This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Tournigand, C. Articles by de Gramont, A. Search for Related Content PubMed Articles by Tournigand, C. Articles by de Gramont, A. Social Bookmarking                            What's this?

OPTIMOX1: A Randomized Study of FOLFOX4 or FOLFOX7 With Oxaliplatin in a Stop-and-Go Fashion in Advanced Colorectal Cancer—A GERCOR Study

From the Hôpital Saint-Antoine; Hôpital Tenon; Sanofi-Aventis, Paris; Clinique Saint Jean, Lyon; Hôpital Devron, Dijon; Clinique Sainte Catherine, Avignon; Hôpital de Senlis, Senlis; Clinique Radiologique Armoricaine, Saint Brieuc, France; Hospital Clínico Universitario, Valencia; Hospital Universitario Marques de Valdecilla, Santander, Spain; Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; and International Drug Development Institute, Brussels, Belgium.

Address reprint requests to A. de Gramont, MD, Hôpital Saint-Antoine, 184, rue du Faubourg Saint-Antoine, 75571 Paris Cedex 12, France; e-mail: aimery.de-gramont{at}sat.ap-hop-paris.fr

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

 
Purpose In metastatic colorectal cancer, a combination of leucovorin (LV) and fluorouracil (FU) with oxaliplatin (FOLFOX) 4 is a standard first-line regimen. The cumulative neurotoxicity of oxaliplatin often requires therapy to be stopped in patients who are still responding. This study evaluates a new strategy of intermittent oxaliplatin treatment that is based on FOLFOX7, a simplified leucovorin and fluorouracil regimen with high-dose oxaliplatin.

Patients and Methods Previously untreated patients were randomly assigned to either FOLFOX4 administered every 2 weeks until progression (arm A) or FOLFOX7 for six cycles, maintenance without oxaliplatin for 12 cycles, and reintroduction of FOLFOX7 (arm B).

Results Six hundred twenty patients were enrolled, including an exploratory cohort of 95 elderly or poor prognosis patients. Median progression-free survival and survival times were 9.0 and 19.3 months, respectively, in patients allocated to arm A compared with 8.7 and 21.2 months, respectively, in patients allocated to arm B (P = not significant). Response rates were 58.5% with arm A and 59.2% with arm B. National Cancer Institute Common Toxicity Criteria grade 3 or 4 toxicity was observed in 54.4% of the patients in arm A v 48.7% of patients in arm B. From cycle 7, fewer patients experienced grade 3 or 4 toxicity in arm B. Grade 3 sensory neuropathy was observed in 17.9% of the patients in arm A v 13.3% of patients in arm B (P = .12). In arm B, oxaliplatin was reintroduced in only 40.1% of the patients but achieved responses or stabilizations in 69.4% of these patients.

Conclusion Oxaliplatin can be safely stopped after six cycles in a FOLFOX regimen. Further study is needed to fully evaluate oxaliplatin reintroduction.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

 
Colorectal cancer is the second leading cause of cancer death in Western countries.¹ First-line therapy of advanced colorectal cancer is now based on oxaliplatin and irinotecan administered in combination with leucovorin (LV) and fluorouracil (FU),^2-4 alongside the introduction of biologic therapies. A combination of LV and FU with oxaliplatin (FOLFOX), the FOLFOX4 regimen, has become established as a standard first-line therapy for advanced disease after the European C95 and the US N9741 studies, which demonstrated superiority of FOLFOX4 over LV/FU and LV/FU bolus plus irinotecan, respectively.^3,5 The two limiting toxicities of FOLFOX4 in these studies were neutropenia and the specific reversible sensory neuropathy of oxaliplatin. The occurrence of sensory neuropathy is significant because it may cause patients who are continuing to respond to treatment to discontinue treatment. The issue of oxaliplatin neurotoxicity also arose in the C97 study, which compared irinotecan and oxaliplatin, both in combination with a simplified LV/FU bolus plus infusion regimen,⁶ and also the FOLFOX7 regimen (Fig 1), in which oxaliplatin is administered at a greater dose-intensity.⁷ In FOLFOX7, FU bolus was not used to reduce the incidence of neutropenia.

View larger version (27K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Chemotherapy regimens: (A) FOLFOX4; (B) FOLFOX7; and (C) simplified LV5FU2. FU, fluorouracil; LV, leucovorin; FOLFOX, leucovorin, fluorouracil, and oxaliplatin.

Therefore, the present study investigated the use of oxaliplatin discontinuation and reintroduction in a novel stop-and-go strategy, OPTIMOX1. This consisted of the FOLFOX7 regimen administered for six cycles (one cycle = 2 weeks) followed by 12 cycles of maintenance and subsequent reintroduction of FOLFOX7 for another six cycles. This regimen was compared with the FOLFOX4 regimen administered until progression or occurrence of unacceptable toxicity.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

 
Patient Selection
The eligibility criteria for inclusion in the study were adenocarcinoma of the colon or rectum; unresectable metastases; at least one bidimensionally measurable lesion of 1 cm or a nonmeasurable assessable lesion; adequate bone marrow, liver (alkaline phosphatase [ALP] < 5x the upper limit of the normal [ULN] value), and renal function (creatinine 3x ULN); WHO performance status (PS) of 0 to 2; age 18 to 80 years; and no previous chemotherapy for metastatic disease. Previous adjuvant chemotherapy was required to have been completed at least 6 months before inclusion. Patients with CNS metastases, second malignancies, bowel obstruction, peripheral neuropathy more than grade 1, symptomatic angina pectoris, or disease confined to previous radiation fields were excluded. Written informed consent was required, and the ethical committee approved the study. The population included an exploratory cohort of elderly patients (age > 75 years) and/or poor prognosis patients (ALP > 3x ULN).

Chemotherapy
In the control arm (arm A), patients received FOLFOX4, which consisted of a 2-hour infusion of leucovorin isomers l-LV (100 mg/m²) or dl-LV (200 mg/m²) followed by an FU bolus (400 mg/m²) and 22-hour infusion (600 mg/m²) for 2 consecutive days every 2 weeks, with oxaliplatin (85 mg/m²) as a 2-hour infusion on day 1. In the investigational OPTIMOX1 arm (arm B), patients received FOLFOX7 for six cycles (consisting of a 2-hour infusion of l-LV 200 mg/m² or dl-LV 400 mg/m² followed by an FU 46-hour infusion of 2,400 mg/m² every 2 weeks, with oxaliplatin 130 mg/m² as a 2-hour infusion on day 1), they then received 12 cycles of the simplified (s) LV5FU2 regimen (consisting of a 2-hour infusion of l-LV 200 mg/m² or dl-LV 400 mg/m² followed by an FU 400 mg/m² bolus and 46-hour 3,000 mg/m² infusion every 2 weeks), and finally, FOLFOX7 was resumed for six additional cycles.

Figure 1 illustrates the chemotherapy regimens. Treatment was continued until progression, unacceptable toxicity, or patient choice. In case of progression during LV5FU2 alone and sensory neuropathy less than grade 2, reintroduction of oxaliplatin was scheduled in arm B and allowed in arm A.

National Cancer Institute Common Toxicity Criteria (NCI-CTC) version 2.0 was used to assess toxicity.¹⁰ In both arms, treatment could be delayed for up to 2 weeks until recovery from stomatitis and diarrhea grade 2, skin toxicity grade 2, and other toxicity grade 2.

In arm A, the FU dose was decreased to 300 mg/m² bolus and 500 mg/m² continuous infusion in case of grade 3 or 4 stomatitis, diarrhea, neutropenia, thrombocytopenia, or skin toxicity or other grade 3 major organ drug-related toxicity. The oxaliplatin dose was decreased to 75 mg/m²/cycle in case of grade 3 or 4 neutropenia or thrombocytopenia, grade 3 diarrhea or stomatitis, any other grade 3 major organ drug-related toxicity, or paresthesia associated with pain. Oxaliplatin was stopped until symptom improvement in case of persistent paresthesia associated with pain or functional impairment persisting between cycles.

In arm B, during FOLFOX7 therapy, the FU dose was decreased to 2,000 mg/m² continuous infusion and the oxaliplatin dose was decreased to 100 mg/m²/cycle in case of the toxicities listed in the previous paragraph. Oxaliplatin was stopped until symptom improvement in case of persistent paresthesia associated with pain or functional impairment persisting between cycles. When toxicity occurred during the sLV5FU2 phase of treatment in arm B, FU bolus was stopped, and FU infusion was dose decreased to 2,400 mg/m² in case of the toxicities listed in the previous paragraph.

In both arms, in case of NCI-CTC grade 2 suspected allergy or in case of pharyngolaryngeal dysesthesias syndrome, oxaliplatin infusion time was increased from 2 to 6 hours. In case of heart toxicity grade 2, FU and LV were permanently interrupted, and patients were withdrawn from the study. In both arms, it was not permitted to re-escalate doses that had been reduced because of toxicity. Prevention of alopecia with cold cap or stomatitis with iced mouth rinses was not permitted. The use of implantable ports and disposable or electronic pumps allowed chemotherapy to be administered on an outpatient basis.

Evaluation Criteria
Computed tomography scans of measurable lesions were assessed at baseline, repeated after four and six cycles, and then repeated every six cycles. Complete response was defined as the complete disappearance of all clinically assessable disease for at least 4 weeks. Partial response was defined as a decrease of at least 50% of the sum of the products of the diameters of measurable lesions for at least 4 weeks. Stable disease was defined as a decrease of less than 50% or an increase of less than 25% of measurable lesions, and progressive disease was defined as an increase of at least 25% of measurable lesions or the appearance of new malignant lesion(s). There was a new baseline measurement in case of FOLFOX reintroduction. External review of computed tomography scans was not performed.

The primary end point was duration of disease control (DDC; Fig 2). ¹¹ The DDC was defined as the PFS, or, if FOLFOX was reintroduced, DDC was defined as the addition of the initial PFS and the PFS of the reintroduction in case of no progression at the first evaluation on FOLFOX reintroduction. Further assessment criteria were PFS, overall survival, response rate, and tolerance.

View larger version (19K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Definition of duration of disease control (DDC). (A) Patient with progression before leucovorin, fluorouracil, and oxaliplatin (FOLFOX) reintroduction. FOLFOX reintroduction achieved partial response (PR) or stabilization (DDC = progression-free survival [PFS] + PFS of FOLFOX reintroduction). (B) Patient with progression before FOLFOX reintroduction. FOLFOX reintroduction achieved progressive disease (PD) at first evaluation (DDC = PFS). (C) Patients without progression before FOLFOX reintroduction (DDC = PFS).

Statistical Considerations
Random assignment was performed using a minimization technique,¹² stratifying patients by center, PS (0 to 1 v 2), number of metastatic sites involved (one v > one site), age (18 to 50 v 51 to 75 v 76 to 80 years), and baseline ALP ( 3x ULN v > 3 to 5x ULN). The primary analysis of the trial had to be performed on all randomly assigned patients, but the results also had to be presented excluding the patients with age more than 75 years and baseline ALP more than 3x ULN for ease of reference to historical figures. Sample size was calculated to fulfill the primary objective of this trial, which was to demonstrate in advanced colorectal cancer that the test treatment extends the DDC compared with the reference treatment (8 v 11 months, respectively). The final sample size was 627 patients; 560 patients were needed to provide 80% power for standard patients, but the sample size was inflated by 12% to account for the exploratory cohort and for the ineligible patients and deviations of protocol.

The Kaplan-Meier method was used to estimate survival and PFS, and the log-rank test was used to compare the curves.¹³ The Mantel-Haenszel test was used to compare proportions.¹⁴ The Cox regression model was used for multivariate analysis of prognostic factors for survival, using a backward selection approach.¹⁵ The cutoff date for the final analysis was October 1, 2004.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

 
Patient Characteristics
From January 2000 to June 2002, 623 patients were randomly assigned at 56 institutions in five countries. Three patients were not analyzed because they were not eligible and not treated. The characteristics of the 620 eligible patients (311 in arm A and 309 in arm B) are listed in Table 1. A total of 261 patients in arm A and 264 patients in arm B had an ALP 3x ULN and age less than 76 years. There were a further 95 patients in the exploratory cohort of elderly and/or poor prognosis patients, and their data will be presented in detail elsewhere.

Second-Line and Subsequent Therapy
In arm A, 224 patients (77.5%) received a second-line chemotherapy, 134 (46.4%) received a third-line therapy, and 53 (18.3%) received a fourth-line therapy. In arm B, 209 patients (72.8%) received a second-line chemotherapy (independently from scheduled oxaliplatin reintroduction), 112 (39%) received a third-line therapy, and 56 (19.5%) received a fourth-line therapy. During the course of second-line and subsequent therapies, 27% of patients in arm A had oxaliplatin reintroduction, 70% received irinotecan-based chemotherapy, and 32% received other chemotherapy regimens. In arm B, 55% of patients had oxaliplatin reintroduction per protocol or later, 61% received irinotecan-based chemotherapy, and 33% received other chemotherapy regimens.

DDC and PFS
In terms of DDC, the results in the two arms were comparable. The median DDC was 9.0 months in arm A and 10.6 months in arm B (hazard ratio = 0.99; 95% CI, 0.81 to 1.15; P = .89; Fig 3). In patients with ALP 3x ULN and age younger than 76 years, the median DDC was 9.2 months in arm A and 10.7 months in arm B (P = .91).

View larger version (16K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 3. Duration of disease control and progression-free survival curves (n = 620). FOLFOX, leucovorin, fluorouracil, and oxaliplatin.

In arm A, oxaliplatin was reintroduced in 23 patients (7.4%), and only eight patients (2.6%) had a longer DDC than PFS. In arm B, oxaliplatin was reintroduced per protocol in 124 patients (40.1%), of whom 53 patients (17.2%) had a longer DDC than PFS, reflecting a successful response to oxaliplatin after reintroduction.

Overall Survival
Median survival time was 19.3 months in patients allocated to arm A compared with 21.2 months in patients allocated to arm B (hazard ratio = 0.93; 95% CI, 0.72 to 1.11; P = .49; Fig 4). The median survival times in patients with ALP 3x ULN and age younger than 76 years were 20.0 and 21.6 months, respectively (P = .68).

View larger version (12K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 4. Overall survival curves. FOLFOX, leucovorin, fluorouracil, and oxaliplatin.

Objective Tumor Responses
Tumor response rates were also similar for the two treatment arms (58.5% in arm A; 95% CI, 54.5% to 62.5%; and 59.2% in arm B; 95% CI, 55.2% to 63.2%; P = not significant). The response rates are listed in Tables 2 and 3. A CEA decline of 50% or more in patients who had an increased baseline CEA level was observed in 121 patients (54.3%) in arm A and 137 patients (61.2%) in arm B (P = .15).

Reintroduction of FOLFOX Therapy
In arm B, only 40.1% of the patients had per-protocol reintroduction. Patients could not have reintroduction because of death or early progression (18.5%), chemotherapy-related toxicity (18.4%, with 11% of the patients having a residual neurotoxicity grade > 1), or secondary surgery (5.5%). For 17.5% of the patients, which represents 30.1% of the patients eligible for reintroduction, oxaliplatin was not reintroduced without specific reason. Of the patients who did proceed to a second period of oxaliplatin treatment, reintroduction was frequently delayed; although scheduled to begin after 18 cycles or 9 months, 73% of the patients who then had no tumor progression had oxaliplatin reintroduction after 10 months. Twelve percent of patients had a complete chemotherapy stop before reintroduction.

Tumor response to per-protocol reintroduction was assessed in 122 of 124 patients in arm B. Overall, reintroduction achieved responses or stabilizations in 69.4% of the patients. Responses are listed in Table 3. In patients without progression at reintroduction (n = 33), the response rate was 24.2%, the stable disease rate was 54.5%, and the progressive disease rate was 3.0%, whereas 18.2% of patients were nonassessable. These patients included three patients who had surgery and one patient who remained in complete response. PFS after reintroduction was not assessable in this subgroup. In patients in whom reintroduction was made after progression (n = 89), the response rate was only 6.7%, the stable disease rate was 42.7%, and the progressive disease rate was 44.9%, whereas 5.6% of the patients were nonassessable. The median PFS from reintroduction was 12 weeks in these patients.

In arm A, tumor response to oxaliplatin reintroduction was assessed in 24 patients, among whom 20 had oxaliplatin reintroduced after progression and four had oxaliplatin reintroduced before progression. The response rate was 12.5%, the stable disease rate was 20.8%, and the progressive disease rate was 45.8%. A further 20.8% of patients proceeded to surgery and were nonassessable. The overall median survival time in centers that had reintroduced oxaliplatin in more than 50% of their patients either during the study or later was 25.5 months (115 patients).

Toxicity
In arm A, patients received a median of 12 cycles of chemotherapy (range, one to 43 cycles), of which a median of 11 cycles were FOLFOX4 (range, one to 30 cycles). Patients who had oxaliplatin reintroduction received a median of five cycles (range, two to 11 cycles). The relative dose-intensity was 88% for oxaliplatin, 89% for FU bolus, and 91% for FU infusion. In arm B, patients received a median of 15 cycles of chemotherapy (range, one to 51 cycles), including a median of six cycles of FOLFOX7 (range, zero to 14 cycles). Patients who had oxaliplatin reintroduction received a median of six cycles (range, one to 14 cycles). The relative dose-intensity during the first six cycles was 79% of the scheduled dose for oxaliplatin and 84% for FU infusion. The median oxaliplatin dose-intensity was 37% higher in arm B compared with arm A.

During early treatment, the tolerability and toxicity profiles of the two regimens were similar. In arm B, fewer patients experienced NCI-CTC grade 3 or 4 neutropenia, but more patients had thrombocytopenia, nausea, mucositis, and hand-foot syndrome. Grade 3 sensory neuropathy was observed in 17.9% of the patients in arm A and 13.3% of patients in arm B (P = .12). Febrile neutropenia occurred in eight patients (2.6%) in arm A and two patients (0.6%) in arm B. Vascular events, phlebitis, and pulmonary embolism were reported in 11 patients (3.5%) in arm A and in two patients (0.6%) in arm B. Overall, 54.4% and 48.2% of patients experienced a grade 3 or 4 toxicity in arm A and arm B, respectively (P = not significant). Table 4 lists the toxicities. During the first 60 days, five patients (1.6%) died in arm A, and eight patients (2.6%) died in arm B (P = .42).

View larger version (20K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 5. Comparison of the proportion of patients who developed a grade 3 or 4 toxicity at each cycle. (A) Number of patients who received each cycle. (B) Percentage of patients with grade 3 or 4 toxicity. (C) Percentage of patients with neurologic grade 3 toxicity. FOLFOX, leucovorin, fluorouracil, and oxaliplatin.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

 
Studies achieving a median survival time of more than 20 months in advanced colon cancer therapy remain few^6,16-19 and have two main characteristics. The first is the use of FU with oxaliplatin, irinotecan, or irinotecan and bevacizumab. The second is that a high proportion (50% to 80%) of patients receive a second-line therapy with active drugs not used in first-line therapy.

In the present OPTIMOX1 study, median survival time exceeded 20 months among patients with initially inoperable metastatic colorectal cancer with less stringent inclusion criteria than in preceding studies undertaken by the same group.^5,6,20 Of note, the FOLFOX4 arm reproduced the results achieved with this regimen in previous studies.^3,5 The proportion of patients who received second-line irinotecan (> 60%) was high in both arms of the trial.

OPTIMOX1 has shown that stopping oxaliplatin after six cycles followed by sLV5FU2 alone achieves the same efficacy results, response rate, PFS, and overall survival as continuing oxaliplatin until progression or toxicity. Furthermore, avoiding oxaliplatin after the sixth cycle greatly reduced the risk of grade 3 to 4 toxicity.

The results of this study are consistent with the proposition that, for most patients, six cycles of FOLFOX7 are sufficient to achieve the full clinical benefits of oxaliplatin treatment. However, it is also possible that other factors may have contributed to the equivalent disease control achieved by the two regimens. For instance, because oxaliplatin dose-intensity was increased by 37% in the FOLFOX7-based arm B, it might be supposed that this contributed to the result by offsetting the effects of discontinuing oxaliplatin. However, response rates were comparable between the two groups during first-line treatment, indicating that this is unlikely. The LV5FU2 regimens also differed between the two arms, but although these differences impact on cost and convenience of treatment, the present study indicates that they do not differ in efficacy. However, it is possible that the use of the full sLV5FU2 regimen in arm B after the six cycles of FOLFOX7 contributed to the clinical response because the median PFS of this regimen alone was found to be unusually prolonged in a previous study.²¹

Oxaliplatin reintroduction, as scheduled in the protocol, was unsuccessful in this study. This does not mean that reintroduction is not active, but protocol violations were so frequent that it raises the question of its feasibility. Furthermore, almost 75% of the patients had delayed oxaliplatin reintroduction, including a significant proportion (12%) even after a complete therapy stop. This poor compliance with the protocol could mean that many investigators were not convinced by the new concept of oxaliplatin reintroduction or that patients feared to resume a regimen more toxic than sLV5FU2. Because a significant number of patients received oxaliplatin-based therapy after the protocol and in both arms of the study, the results do not make it possible to draw final conclusions about oxaliplatin reintroduction. Nevertheless, detailed consideration of the results suggests that reintroduction could have a significant impact on survival; reintroduction rate among centers was an independent prognostic factor for prolonged survival, which suggests that a more favorable population is not the sole explanation of the 25-month median survival time observed in centers that reintroduced oxaliplatin in more than 50% of their patients.

To further assess oxaliplatin reintroduction, we have conducted a new study, OPTIMOX2, which is designed to evaluate the feasibility of oxaliplatin reintroduction after LV5FU2 maintenance in selected centers and to further evaluate a complete chemotherapy stop-and-go regimen wherein reintroduction is performed in non–FU-resistant tumors.

Given the results of the present study, we now consider that six cycles of FOLFOX7 is the optimal duration of the combined chemotherapy for most patients with advanced colorectal cancer. However, considering these results, we modified the FOLFOX7 schedule and now use a dose of oxaliplatin of 100 mg/m² associated with an increased dose of FU (3,000 mg/m²). Modified FOLFOX7 and XELOX (oxaliplatin) regimens, combined with angiogenesis and epidermal growth factor receptor inhibitors, are currently being evaluated in the double inhibition, reintroduction, avastin (Genentech Inc, South San Francisco, CA), metastic colorectal cancer (DREAM)/OPTIMOX3 study.

	Appendix

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

 
The Appendix is included in the full-text version of this article, available online at www.jco.org. It is not included in the PDF (via Adober Acrobat Readerr) version.

	Authors' Disclosures of Potential Conflicts of Interest

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

	Author Contributions

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

 

Conception and design: Christophe Tournigand, Marc Buyse, Laurent Mineur, Christophe Louvet, Isabelle Tabah-Fisch, Aimery de Gramont Financial support: Isabelle Tabah-Fisch Provision of study materials or patients: Andres Cervantes, Arie Figer, Gérard Lledo, Michel Flesch, Laurent Mineur, Elisabeth Carola, Pierre-Luc Etienne, Fernando Rivera, Isabel Chirivella, Christophe Louvet, Thierry André, Isabelle Tabah-Fisch, Aimery de Gramont Collection and assembly of data: Christophe Tournigand, Andres Cervantes, Arie Figer, Gérard Lledo, Marc Buyse, Laurent Mineur, Elisabeth Carola, Fernando Rivera, Isabel Chirivella, Nathalie Perez-Staub, Thierry André, Aimery de Gramont Data analysis and interpretation: Christophe Tournigand, Marc Buyse, Nathalie Perez-Staub, Aimery de Gramont Manuscript writing: Christophe Tournigand, Nathalie Perez-Staub, Thierry André, Aimery de Gramont Final approval of manuscript: Christophe Tournigand, Andres Cervantes, Marc Buyse, Laurent Mineur, Pierre-Luc Etienne, Christophe Louvet, Thierry André, Isabelle Tabah-Fisch, Aimery de Gramont

 

	NOTES

 
Supported by the GERCOR, Paris, France.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

 
1. Jemal A, Thomas A, Murray T, et al: Cancer statistics, 2002. CA Cancer J Clin 52:23-47, 2002[Abstract/Free Full Text]

2. 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. Lancet 355:1041-1047, 2000[CrossRef][Medline]

3. 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 22:23-30, 2004[Abstract/Free Full Text]

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

5. 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 18:2938-2947, 2000[Abstract/Free Full Text]

6. Tournigand C, Andre T, Achille E, et al: FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: A randomized GERCOR study. J Clin Oncol 22:229-237, 2004[Abstract/Free Full Text]

7. Maindrault-Goebel F, de Gramont A, Louvet C, et al: High-dose intensity oxaliplatin added to the simplified bimonthly leucovorin and 5-fluorouracil regimen as second-line therapy for metastatic colorectal cancer (FOLFOX 7). Eur J Cancer 37:1000-1005, 2001[CrossRef][Medline]

8. Maindrault-Goebel F, de Gramont A, Louvet C, et al: Evaluation of oxaliplatin dose intensity in bimonthly leucovorin and 48-hour 5-fluorouracil continuous infusion regimens (FOLFOX) in pretreated metastatic colorectal cancer: Oncology Multidisciplinary Research Group (GERCOR). Ann Oncol 11:1477-1483, 2000[Abstract/Free Full Text]

9. Maindrault-Goebel F, Tournigand C, Andre T, et al: Oxaliplatin reintroduction in patients previously treated with leucovorin, fluorouracil and oxaliplatin for metastatic colorectal cancer. Ann Oncol 15:1210-1214, 2004[Abstract/Free Full Text]

10. National Cancer Institute: National Cancer Institute Common Toxicity Criteria, version 2.0.

11. Maindrault F, Louvet C, André T, et al: Time to disease control (TDC) to evaluate the impact on survival of three chemotherapy lines in metastatic colorectal cancer (MRC) based on 5-fluorouracil, oxaliplatin and irinotecan (GERCOR). Proc Am Soc Clin Oncol 20:146a, 2001 (suppl; abstr 581)

12. Pocock SJ, Simon R: Sequential treatment assignment with balancing for prognostic factors in the controlled clinical trials. Biometrics 31:103-115, 1975[CrossRef][Medline]

13. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457-481, 1958[CrossRef]

14. Mantel NHW: Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 22:719-748, 1959[Medline]

15. Cox DR: Regression models and life-tables. J R Stat Soc B 34:187-220, 1972

16. Hurwitz H, Fehrenbacher L, Novotny W, et al: Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350:2335-2342, 2004[Abstract/Free Full Text]

17. Köhne C, Van Cutsem E, Wils JA, et al: Irinotecan improves the activity of the AIO regimen in metastatic colorectal cancer: Results of the EORTC GI Group Study 40986. Proc Am Clin Oncol 22:254, 2003 (suppl; abstr 1018)

18. Grothey A, Deschler B, Kroening H, et al: Phase III study of bolus 5-fluorouracil (5FU)/folinic acid (FA) (Mayo) vs weekly high-dose 24h 5-FU infusion/ FA + oxaliplatin (OXA) (FUFOX) in advanced colorectal cancer (ACRC). Proc Am Clin Oncol 21:129a, 2002 (suppl; abstr 512)

19. Goldberg R, Sargent DJ, Morton RF, et al: N9741: FOLFOX (oxaliplatin (Oxal)/ 5-fluorouracil (5-FU)/ leucovorin (LV) or reduced dose R-IFL (CPT-11 + 5-FU/LV) in advanced colorectal, cancer (CRC): Final efficacy data from an intergroup study. J Clin Oncol 22:275s, 2004 (suppl; abstr 3621)

20. 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 15:808-815, 1997[Abstract/Free Full Text]

21. de Gramont A, Louvet C, André T, et al: Infusional 5-fluorouracil: The bimonthly approach, in Bleiberg H, Kemeny N, Rougier P, et al (eds): Colorectal Cancer: A Clinical Guide to Therapy. London, United Kingdom, Dunitz, 2002, pp 0463-466

Submitted June 8, 2005; accepted October 24, 2005.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

				E. D. Saad, A. Katz, P. M. Hoff, and M. Buyse Progression-free survival as surrogate and as true end point: insights from the breast and colorectal cancer literature Ann. Onc., November 9, 2009; (2009) mdp523v1. [Abstract] [Full Text] [PDF]

				R. K. Ramanathan, M. L. Rothenberg, A. de Gramont, C. Tournigand, R. M. Goldberg, S. Gupta, and T. Andre Incidence and evolution of oxaliplatin-induced peripheral sensory neuropathy in diabetic patients with colorectal cancer: a pooled analysis of three phase III studies Ann. Onc., November 3, 2009; (2009) mdp509v1. [Abstract] [Full Text] [PDF]

				A. Grothey and D. J. Sargent Reply to F. Montagnani et al J. Clin. Oncol., October 1, 2009; 27(28): e134 - e135. [Full Text] [PDF]

				A. Grothey Review: Medical treatment of advanced colorectal cancer in 2009 Therapeutic Advances in Medical Oncology, September 1, 2009; 1(2): 55 - 68. [Abstract] [PDF]

				B. Chibaudel, C. Tournigand, P. Artru, T. Andre, A. Cervantes, A. Figer, G. Lledo, M. Flesch, M. Buyse, L. Mineur, et al. FOLFOX in patients with metastatic colorectal cancer and high alkaline phosphatase level: an exploratory cohort of the GERCOR OPTIMOX1 study Ann. Onc., August 1, 2009; 20(8): 1383 - 1386. [Abstract] [Full Text] [PDF]

				T. Andre, C. Boni, M. Navarro, J. Tabernero, T. Hickish, C. Topham, A. Bonetti, P. Clingan, J. Bridgewater, F. Rivera, et al. Improved Overall Survival With Oxaliplatin, Fluorouracil, and Leucovorin As Adjuvant Treatment in Stage II or III Colon Cancer in the MOSAIC Trial J. Clin. Oncol., July 1, 2009; 27(19): 3109 - 3116. [Abstract] [Full Text] [PDF]

				F.-C. Bidard, C. Tournigand, T. Andre, M. Mabro, A. Figer, A. Cervantes, G. Lledo, L. Bengrine-Lefevre, F. Maindrault-Goebel, C. Louvet, et al. Efficacy of FOLFIRI-3 (irinotecan D1,D3 combined with LV5-FU) or other irinotecan-based regimens in oxaliplatin-pretreated metastatic colorectal cancer in the GERCOR OPTIMOX1 study Ann. Onc., June 1, 2009; 20(6): 1042 - 1047. [Abstract] [Full Text] [PDF]

				D. J. Sargent, C. H. Kohne, H. K. Sanoff, B. M. Bot, M. T. Seymour, A. de Gramont, R. Porschen, L. B. Saltz, P. Rougier, C. Tournigand, et al. Pooled Safety and Efficacy Analysis Examining the Effect of Performance Status on Outcomes in Nine First-Line Treatment Trials Using Individual Data From Patients With Metastatic Colorectal Cancer J. Clin. Oncol., April 20, 2009; 27(12): 1948 - 1955. [Abstract] [Full Text] [PDF]

				A. Grothey Optimized Treatment of Metastatic Colorectal Cancer ASCO Educational Book, January 1, 2009; 2009(1): 209 - 211. [Abstract] [Full Text] [PDF]

				T. McKibbin and J. M. Koeller In Reply Oncologist, January 1, 2009; 14(1): 106 - 107. [Full Text] [PDF]

				H. K. Sanoff, D. J. Sargent, M. E. Campbell, R. F. Morton, C. S. Fuchs, R. K. Ramanathan, S. K. Williamson, B. P. Findlay, H. C. Pitot, and R. M. Goldberg Five-Year Data and Prognostic Factor Analysis of Oxaliplatin and Irinotecan Combinations for Advanced Colorectal Cancer: N9741 J. Clin. Oncol., December 10, 2008; 26(35): 5721 - 5727. [Abstract] [Full Text] [PDF]

				K. M. Field, S. Kosmider, M. Jefford, R. Jennens, M. Green, and P. Gibbs Chemotherapy Treatments for Metastatic Colorectal Cancer: Is Evidence-Based Medicine in Practice? J. Oncol. Pract, November 1, 2008; 4(6): 271 - 276. [Abstract] [Full Text] [PDF]

				B. H. O'Neil and R. M. Goldberg Innovations in Chemotherapy for Metastatic Colorectal Cancer: An Update of Recent Clinical Trials Oncologist, October 1, 2008; 13(10): 1074 - 1083. [Abstract] [Full Text] [PDF]

				S. J. Cohen, C. J.A. Punt, N. Iannotti, B. H. Saidman, K. D. Sabbath, N. Y. Gabrail, J. Picus, M. Morse, E. Mitchell, M. C. Miller, et al. Relationship of Circulating Tumor Cells to Tumor Response, Progression-Free Survival, and Overall Survival in Patients With Metastatic Colorectal Cancer J. Clin. Oncol., July 1, 2008; 26(19): 3213 - 3221. [Abstract] [Full Text] [PDF]

				C. Qvortrup, M. Yilmaz, D. Ogreid, A. Berglund, L. Balteskard, J. Ploen, T. Fokstuen, H. Starkhammar, H. Sorbye, K. Tveit, et al. Chronomodulated capecitabine in combination with short-time oxaliplatin: a Nordic phase II study of second-line therapy in patients with metastatic colorectal cancer after failure to irinotecan and 5-flourouracil Ann. Onc., June 1, 2008; 19(6): 1154 - 1159. [Abstract] [Full Text] [PDF]

				D. Machover, A. Ulusakarya, and E. Goldschmidt Modulation of FU With High-Dose Folinic Acid Is Effective for Treatment of Patients With Gastric Carcinoma J. Clin. Oncol., January 1, 2008; 26(1): 164 - 164. [Full Text] [PDF]

				P. A. Tang, S. M. Bentzen, E. X. Chen, and L. L. Siu Surrogate End Points for Median Overall Survival in Metastatic Colorectal Cancer: Literature-Based Analysis From 39 Randomized Controlled Trials of First-Line Chemotherapy J. Clin. Oncol., October 10, 2007; 25(29): 4562 - 4568. [Abstract] [Full Text] [PDF]

				H. Sorbye, C.-H. Kohne, D. J. Sargent, and B. Glimelius Patient characteristics and stratification in medical treatment studies for metastatic colorectal cancer: A proposal for standardization of patient characteristic reporting and stratification Ann. Onc., October 1, 2007; 18(10): 1666 - 1672. [Abstract] [Full Text] [PDF]

				T. Yoshino, N. Boku, Y. Onozawa, S. Hironaka, A. Fukutomi, Y. Yamaguchi, N. Hasuike, K. Yamazaki, N. Machida, and H. Ono Efficacy and Safety of an Irinotecan plus Bolus 5-Fluorouracil and L-Leucovorin Regimen for Metastatic Colorectal Cancer in Japanese Patients: Experience in a Single Institution in Japan Jpn. J. Clin. Oncol., September 1, 2007; 37(9): 686 - 691. [Abstract] [Full Text] [PDF]

				C. Allegra, C. Blanke, M. Buyse, R. Goldberg, A. Grothey, N. J. Meropol, L. Saltz, A. Venook, G. Yothers, and D. Sargent End Points in Advanced Colon Cancer Clinical Trials: A Review and Proposal J. Clin. Oncol., August 20, 2007; 25(24): 3572 - 3575. [Full Text] [PDF]

				G. K. Dy, J. E. Krook, E. M. Green, D. J. Sargent, T. Delaunoit, R. F. Morton, C. S. Fuchs, R. K. Ramanathan, S. K. Williamson, B. P. Findlay, et al. Impact of Complete Response to Chemotherapy on Overall Survival in Advanced Colorectal Cancer: Results From Intergroup N9741 J. Clin. Oncol., August 10, 2007; 25(23): 3469 - 3474. [Abstract] [Full Text] [PDF]

				D. Sargent and A. Grothey Sound Footing or Slippery Slope? The Value of Secondary Analyses of Randomized Trials J. Clin. Oncol., August 1, 2007; 25(22): 3191 - 3193. [Full Text] [PDF]

				A. de Gramont, M. Buyse, J. C. Abrahantes, T. Burzykowski, E. Quinaux, A. Cervantes, A. Figer, G. Lledo, M. Flesch, L. Mineur, et al. Reintroduction of Oxaliplatin Is Associated With Improved Survival in Advanced Colorectal Cancer J. Clin. Oncol., August 1, 2007; 25(22): 3224 - 3229. [Abstract] [Full Text] [PDF]

				H. K. Sanoff, H. Bleiberg, and R. M. Goldberg Managing Older Patients With Colorectal Cancer J. Clin. Oncol., May 10, 2007; 25(14): 1891 - 1897. [Abstract] [Full Text] [PDF]

				W.-S. Wang, J.-K. Lin, T.-C. Lin, W.-S. Chen, J.-K. Jiang, H.-S. Wang, T.-J. Chiou, J.-H. Liu, C.-C. Yen, and P.-M. Chen Oral Glutamine Is Effective for Preventing Oxaliplatin-Induced Neuropathy in Colorectal Cancer Patients Oncologist, March 1, 2007; 12(3): 312 - 319. [Abstract] [Full Text] [PDF]

				T Andre, C Tournigand, L Mineur, R Fellague-Chebra, M Flesch, M Mabro, M Hebbar, S Postel Vinay, F. Bidard, C Louvet, et al. Phase II study of an optimized 5-fluorouracil-oxaliplatin strategy (OPTIMOX2) with celecoxib in metastatic colorectal cancer: a GERCOR study Ann. Onc., January 1, 2007; 18(1): 77 - 81. [Abstract] [Full Text] [PDF]

				S. Gill, A. W. Blackstock, and R. M. Goldberg Colorectal Cancer Mayo Clin. Proc., January 1, 2007; 82(1): 114 - 129. [Abstract] [Full Text] [PDF]

				R. M. Goldberg, M. L. Rothenberg, E. Van Cutsem, A. B. Benson III, C. D. Blanke, R. B. Diasio, A. Grothey, H.-J. Lenz, N. J. Meropol, R. K. Ramanathan, et al. The Continuum of Care: A Paradigm for the Management of Metastatic Colorectal Cancer Oncologist, January 1, 2007; 12(1): 38 - 50. [Abstract] [Full Text] [PDF]

				D. D. Rosa, G. F.V. Ismael, E. de Azambuja, S. Braga, F. Cardoso, and H. Bleiberg OPTIMOX1 in Advanced Colorectal Cancer: Lack of Evidence for a Stop-and-Go Strategy J. Clin. Oncol., November 10, 2006; 24(32): 5176 - 5177. [Full Text] [PDF]

				A. de Gramont, C. Tournigand, and M. Buyse In Reply J. Clin. Oncol., November 10, 2006; 24(32): 5177 - 5177. [Full Text] [PDF]

				N. J. Meropol Turning Point for Colorectal Cancer Clinical Trials J. Clin. Oncol., July 20, 2006; 24(21): 3322 - 3324. [Full Text] [PDF]

This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Tournigand, C. Articles by de Gramont, A. Search for Related Content PubMed Articles by Tournigand, C. Articles by de Gramont, A. Social Bookmarking                            What's this?