharmacology of the combination of the DNA topoisomerase I inhibitor SN-38 and the diaminocyclohexane platinum derivative oxaliplatin. Clin Cancer Res 5:1189–1196.
23. Bissery MC, Vrignaud P, Lavelle F. (1998) In vivo evaluation of the irinotecan-oxaliplatin combination. Proc Am Assoc Cancer Res 39:526.
24. Masi G, Allegrini G, Cupini S, et al. (2004) First-line treatment of metastatic colorectal cancer with irinotecan, oxaliplatin and 5-fluorouracil/leucovorin (FOLFOXIRI): results of a phase II study with a simplified biweekly schedule. Ann Oncol 15:1766–1772.
25. Conroy T, Paillot B, Francois E, et al. (2005) Irinotecan plus oxaliplatin and leucovorin-modulated fluorouracil in advanced pancreatic cancer—a Groupe Tumeurs Digestives of the Federation Nationale des Centres de Lutte Contre le Cancer study. J Clin Oncol 23:1228–1236.
26. Therasse P, Arbuck SG, Eisenhauer EA, et al. (2000) New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92:205–216.
27. Simon R. (1989) Optimal two-stage designs for phase II clinical trials. Control Clin Trials 10:1–10.[Medline]
28. Falcone A, Masi G, Allegrini G, et al. (2002) Biweekly chemotherapy with oxaliplatin, irinotecan, infusional fluorouracil, and leucovorin: a pilot study in patients with metastatic colorectal cancer. J Clin Oncol 20:4006–4014.
29. Souglakos J, Mavroudis D, Kakolyris S, et al. (2002) Triplet combination with irinotecan plus oxaliplatin plus continuous-infusion fluorouracil and leucovorin as first-line treatment in metastatic colorectal cancer: a multicenter phase II trial. J Clin Oncol 20:2651–2657.
30. Martinez J, Martin C, Chacon M, et al. (2006) Irinotecan, oxaliplatin plus bolus 5-fluorouracil and low dose folinic acid every 2 weeks: a feasibility study in metastatic colorectal cancer patients. Am J Clin Oncol 29:45–51.[CrossRef][ISI][Medline]
31. Ajani JA. (2005) Evolving chemotherapy for advanced gastric cancer. Oncologist 10:Suppl 3, 49–58.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  S. H. Park, E. Nam, J. Park, E. K. Cho, D. B. Shin, J. H. Lee, W. K. Lee, M. Chung, and S. I. Lee Randomized phase II study of irinotecan, leucovorin and 5-fluorouracil (ILF) versus cisplatin plus ILF (PILF) combination chemotherapy for advanced gastric cancer Ann. Onc., April 1, 2008; 19(4): 729 - 733. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||