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Annals of Oncology Advance Access published online on September 4, 2007
Annals of Oncology, doi:10.1093/annonc/mdm379
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© 2007 European Society for Medical Oncology

A randomized phase II trial evaluating safety and efficacy of an experimental chemotherapy regimen (irinotecan + oxaliplatin, IRINOX) and two standard arms (LV5–FU2 + irinotecan or LV5–FU2 + oxaliplatin) in first-line metastatic colorectal cancer: a study of the Digestive Group of the Fédération Nationale des Centres de Lutte Contre le Cancer

Y Bécouarn1,*, P Senesse2, S Thézenas2, E Boucher3, A Adenis4, L Cany5, JH Jacob6, F Cvitkovic7, C Montoto-Grillot8 and M Ychou2

1 Department of Digestive Oncology, Institut Bergonié, Regional Cancer Center, Bordeaux
2 Centre Régional de Lutte contre le Cancer Val d'Aurelle-Paul Lamarque, Montpellier
3 Centre Eugène Marquis, Rennes
4 Centre Oscar Lambret, Lille
5 Clinique Francheville, Périgueux
6 Centre François Baclesse, Caen
7 Centre René Huguenin, Saint-Cloud
8 Fédération Nationale des Centres de Lutte Contre le Cancer, Paris, France

* Correspondence to: Dr Y. Bécouarn, Department of Digestive Oncology, Institut Bergonié, Regional Cancer Center, 229 cours de l'Argonne, 33076 Bordeaux Cedex, France. Tel: +33-5-56-33-33-33; Fax: +33-5-56-33-33-83; E-mail: becouarn{at}bergonie.org


   Abstract
Top
 Abstract
introduction
 patients and methods
 results
 discussion
 funding
 Acknowledgements
 References
 
Background: To assess activity and safety of an experimental combination of irinotecan and oxaliplatin (IRINOX) as first-line treatment in advanced colorectal cancer.

Patients and methods: In this randomized phase II trial, 80 patients were treated: arm A (IRINOX) in 40 patients received at day 1 oxaliplatin 85 mg/m2 and irinotecan 180 mg/m2 biweekly, standard arm B received a biweekly simplified LV5–FU2, folinic acid (FA) 200 mg/m2 in a 2-h infusion and bolus injection of 5FU 400 mg/m2 on day 1, then a two 400 mg/m2 continuous infusion of FU on days 1 and 2 with either oxaliplatin 85 mg/m2 (20 patients) or irinotecan 180 mg/m2 (20 patients).

Results: Twenty-one partial responses (52.5%, median duration 7.2 months) were observed with the IRINOX arm and two complete and 20 partial responses PRs (55%, median duration 6.4 months) with arm B. Median progression-free and overall survival times were 8.4 and 19 months, respectively, in the IRINOX arm and 8.1 and 20.4 months in arm B. Main grade 3/4 toxic effects were, respectively, neutropenia 42.5% and 32.5%; febrile neutropenia 10% and 5%; diarrhea 32.5% and 7.5%; vomiting 10.0% and 5%; neurosensory toxicity 17.5% and 7.5%.

Conclusion: The IRINOX arm has a manageable toxicity and is active.

advanced colorectal cancer, first-line treatment, FU, irinotecan, oxaliplatin


   introduction
Top
 Abstract
 introduction
patients and methods
 results
 discussion
 funding
 Acknowledgements
 References
 
Colorectal cancer (CRC) is a major public health problem. In France, its incidence has increased by ~50% within 20 years [1], and its prognosis remains poor [2]. More than 50% of patients will have metastatic disease and are candidates for palliative chemotherapy [3]. After 40 years of treatment based on fluorouracil (FU) alone, the FA modulation of FU was a clear progress in terms of efficacy [4]. Then, the ‘LV5–FU2’ regimen emerged in France and elsewhere as a new reference, enhancing response rates (RR) and decreasing hematological toxicity compared with the FA + FU bolus combination [5]. In France, the ‘simplified LV5–FU2’ regimen replaced the original regimen to allow for complete outpatient treatment, with a single high-dose FA and FU bolus injection at day 1 and a 46-h continuous infusion of FU [6]. Two antineoplastic agents, irinotecan and oxaliplatin (IRINOX), emerged and have been proven active in advanced CRC patients, alone or combined with FU [7–14]. The LV5–FU2 regimen with oxaliplatin or irinotecan has been approved in France for first-line treatment of advanced CRC and has become standard treatment.

A cytotoxic synergism between oxaliplatin and SN38 (a highly active metabolite of irinotecan) has been demonstrated in vitro against the human colon cancer cell line HT29 [15]. In phase I studies evaluating the oxaliplatin/irinotecan combination with weekly, biweekly and triweekly regimens, the combinations appeared active with a manageable toxicity profile [16–19]. Phase II studies have shown promising efficacy in second-line treatment (RRs ranging from 15% to 40%) where grade 3–4 toxic effects were mainly neutropenia (20%–47%) and diarrhea (10%–33%) [20–22]. To assess the efficacy and safety profile of the oxaliplatin/irinotecan combination in first-line treatment for advanced CRC patients, we designed a randomized phase II trial in which: (i) the most promising experimental schedule was a biweekly combination [19] at the time the present study was initiated; (ii) the control arm was a standard arm in our country, the patients being randomly assigned to receive either simplified LV5–FU2/irinotecan or simplified LV5–FU2/oxaliplatin regimens.


   patients and methods
Top
 Abstract
 introduction
 patients and methods
results
 discussion
 funding
 Acknowledgements
 References
 
patients
From September 2002 to April 2005, 80 patients were enrolled in this study. The protocol was approved by the Ethics Review Committee of Bordeaux before any enrollment. All patients were informed of the investigational nature of the study and each patient provided written informed consent before registration for the study.

Inclusion criteria were as follows: histologically proven adenocarcinoma of the colon or rectum; nonresectable metastatic disease; no prior chemotherapy unless adjuvant chemotherapy, providing that it had been discontinued >6 months before study entry and did not contain irinotecan and/or oxaliplatin; World Health Organization (WHO) performance status of zero to two; age between 18 and 75 years; measurable metastatic disease according to the Response Evaluation Criteria in Solid Tumors (RECIST) [23]; adequate hematologic function (hemoglobin ≥10 g/dl, absolute neutrophil count ≥2 x 109/l, platelets ≥100 x 109/l); adequate renal and hepatic functions (creatinine ≤1.25 x the upper limit of the normal value (ULN), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3 x ULN, total bilirubin ≤1.25 x ULN (in case of liver metastases, total bilirubin ≤1.5 x ULN and AST and ALT ≤5 x ULN); intervals since randomization of 4 weeks for eventual surgery or radiotherapy; ability to comply with scheduled follow-up and management of toxicity.

Exclusion criteria included histology other than adenocarcinoma; nonmeasurable disease; adjuvant chemotherapy within previous 6 months or which contained irinotecan or oxaliplatin; unresolved bowel obstruction or partial bowel obstruction; history of chronic diarrhea; severe gastrointestinal toxicity while receiving FU; current uncontrolled infection; other serious illness or medical condition, including contraindication to FU; past or current history of cancer other than colorectal carcinoma, except curatively treated nonmelanoma skin cancer or in situ cervical cancer; concomitant treatment with any other investigational drug and pregnancy.

methods
The primary end point of this study was RR of the schedules, which was evaluated according to the RECIST criteria and was reviewed by an independent expert committee in the event of objective response or disease stabilization ≥3 months. Patients were considered assessable for response if they had received at least four cycles of chemotherapy whatever the treatment allocated.

Before chemotherapy, all patients were checked for eligibility before admittance to the study. An initial radiologic assessment was conducted within 2 weeks before inclusion. A clinical evaluation and biological assessment were conducted within 1 week before inclusion. The first treatment administration occurred within 8 days of the randomization date.

The arm B cases (simplified LV5–FU2–oxaliplatin or simplified LV5–FU2–irinotecan) were allocated to strict randomization.

During treatment, clinical and biological assessments were conducted on day 1 of each cycle. Blood analysis was conducted each week. Radiologic assessment was carried out every four cycles (8 weeks) in both arms. Treatment toxicity was evaluated before each cycle according to the National Cancer Institute—Common Toxicity Criteria (NCI-CTC) [24].

Treatment was discontinued in the event of disease progression, unacceptable toxicity or patient refusal. Patients were followed up every 2 months after treatment discontinuation.

treatment
Patients were randomly assigned to receive the experimental arm A (IRINOX) or a control arm B (simplified LV5–FU2–oxaliplatin or simplified LV5–FU2–irinotecan), with entry stratified according to center. In the IRINOX arm, a 2-h i.v. infusion of oxaliplatin (85 mg/m2) on day 1 was followed, after a 1-h rest, by a 90-min i.v. infusion of irinotecan (180 mg/m2 for WHO patients ≤1 and 150 mg/m2 for WHO patients ≥2), with a biweekly treatment. In arm B, treatment was (i) for half of the patients in this arm (n = 20), a 90-min i.v. infusion of irinotecan (180 mg/m2 on day 1), followed by a simplified LV5–FU2 regimen [FA 200 mg/m2 as a 2-h infusion, followed by a FU bolus i.v. injection (400 mg/m2) on day 1 and a FU continuous infusion (2400 mg/m2) on days 1–2], with a biweekly treatment and (ii) for the other half of the patients (n = 20), a 2-h infusion of oxaliplatin (85 mg/m2) on day 1, followed by the same simplified LV5–FU2 regimen, delivered biweekly.

Simplified LV5–FU2, oxaliplatin and irinotecan doses and schedules were adjusted in the event of NCI toxic effects, according to the following guidelines. Hematologic toxicity was evaluated during each cycle. In the event of myelosuppression (i.e. absolute neutrophil count <1.5 x 109/l and/or platelets <75 x 109/l) at the planned date for the next cycle of chemotherapy, treatment was postponed for 1 or 2 weeks until recovery. After a 2-week delay with no recovery, the patient left the study. In the event of recovery in the IRINOX arm, the irinotecan dose was reduced to 150 mg/m2 while the oxaliplatin dose was not reduced if the toxicity concerned the absolute neutrophil count. If toxicity concerned the platelets, the oxaliplatin dose was reduced to 60 mg/m2 while the irinotecan dose was not reduced. In the event of recovery in the irinotecan–LV5–FU2 arm or in the oxaliplatin–LV5–FU2 arm, the FU bolus at day 1 was deleted if the toxicity concerned the neutrophil count and the continuous FU infusion at day 1 and 2 was reduced by 25% if the toxicity concerned the platelet count. The IRINOX doses were not modified whatever the case. The same dose reductions were implemented in the event of grade 4 neutropenia or thrombocytopenia or grade 3 neutropenia associated with fever. After two dose reductions, patients left the study. In the event of grade 3 or 4 diarrhea requiring i.v. rehydration in the IRINOX arm, the irinotecan dose was reduced to 150 mg/m2, while in the event of a second episode of severe diarrhea, the oxaliplatin dose was also reduced to 60 mg/m2. In the irinotecan–LV5–FU2 arm, the irinotecan dose was reduced to 150 mg/m2 and the FU bolus was deleted at day 1. In the oxaliplatin–LV5–FU2 arm, the oxaliplatin dose was reduced to 60 mg/m2 and the FU bolus was deleted. In the event of a second episode of severe diarrhea in the two regimens containing LV5–FU2, the FU continuous infusion was reduced by 25%. In the event of grade 3 or 4 mucositis or hand–foot syndrome in arm B, a 25% dose reduction of FU bolus and FU continuous infusion was carried out. In the event of peripheral neuropathy in the IRINOX arm or in the oxaliplatin LV5–FU2 arm, patients left the study if grade 4 toxicity occurred. For a grade 3 neuropathy, oxaliplatin doses were decreased to 60 mg/m2 and then to 50 mg/m2 if the neuropathy persisted. If there was no recovery after these two dose reductions, treatment was discontinued.

statistical considerations
RR was the primary end point in this trial. Secondary end points were progression-free survival (PFS), duration of response, overall survival (OS) and toxicity. PFS was calculated from the time of the first infusion to disease progression or death, and duration of response from the time of the documented response to the progression date.

All statistical analyses were done according to arm A or arm B. Patients' characteristics were compared with a chi-square test for qualitative variables and with a Wilcoxon test for quantitative variables. The RR was calculated for eligible patients in intent-to-treat, with a 90% confidence interval (CI). Survival analysis and PFS were calculated by the Kaplan–Meier method, and were compared via the log-rank test with a significant level of 5%.

A two-stage Fleming design [25] was used for the design of the trial. With a minimum efficacy level of 50% and a maximum inefficacy level of 30%, a global ‘a’ risk = 0.118 and a ‘b’ risk = 0.101, 40 patients were to be included in each arm (40 in IRINOX arm, 40 in arm B with 20 LV5–FU2–oxaliplatin and 20 LV5–FU2–irinotecan), for a total number of 80 patients. After the inclusion of 20 assessable patients in the IRINOX arm, the regimen was considered inactive if ≤6 out of 20 objective responses were noted and the trial had to be stopped; it was considered active if ≥10 out of 20 objective responses were noted, otherwise the trial was to be continued.

Statistical analysis was carried out using STATA software release 9 (StatCorp LP, College Station, TX).


   results
Top
 Abstract
 introduction
 patients and methods
 results
discussion
 funding
 Acknowledgements
 References
 
patients' characteristics
From September 2002 to April 2005, 80 patients were enrolled in this trial. All patients received at least one cycle and were therefore assessable for toxicity. Seventy-two patients were assessable for response according to the Review Committee (34 of 40 in the IRINOX arm and 38 of 40 in the arm B). Six patients were considered not assessable in the IRINOX arm: four patients had their treatment stopped after first cycle because of toxicity, and two patients decided to withdraw from the study. Two patients were considered not assessable in arm B: one had his treatment stopped because of toxicity after first cycle while the other died of causes not related to the trial. Therefore, these eight patients were kept in the statistical analysis. Patients, tumors and previous treatment characteristics are presented in Table 1.


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  		Table 1 Patient and tumor characteristics at baseline

 
efficacy and survival
At the cut-off date, median follow-up time was 36.8 months (range 0.6–46.1 months) and no patient was still on treatment.

Efficacy could be evaluated in 72 of the 80 patients. The results are expressed as intent-to-treat for all patients and are shown in Table 2.


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  		Table 2 Response rate (external review committee)

 
Median OS was 19 months (95% CI, 14.0% to 27.1%) and median PFS was 8.4 months (95% CI, 6.4% to 11%) in the IRINOX arm. In arm B, median OS was 20.4 months (95% CI, 14.1% to 27.1%) and median PFS was 8.1 months (95% CI, 6.2% to 9.3%). One-year survival seemed slightly longer in arm B than in arm A (75% versus 68%).

extent of exposure and cycle delays
The extent of exposure is presented in Table 3.


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  		Table 3 Extent of exposure

 
Cycle delays (i.e. delay in schedule of >3 days) appeared similar in the IRINOX arm (72.2% of patients and 26.6% of cycles) and in arm B (76.9% of patients and 18.8% of cycles). The reasons for cycle delays in both arms were mainly hematologic toxicity (33.3% in arm A and 40.6% in arm B), although patients' requests for a treatment delay accounted for up to 25%.

toxicity
All 80 patients were assessable for toxicity and no toxic deaths occurred. The incidences of the main toxic effects according to the NCI-CTC scale are listed in Table 4 as the maximum grade seen per patient.


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  		Table 4 Drug-related toxicity per patient

 
In the IRINOX arm, 17 patients (42.5%) presented grade 3/4 neutropenia and four (10%) experienced severe febrile neutropenia. In arm B, 13 patients (32.5%) presented grade 3/4 neutropenia and two (5%) had severe febrile neutropenia.

Thirteen patients (32.5%) in the IRINOX arm experienced severe diarrhea (with one grade 3 for two cycles and one grade 4), although three patients (7.5%) in arm B also experienced severe diarrhea.

Severe vomiting was reported in four patients (10.0%) in the IRINOX arm and in two patients (5%) in arm B.

The neurotoxicities encountered were classified as neurosensory, none as neuromotor. In the IRINOX arm, seven (17.5%) severe neurosensory toxic effects were encountered, two grade 4 and five grade 3. In arm B, neurosensory toxicity was due only to the oxaliplatin-containing regimen. Three severe toxic effects (7.5%) were noted, including two grade 4.

A total of 19 patients discontinued treatment as a result of toxicity, 14 in the IRINOX arm and five in arm B. In the IRINOX arm, discontinuations were due to neurosensory toxicity (two grade 4 and two grade 3), severe diarrhea (one grade 4 and one grade 3), severe febrile neutropenia (three grade 3), one grade 4 allergic reaction to oxaliplatin, one severe digestive bleeding (the expert panel considered that, if not clearly induced by it, this complication was facilitated by the chemotherapy protocol), severe asthenia (two grade 3) and one grade 3 alkaline phosphatases elevation not due to disease progression. In arm B, discontinuations were due to two grade 4 neurosensory toxic effects, two grade 3 febrile neutropenia and one grade 3 thrombocytopenia.

second-line therapy
The proportion of patients receiving a second-line therapy after progression was high: 82% in the IRINOX arm and 77.5% in arm B. Patients progressing under IRINOX mainly received a combination of FU and irinotecan (40%), FU and oxaliplatin (20%) or FU alone (20%). In arm B, when patients progressed under the simplified LV5–FU2–irinotecan scheme, 83% of them received a FU–oxaliplatin combination; when they progressed under the simplified LV5–FU2–oxaliplatin scheme, 85% of them received a FU–irinotecan combination.


   discussion
Top
 Abstract
 introduction
 patients and methods
 results
 discussion
funding
 Acknowledgements
 References
 
CRC has become a public health problem in the last 20 years. For advanced CRC patients, major improvements in treatments have led to better efficacy, longer survival and better quality of life.

Alternative treatments still need to be tested in prospective trials. We previously reported [21] the results of a combination of irinotecan and oxaliplatin in advanced FU-resistant CRC patients. A 23% RR was noted, with a median OS of 12.3 months and a median PFS of 8.3 months.

In the present randomized phase II study, the experimental arm combining irinotecan and oxaliplatin was the one published by Goldwasser et al. [19] which appeared to be a more promising schedule with an intensified biweekly scheme. The second arm was the standard arm in France. As two protocols have received government approval as first-line treatment, we used both schedules, i.e. simplified LV5–FU2 with irinotecan or oxaliplatin.

However, when the randomized phase III study by Goldberg et al. [26] was published in 2004, our study was still ongoing. One of the arms of that study was an irinotecan and oxaliplatin combination (named IROX), which had a lower efficacy, a shorter time to progression and a shorter survival time than the FOLFOX® schedule. For this reason, we wondered whether we should prematurely close our trial but the investigators of the Fédération Nationale des Centres de Lutte Contre le Cancer decided to pursue it, as our IROX schedule had not the same dose intensity than the IROX schedule.

The objective RR in intent-to-treat was the primary end point of the study. In the IRINOX arm, the RR was 52.5%, with no complete response and 21 partial responses. This RR compares favorably with other reported irinotecan–oxaliplatin combinations for first-line advanced CRC patients [26, 27]: (i) it appears higher than the 35% RR reported by Goldberg et al. [26] and (ii) it seems similar to another IROX combination reported by Schalhorn et al. [27] as first-line treatment, 50%, yet with a higher drug dose intensity than in the present study (irinotecan 80 mg/m2/week and oxaliplatin 85 mg/m2/week). In arm B (simplified LV5–FU2 with irinotecan or oxaliplatin), the RR was 55% with two complete responses (one in each treatment schedule) and 20 partial responses. This RR was similar to what was expected for LV5–FU2–irinotecan or LV5–FU2–oxaliplatin as first-line therapy [10, 11, 14, 26, 27]. Median PFS was 8.4 months in the IRINOX arm and 7.9 months in arm B. These results compare well with other IROX schedules: 7.3 months in the Schalhorn study [27], 6.5 months in the Goldberg study [26]. OS in the IRINOX arm was 18.4 months and was comparable with that reported (18.6 months [27] and 17.4 months [26]) for the IROX arms, even if second-line therapy may have contributed to OS.

Severe toxic effects were mostly hematologic and, less frequently, gastrointestinal. Neutropenia and febrile neutropenia were present in both arms and were easily dealt with. Some severe diarrhea occurred in the IRINOX arm, leading to treatment discontinuation in two patients. Diarrhea in the IRINOX arm was somewhat higher than what was described in the IROX arm of the Goldberg et al. study [26], 32.5% versus 24%. Severe peripheral neuropathy in the IRINOX arm (17.5%) led to treatment discontinuation in four patients, and was higher than that reported by Goldberg et al. with the IROX arm (7%). These events could be due to the higher drug dose intensity of our combination.

In conclusion, this randomized phase II study demonstrates that the combination of irinotecan and oxaliplatin appears active (52.5% RR in intent-to-treat) with a manageable toxicity at these doses delivered biweekly in first-line metastatic CRC patients. IRINOX may be a treatment option in patients for whom FU or FU prodrugs are contraindicated.


   funding
Top
 Abstract
 introduction
 patients and methods
 results
 discussion
 funding
Acknowledgements
 References
 
The Fédération Nationale des Centres de Lutte Contre le Cancer; Ligue contre le Cancer, Pfizer France, Sanofi Aventis France.


   Acknowledgements
Top
 Abstract
 introduction
 patients and methods
 results
 discussion
 funding
 Acknowledgements
References
 
Presented in part at the 42th Annual Meeting of the American Society of Clinical Oncology, Atlanta, GA, 2–6 June 2006.

Received for publication June 4, 2007. Accepted for publication July 2, 2007.


   References
Top
 Abstract
 introduction
 patients and methods
 results
 discussion
 funding
 Acknowledgements
 References
 
1. Bouvier AM, Remontet L, Jougla E, et al. Incidence of gastrointestinal cancers in France. Gastroenterol Clin Biol (2004) 28:877–881.[Web of Science][Medline]

2. Colonna M, Hedelin G, Esteve J, et al. National cancer prevalence estimation in France. Int J Cancer (2000) 87:301–304.[CrossRef][Web of Science][Medline]

3. Bécouarn Y, Brunet R, Ravaud A, et al. Chimiothérapie systémique des adénocarcinomes colorectaux métastatiques. Gastroenterol Clin Biol (1992) 16:166–176.[Web of Science][Medline]

4. Advanced Colorectal Cancer Meta-Analysis Project. Modulation of fluorouracil by leucovorin in patients with advanced colorectal cancer: evidence in terms of response rate. J Clin Oncol (1992) 10:896–903.[Abstract]

5. de Gramont A, Bosset JF, Milan C, et al. Randomized trial comparing monthly low-dose leucovorin and fluorouracil bolus with bimonthly high-dose leucovorin and fluorouracil bolus plus continuous infusion for advanced colorectal cancer: a French intergroup study. J Clin Oncol (1997) 15:808–815.[Abstract/Free Full Text]

6. Tournigand C, de Gramont A, Louvet C, et al. A simplified bi-monthly regimen with leucovorin (LV) and 5-fluorouracil (5FU) for metastatic colorectal cancer (MCRC). Proc Am Soc Clin Oncol (1998) 17:247a. Abstr 1052.

7. Rougier P, Van Cutsem E, Bajetta E, et al. Randomised trial of irinotecan versus fluorouracil by continuous infusion after fluorouracil failure in patients with metastatic colorectal cancer [erratum in Lancet 1998; 352: 1634]. Lancet (1998) 352:1407–1412.[CrossRef][Web of Science][Medline]

8. Cunningham D, Pyrhonen S, James RD, et al. Randomised trial of irinotecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer. Lancet (1998) 352:1413–1418.[CrossRef][Web of Science][Medline]

9. André T, Louvet C, Maindrault-Goebel F, et al. CPT-11 (irinotecan) addition to bimonthly, high-dose leucovorin and bolus and continuous-infusion 5-fluorouracil (FOLFIRI) for pretreated metastatic colorectal cancer. GERCOR. Eur J Cancer (1999) 35:1343–1347.[CrossRef][Web of Science][Medline]

10. Douillard JY, Cunningham D, Roth AD, et al. Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial [erratum in Lancet 2000; 355: 1372]. Lancet (2000) 355:1041–1047.[CrossRef][Web of Science][Medline]

11. Saltz LB, Cox JV, Blanke C, et al. Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan Study Group. N Engl J Med (2000) 343:905–914.[Abstract/Free Full Text]

12. Bécouarn Y, Rougier P. Clinical efficacy of oxaliplatin monotherapy: phase II trials in advanced colorectal cancer. Semin Oncol (1998) 25(Suppl 5):23–31.[Web of Science][Medline]

13. André T, Bensmaine MA, Louvet C, et al. Multicenter phase II study of bimonthly high-dose leucovorin, fluorouracil infusion, and oxaliplatin for metastatic colorectal cancer resistant to the same leucovorin and fluorouracil regimen. J Clin Oncol (1999) 17:3560–3568.[Abstract/Free Full Text]

14. 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.[Abstract/Free Full Text]

15. Zeghari-Squalli N, Raymond E, Cvitkovic E, Goldwasser F. Cellular pharmacology of the combination of the DNA topoisomerase I inhibitor SN-38 and the diamino-cyclohexane platinum derivative oxaliplatin. Clin Cancer Res (1999) 5:1189–1196.[Abstract/Free Full Text]

16. Rothenberg ML, McKinney J, Hande KR, et al. A Phase I Clinical and Pharmacokinetic Trial of Oxaliplatin and Irinotecan Given Every Two Weeks to Patients with Refractory Solid Tumors. (1999) 18. Washington, USA: ACR-NCI-EORTC International Conference. 125. (abstr).

17. Wasserman E, Cuvier C, Lokiec F, et al. Combination of oxaliplatin plus irinotecan in patients with gastrointestinal tumors: results of two independent phase I studies with pharmacokinetics. J Clin Oncol (1999) 17:1751–1759.[Abstract/Free Full Text]

18. Kemeny N, Tong W, Stockman J, et al. Phase I trial of weekly oxaliplatin and irinotecan in previously treated patients with metastatic colorectal cancer. Proc Am Soc Clin Oncol (2000) 19. 245a (Abstr 948).

19. Goldwasser F, Gross-Goupil M, Tigaud JM, et al. Dose escalation of CPT-11 in combination with oxaliplatin using an every two weeks schedule: a phase I study in advanced gastrointestinal cancer patients. Ann Oncol (2000) 11:1463–1470.[Abstract/Free Full Text]

20. Scheithauer W, Kornek GV, Raderer M, et al. Combined irinotecan and oxaliplatin plus granulocyte colony-stimulating factor in patients with advanced fluoropyrimidine/leucovorin-pretreated colorectal cancer. J Clin Oncol (1999) 17:902–906.[Abstract/Free Full Text]

21. Bécouarn Y, Gamelin E, Coudert B, et al. Randomized multicenter phase II study comparing a combination of fluorouracil and folinic acid and alternating irinotecan and oxaliplatin with oxaliplatin and irinotecan in fluorouracil-pretreated metastatic colorectal cancer patients. J Clin Oncol (2001) 19:4195–4201.[Abstract/Free Full Text]

22. Rougier P, Lepille D, Bennouna J, et al. Antitumour activity of three second-line treatment combinations in patients with metastatic colorectal cancer after optimal 5-FU regimen failure: a randomised, multicentre phase II study. Ann Oncol (2002) 13:1558–1567.[Abstract/Free Full Text]

23. Therasse P, Arbuck SG, Eisenhauer EA, et al. 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 (2000) 92:205–216.[Abstract/Free Full Text]

24. Common Terminology Criteria for Adverse Events (CTCAE), Version 3.0, DCTD, NCT, NIH, DHHS. March 31, 2003. http://ctep.cancer.gov (9 August 2006 date last accessed).

25. Fleming TR. One-sample multiple testing procedure for phase II clinical trials. Biometrics (1982) 38:143–151.[CrossRef][Web of Science][Medline]

26. 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.[Abstract/Free Full Text]

27. Schalhorn A, Fischer von Weikersthal L, Quietzsch D, et al. Phase III trial of irinotecan plus oxaliplatin (IROX) versus irinotecan plus 5-FU/folinic acid (FOLFIRI) as first-line treatment of metastatic colorectal cancer (CRC): the FIRE-Trial. Proc Am Soc Clin Oncol (2005) 24:250s. (Abstr 3516).


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18/12/2000    most recent
mdm379v1
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