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 Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Falcone, A. Articles by Masi, G. Search for Related Content PubMed PubMed Citation Articles by Falcone, A. Articles by Masi, G.

Phase III Trial of Infusional Fluorouracil, Leucovorin, Oxaliplatin, and Irinotecan (FOLFOXIRI) Compared With Infusional Fluorouracil, Leucovorin, and Irinotecan (FOLFIRI) As First-Line Treatment for Metastatic Colorectal Cancer: The Gruppo Oncologico Nord Ovest

Alfredo Falcone, Sergio Ricci, Isa Brunetti, Elisabetta Pfanner, Giacomo Allegrini, Cecilia Barbara, Lucio Crinò, Giovanni Benedetti, Walter Evangelista, Laura Fanchini, Enrico Cortesi, Vincenzo Picone, Stefano Vitello, Silvana Chiara, Cristina Granetto, Gianfranco Porcile, Luisa Fioretto, Cinzia Orlandini, Michele Andreuccetti, Gianluca Masi

From the U.O. Oncologia Medica, Istituto Toscano Tumori, Livorno; S.C. di Oncologia Medica, Ospedale S. Maria della Misericordia, Perugia; U.O. Oncologia Medica, Ospedale di Macerata, Macerata; Centro Oncologico ed Ematologico Subalpino, ASO Ospedale S. Giovanni Battista Le Molinette, Torino; Dipartimento di Medicina Sperimentale e Patologia, Oncologia Medica, Università la Sapienza, Roma; U.O. Oncologia Medica, Ospedale S. Elia, Caltanissetta; Istituto Nazionale per la Ricerca sul Cancro, Genova; S.C. di Oncologia, Azienda Ospedaliera S. Croce e Carle, Cuneo; Oncologia Medica, P.O. S. Lazzaro, Alba; Oncologia Medica, Ospedale S. Maria Annunziata, Istituto Toscano Tumori, Firenze, Italy; U.O. Oncologia Medica, Azienda Ospedaliero-Universitaria, Istituto Toscano Tumori; and Dipartimento di Oncologia, dei Trapianti e Nuove Tecnologie in Medicina, Università degli Studi, Pisa, Italy

Address reprint requests to Alfredo Falcone, MD, Cattedra di Oncologia Medica, University of Pisa, Department of Oncology, Azienda USL-6 of Livorno, Viale Alfieri, 36, 57124 Livorno, Italy; e-mail: a.falcone{at}med.unipi.it

	ABSTRACT

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Purpose: The Gruppo Oncologico Nord Ovest (GONO) conducted a phase III study comparing fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI [irinotecan 165 mg/m² day 1, oxaliplatin 85 mg/m² day 1, leucovorin 200 mg/m² day 1, fluorouracil 3,200 mg/m² 48-hour continuous infusion starting on day 1, every 2 weeks]) with infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI).

Methods: Selection criteria included unresectable metastatic colorectal cancer, age 18 to 75 years, and no prior chemotherapy for advanced disease. The primary end point was response rate (RR).

Results: A total of 244 patients were randomly assigned. An increase of grade 2 to 3 peripheral neurotoxicity (0% v 19%; P < .001), and grade 3 to 4 neutropenia (28% v 50%; P < .001) were observed in the FOLFOXIRI arm. The incidence of febrile neutropenia (3% v 5%) and grade 3 to 4 diarrhea (12% v 20%) were not significantly different. Responses, as assessed by investigators, were, for FOLFIRI and FOLFOXIRI, respectively, complete, 6% and 8%; and partial, 35% and 58%, (RR, 41% v 66%; P = .0002). RR confirmed by an external panel was 34% versus 60% (P < .0001). The R0 secondary resection rate of metastases was greater in the FOLFOXIRI arm (6% v 15%; P = .033, among all 244 patients; and 12% v 36%; P = .017 among patients with liver metastases only). Progression-free survival (PFS) and overall survival (OS) were both significantly improved in the FOLFOXIRI arm (median PFS, 6.9 v 9.8 months; hazard ratio [HR], 0.63; P = .0006; median OS, 16.7 v 22.6 months; HR, 0.70; P = .032).

Conclusion: The FOLFOXIRI regimen improves RR, PFS, and OS compared with FOLFIRI, with an increased, but manageable, toxicity in patients with metastatic colorectal cancer with favorable prognostic characteristics. Further studies of FOLFOXIRI in combination with targeted agents and in the neoadjuvant setting are warranted.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Colorectal carcinoma (CRC) is the second cause of cancer-related death in developed countries.¹ The combinations of irinotecan (CPT-11) + fluorouracil (FU)/leucovorin (LV) and oxaliplatin (LOHP) + FU/LV have demonstrated increased efficacy compared with FU/LV alone in randomized studies.^2-6 These data have established that in metastatic colorectal cancer, a more active first-line treatment can be also more effective in terms of improved progression-free survival (PFS) and overall survival (OS).⁷

A study by the Groupe Coopérateur Multidisciplinaire en Oncologie (GERCOR)⁸ suggested that the exposure of metastatic colorectal cancer patients to all the three most active agents, irrespective of their sequence, is associated with promising survival. Moreover, a pooled analysis of seven phase III trials demonstrated that survival is correlated with the proportion of patients who received all the three active drugs in the course of their disease, but not with the proportion of patients who received any second-line therapy.⁹ This analysis also shows that, in a sequential strategy, not all patients who progress after first-line chemotherapy are able to receive second-line treatment (50% to 80%) and, therefore, can be exposed to the three active agents.

A way to further improve the outcome of metastatic colorectal cancer patients could be to administer a first-line regimen containing the three active agents (LOHP, CPT-11 and FU/LV). This regimen, if feasible, could expose all patients to these drugs. If this regimen will be more active than a standard two-drug combination, it could also increase the postchemotherapy resection rate of metastases and, therefore, the long-term control of disease. In fact, studies conducted with LOHP- and FU-based regimens^10,11 and, more recently, also with different combinations,¹² indicate that an active first-line chemotherapy in initially unresectable patients can allow a radical resection of metastatic disease and 20% to 40% of these resected patients are long-term survivors. In particular, an analysis conducted by Folpercht et al¹³ demonstrates a correlation between the response rate to chemotherapy and the postchemotherapy radical resection rate of metastases.

Therefore, we studied the feasibility and the activity of a triplet combination containing FU/LV, LOHP, and CPT-11. In an initial phase I-II study¹⁴ a chronomodulated infusion of FU was used, and in a subsequent phase II study, a simplified FU/LV, LOHP, and CPT-11 (FOLFOXIRI) regimen was developed.¹⁵ Treatment was well tolerated, response rate was 72%, with a median PFS of 10.8 months and median OS of 28.4 months. The combined analysis of the two above-mentioned studies demonstrated that in 26% of initially unresectable patients, a radical resection of residual metastatic disease could be performed. The 4-year survival of these patients was 37%.¹⁶

On the basis of these results, the Gruppo Oncologico Nord Ovest (GONO) launched a phase III randomized trial to compare the simplified FOLFOXIRI regimen to a standard combination of FU/LV and CPT-11 (FOLFIRI) that had demonstrated improved efficacy in comparison to FU/LV.³

	METHODS

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Patient Selection
From November 2001 to April 2005, we enrolled patients who met the following eligibility criteria: adenocarcinoma of the colon or rectum, unresectable metastatic disease, age 18 to 75 years, Eastern Cooperative Oncology Group (ECOG) performance status of 2 or lower if age 70 years or younger or ECOG performance status of 0 if age 71 to 75 years, measurable disease according to WHO criteria, leukocyte count of at least 3,500/mm³, neutrophils count of at least 1,500/mm³, platelet count of at least 100,000/mm³, serum creatinine of 1.3 mg/dL or less, serum bilirubin less than 1.5 mg/dL and AST, ALT, and alkaline phosphatase 2.5 x normal values or less ( 5 if liver metastases). Previous fluoropyrimidine-based adjuvant chemotherapy was allowed if ended more than 6 months before random assignment. Exclusion criteria were previous palliative chemotherapy for metastatic disease; previous chemotherapy including irinotecan or oxaliplatin, symptomatic cardiac disease, myocardial infarction in the last 24 months or uncontrolled arrhythmia, active infections, inflammatory bowel disease; and total colectomy. The study was conducted in accordance to Helsinki declaration and to Good Clinical Practice guidelines, and patients were informed of the investigational nature of the study and provided their written informed consent before registration onto the study. The protocol was approved by the ethics committee of all participating institutions.

Stratification, Random Assignment, and Treatment
Patients were stratified according to center, ECOG performance status (0 v 1 to 2) and history of adjuvant therapy (yes v no) and then were randomly assigned to FOLFIRI (arm A) or FOLFOXIRI (arm B; Fig 1). Treatment was administered every 2 weeks until evidence of progression, unacceptable toxicity, patient refusal, or for a maximum of 12 cycles. Adverse events were evaluated according to National Cancer Institute Common Toxicity Criteria version 2.0. No prophylactic treatment for neutropenia was recommended.

View larger version (32K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Treatment schedule for (A) FOLFIRI and (B) FOLFOXIRI. IV, intravenous; CI, continuous infusion; CPT-11, irinotecan; FU, fluorouracil; LV, leucovorin; LOHP, oxaliplatin; FOLFOXIRI, fluorouracil, leucovorin, oxaliplatin, and irinotecan; FOLFIRI, fluorouracil, leucovorin, and irinotecan.

Statistical Analysis
The primary study end point was the externally reviewed response rate (RR). Secondary end points were PFS, OS, postchemotherapy R0 surgical resections, safety, and quality of life. We selected RR as the primary end point because three meta-analyses of randomized studies in metastatic colorectal cancer had demonstrated a clear correlation between RR and OS and between the RR and the rate of radical secondary surgery on metastases, supporting the use of RR as a surrogate end point. PFS was defined as the length of time from random assignment to disease progression or to death resulting from any cause, whichever occurred first, or to last contact. The evaluation of PFS was based on investigators' assessment. OS was defined as the length of time from random assignment to death or to last contact.

Assuming an RR of 40% in the FOLFIRI arm, to demonstrate an improvement of 20% in with FOLFOXIRI (60%), using a two-sided ² test with a power of 0.80 and an alpha-error of 0.05, and considering approximately 10% of patients nonassessable, we planned to randomly assign a total of 240 patients. With this sample size, and assuming that we would observe the same results reported by Douillard³ with FOLFIRI in terms of PFS, the study was also able to demonstrate, after 218 events had occurred, by two-tailed log-rank test (alpha-error = 0.05, power 0.80), a prolongation in PFS of 3.1 months (from 6.7 to 9.8 months). For primary and secondary objectives we analyzed the intention-to-treat population, using ² tests (or Fisher's exact test, if indicated) to compare categoric variables between treatment groups. We estimated survival curves by the Kaplan-Meier method, and compared the groups by the log-rank test. We tested the 14 following variables as possible predictive factors for objective response or surgical R0 resection and as possible prognostic factors: treatment, sex, age (< or 65 years), WHO performance status (0 or 1 to 2), primary tumor site (colon or rectum), number of organs involved (single or multiple), sites of disease (liver only or other sites), liver involvement (< or 25%), time from first diagnosis to first metastasis (0 to 3, 3 to 12, or > 12 months), previous adjuvant therapy (yes or no), baseline lactate dehydrogenase (normal or upper limit of normal), baseline carcinoembryonic antigen (< or 100 ng/mL), baseline leukocytes (< or 8,000/mL), and baseline hemoglobin (< or 10 g/dL). All multivariate analyses used a step-down procedure based on the likelihood ratio test. Multivariate analyses were done on the intention-to-treat population. A logistic-regression model was used to identify the predictive factors for objective response and surgical R0 resection. For time to progression and OS, Cox's proportional hazards modeling was used. The QLQ-C30 questionnaire was analyzed with the global health status/quality-of-life scale as the primary end point and the other 10 scales as secondary end points. Statistical analysis was performed using SPSS/PC+11.5 statistical software (SPSS Inc, Chicago, IL).

	RESULTS

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Patients
A total of 244 patients from 15 Italian centers were enrolled onto the study and randomly assigned to FOLFIRI (n = 122) or FOLFOXIRI (n = 122). Table 1 presents the characteristics of the patients, which were balanced among the treatment groups. Overall, the study population was relatively selected to exclude elderly and frail patients with an expected increased risk of toxicity by using combination chemotherapy.

PFS and Second-Line Treatment
The improved activity of FOLFOXIRI resulted in an increased PFS; in particular, 104 patients in the experimental arm (FOLFOXIRI) versus 112 patients in the reference arm (FOLFIRI) have progressed, and the median PFS is 9.8 months versus 6.9 months (P = .0006) with an HR for progression of 0.63 (95% CI, 0.47 to 0.81; Fig 2). In addition, the rate of early progression (patients who progressed within 6 months from the treatment onset) was significantly lower in the FOLFOXIRI arm (18% v 45%; P < .0001). The Cox's multivariate analysis demonstrates that independent prognostic factors for reduction of the progression risk were: treatment arm (HR, 0.60; 95% CI, 0.46 to 0.79; P < .001), male sex (HR, 0.68; 95% CI, 0.51 to 0.91; P = .01), and leukocyte count less than 8,000/mm³ (HR, 0.60; 95% CI, 0.45 to 0.81; P = .003).

View larger version (14K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Kaplan-Meier estimates of (A) progression-free survival and (B) overall survival. FOLFOXIRI, fluorouracil, leucovorin, oxaliplatin, and irinotecan; FOLFIRI, fluorouracil, leucovorin, and irinotecan.

OS
After a median follow-up of 18.4 months, 65 patients in the experimental arm and 81 in the reference arm have died, and the median OS is significantly longer for FOLFOXIRI (22.6 v 16.7 months; P = .032), corresponding to an HR for death of 0.70 (95% CI, 0.50 to 0.96; Fig 2). The Cox's multivariate analysis demonstrates that the only independent prognostic factors for reduction of the death risk was liver involvement less than 25% (HR, 0.57; 95% CI, 0.39 to 0.84; P = .005). Treatment with FOLFOXIRI was significantly predictive of prolonged survival in the univariate analysis (P = .032), but in the multivariate analysis, it was borderline significant (P = .054).

Quality of Life
Eighty-nine patients (36% in the FOLFIRI arm and 37% in the FOLFOXIRI arm) were assessable for quality of life. Although the number of patients from whom quality-of-life questionnaires were obtained was probably too low to make clear conclusions, there were no significant differences between the two arms.

	DISCUSSION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
During recent years, the treatment of metastatic colorectal cancer has achieved considerable progress, mainly improvements in the efficacy of chemotherapy, for increased use of surgery on metastases,¹⁷ and, more recently, the use of targeted agents.^18,19 Data have suggested that exposure to all the three main active cytotoxic agents obtains the best outcome in unresectable patients,⁹ but that only 50% to 80% of patients can be exposed to all three drugs in a sequential strategy with doublets. Furthermore, there is consistent evidence that by increasing the activity of chemotherapy, a greater proportion of patients can undergo a secondary surgery on metastases, and that this can allow long-term survival in a fraction of them.¹³

On the basis of these data, several groups have developed three-drug combinations including FU, CPT-11 and LOHP.^20-25 In the present trial, we selected the schedule we had previously developed¹⁵ because it was particularly convenient, well tolerated, and active compared with other three-drug combinations. We used a biweekly schedule, and we omitted the administration of FU by intravenous bolus to deliver elevated dose intensities of CPT-11, LOHP, and infusional FU.

Results obtained in the FOLFIRI arm are in line with those reported in most other randomized studies.^2,8,26-29 With regard to FOLFOXIRI, results demonstrate that toxicities are moderately increased, mainly neurotoxicity and uncomplicated neutropenia, but this combination remains feasible and well tolerated. FOLFOXIRI clearly increased RR, which is among the highest ever reported in any randomized study of metastatic colorectal cancer. This improved activity allowed a significant increase in the rate of radical secondary surgery of metastases, and the rate of R0 patients achieved with FOLFOXIRI was particularly impressive in patients with liver metastases only (12% v 36%; P = .017). The baseline unresectability of metastases was a key inclusion criterion of the trial, and centers were strongly encouraged to exclude patients with resectable metastases. However, this is was a multicenter trial, and the evaluation of resectability was not centralized, but was performed independently by the multidisciplinary team of each center. In particular, the resection rate observed with FOLFIRI was comparable to that reported in the literature; hence, it is unlikely that the improvement obtained with FOLFOXIRI resulted from different patient selection. Treatment with FOLFOXIRI was the only significant independent predictive factor for obtaining an objective response and an R0 resection. Furthermore, FOLFOXIRI significantly increased PFS by approximately 3 months, and it halved the risk of early progression. Finally, survival, with the limits that this was not a primary end point and that the number of patients is relatively low, was significantly improved.

These results support the hypothesis that this three-drug up-front exposure strategy is more active and probably more effective than the initial use of a doublet compared with FOLFIRI. No conclusion can be drawn with regard to the comparison with FOLFOX. However, although FOLFOX has more data with regard to the capacity to induce resectability in previously unresectable patients, similar results have been reported with FOLFIRI as well.¹² Furthermore, comparisons of FOLFOX with FOLFIRI in randomized studies have reported equivalent activity and efficacy.^8,26

The Hellenic Oncology Research Group (HORG) reported the results of a study comparing FOLFIRI to a combination of FU, CPT-11, and LOHP. This study, although indicating some improvements for the triplet combination in terms of RR, surgical R0 resections, PFS, and OS, failed to demonstrate statistically significant benefits in favor of the triplet.²⁹ There are two substantial differences between the HORG study and the present study. First, in the schedule used by HORG, the FU bolus was maintained, and this required the use of a dose of LOHP and CPT-11 significantly lower than used in our study (65 v 85 mg/m² for LOHP and 150 v 165 mg/m² for CPT-11). Despite this, diarrhea was substantial (grade 3 to 4, 27.7%) and more frequent than with our combination. The second relevant difference is the study population, which was older and with a poorer performance status. In fact, in the HORG study, patients older than 75 years or between 71 and 75 but with an ECOG performance status of 1 or higher were not excluded; median age was also greater in the HORG study (66 v 62 years). In addition, only 36% of patients in the HORG study had an ECOG performance of 0 (61% in our study), and more patients had an ECOG performance status of 2 (11% v 2%). Indeed, Souglakos et al²⁹ report a significantly higher incidence of toxicity in older patients and those with a performance status of 2.

In conclusion, FOLFOXIRI represents the first studied combination demonstrated to be superior to an infusional FU-containing doublet compared with FOLFIRI, and this improvement in efficacy, coupled with a manageable toxicity profile, supports the use of FOLFOXIRI as a first-line option of care for selected patients with metastatic colorectal cancer. In particular, patients appropriate for FOLFOXIRI should have characteristics similar to those included in our study; therefore, patients aged more than 75 years or 71 to 75 years but with an ECOG performance status of at least 1, or with expected increased risk of toxicity (performance status of 2), should not receive this triplet. We believe that the use of FOLFOXIRI should be of particular interest in a neoadjuvant strategy in initially unresectable patients and perhaps, also, in patients with few chances to achieve a three-drug exposure in a sequential strategy. Future developments should evaluate the integration of FOLFOXIRI with targeted agents.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Although all authors completed the disclosure declaration, the following author or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment: N/A Leadership: N/A Consultant: Alfredo Falcone, Roche, Sanofi-aventis, Pfizer, Baxter Stock: N/A Honoraria: Alfredo Falcone, Roche, Sanofi-aventis, Pfizer Research Funds: N/A Testimony: N/A Other: N/A

	AUTHOR CONTRIBUTIONS

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Conception and design: Alfredo Falcone, Giacomo Allegrini, Cinzia Orlandini, Michele Andreuccetti, Gianluca Masi

Administrative support: Michele Andreuccetti

Provision of study materials or patients: Alfredo Falcone, Sergio Ricci, Isa Brunetti, Elisabetta Pfanner, Giacomo Allegrini, Lucio Crinò, Giovanni Benedetti, Walter Evangelista, Laura Fanchini, Enrico Cortesi, Vincenzo Picone, Stefano Vitello, Silvana Chiara, Cristina Granetto, Gianfranco Porcile, Luisa Fioretto, Gianluca Masi

Collection and assembly of data: Cecilia Barbara, Michele Andreuccetti, Gianluca Masi

Data analysis and interpretation: Alfredo Falcone, Cecilia Barbara, Cinzia Orlandini, Michele Andreuccetti, Gianluca Masi

Manuscript writing: Alfredo Falcone, Michele Andreuccetti, Gianluca Masi

Final approval of manuscript: Alfredo Falcone, Gianluca Masi

	Appendix

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
We thank the following investigators for their contribution to this randomized multicenter trial: Rita Murr (U.O. Oncologia Medica, Azienda Ospedaliero-Universitaria di Pisa, Istituto Toscano Tumori, Pisa, Italy); Elisa Cerri, Fotios Loupakis, Simona Bursi (U.O. Oncologia Medica, Azienda USL-6 di Livorno, Istituto Toscano Tumori, Livorno, Italy); Stefania Bartolini (U.O. Oncologia Medica, Ospedale Bellaria, Bologna, Italy); Oscar Berretto (Centro Oncologico ed Ematologico Subalpino, ASO Ospedale S. Giovanni Battista Le Molinette, Torino, Italy); Roberta Ferraldeschi (Dipartimento di Medicina Sperimentale e Patologia, Oncologia Medica, Università la Sapienza, Roma, Italy); Emilio Triglia, Giuseppe Giarratano (Sezione di Oncologia Medica, Ospedale S. Elia, Caltanissetta, Italy); Riccardo Rosso (Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy); Marco Merlano, Elena Fea (SC di Oncologia, Azienda Ospedaliera S. Croce e Carle, Cuneo, Italy); Maria Giovanna Boe (Oncologia Medica, P.O. S. Lazzaro, Alba, Italy); Angela Ribecco (Oncologia Medica, Ospedale S. Maria Annunziata, Firenze, Italy); Oscar Alabisio, Stefania Miraglia (U.O. Oncologia Medica, Ospedale Maggiore della Carità, Novara, Italy); Stefano Cascinu, Renata Todeschini, Roberta Camisa (U.O. Oncologia Medica, Azienda Ospedaliera, Parma, Italy); Alberto Bagnulo, Alessandra Zoboli (Day Hospital Oncologico, Ospedale S. Sebastiano Mandriolo Superiore Correggio, Italy); Marco Di Lieto (U.O. Radioterapia Oncologica Azienda ULS-3 Spedali Riuniti, Pistoia, Italy); Samanta Cupini, Lorenzo Marcucci, Mario Filidei (Sezione di Oncologia Medica, Ospedale Lotti, Pontedera, Italy); and Carlo Aschele (U.O. Oncologia Medica, Ospedale Galliera, Genova).

	ACKNOWLEDGMENTS

 
We thank Michele Malventi, MD, for coordinating the external radiological review panel and Simona Giannace for data management and technical assistance.

	NOTES

 
Supported in part by a research grant of the Associazione Italiana Ricerca Cancro (A.I.R.C.) and by the Fondazione A.R.C.O.

Presented at the 42nd Annual Meeting of the American Society of Clinical Oncology, Atlanta, GA, June 2-6, 2006, and at the American Society of Clinical Oncology 2006 Gastrointestinal Cancers Symposium, San Francisco, CA, January 24-27, 2006.

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

	REFERENCES

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
1. Colorectal cancer, in Steward BW, Kleihues P (eds): World Cancer Report. Lyon, France, IACR Press, 2003, pp 198-202

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

4. Kohne CH, van Cutsem E, Wils J, et al: Phase III study of weekly high-dose infusional fluorouracil plus folinic acid with or without irinotecan in patients with metastatic colorectal cancer: European Organisation for Research and Treatment of Cancer Gastrointestinal Group study 40986. J Clin Oncol 23:4856-4865, 2005[Abstract/Free Full Text]

5. Giacchetti S, Perpoint B, Zidani R, et al: Phase III multicenter randomized trial of oxaliplatin added to chronomodulated fluorouracil-leucovorin as first-line treatment of metastatic colorectal cancer. J Clin Oncol 18:136-147, 2000[Abstract/Free Full Text]

6. 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]

7. Buyse M, Thirion P, Carlson RW, et al: Relation between tumor response to first-line chemotherapy and survival in advanced colorectal cancer: A meta-analysis. Lancet 356:373-378, 2000[CrossRef][Medline]

8. 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]

9. Grothey A, Sargent D, Goldberg RM, et al: Survival of patients with advanced colorectal cancer improves with the availability of fluorouracil-leucovorin, irinotecan, and oxaliplatin in the course of treatment. J Clin Oncol 22:1209-1214, 2004[Abstract/Free Full Text]

10. Giacchetti S, Itzhaki M, Gruia G, et al: Long-term survival of patients with unresectable colorectal cancer liver metastases following infusional chemotherapy with 5-fluorouracil, leucovorin, oxaliplatin and surgery. Ann Oncol 10:663-669, 1999[Abstract/Free Full Text]

11. Adam R, Avisar E, Ariche A, et al: Five-year survival following hepatic resection after neoadjuvant therapy for nonresectable colorectal. Ann Surg Oncol 8:347-353, 2001[Abstract/Free Full Text]

12. Pozzo C, Basso M, Cassano A, et al: Neoadjuvant treatment of unresectable liver disease with irinotecan and 5-fluorouracil plus folinic acid in colorectal cancer patients. Ann Oncol 15:933-939, 2004[Abstract/Free Full Text]

13. Folprecht G, Grothey A, Alberts S, et al: Neoadjuvant treatment of unresectable colorectal liver metastases: Correlation between tumour response and resection rates. Ann Oncol 16:1311-1319, 2005[Abstract/Free Full Text]

14. Falcone A, Masi G, Allegrini G, et al: Biweekly chemotherapy with oxaliplatin, irinotecan, infusional Fluorouracil, and leucovorin: A pilot study in patients with metastatic colorectal cancer. J Clin Oncol 20:4006-4014, 2002[Abstract/Free Full Text]

15. Masi G, Allegrini G, Cupini S, et al: First line treatment of metastatic colorectal cancer with irinotecan, oxaliplatin and 5-fluorouracil/leucovorin (FOLFOXIRI): Results of phase II study with a simplified biweekly schedule. Ann Oncol 15:1766-1772, 2004[Abstract/Free Full Text]

16. Masi G, Cupini S, Marcucci L, et al: Treatment with 5-fluorouracil/folinic acid, oxaliplatin and irinotecan (FOLFOXIRI) enables surgical resection of metastases in patients with initially unresectable metastatic colorectal cancer. Ann Surg Oncol 13:58-65, 2006[Abstract/Free Full Text]

17. Gill S, Goldberg RM: First-line treatment strategies to improve survival in patients with advanced colorectal cancer. Drugs 64:27-44, 2004[Medline]

18. 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]

19. Cunningham D, Humblet Y, Siena S, et al: Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 351:337-345, 2004[Abstract/Free Full Text]

20. Souglakos J, Mavroudis D, Kakolyris S, et al: 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, 2002[Abstract/Free Full Text]

21. Ychou M, Conroy T, Seitz JF, et al: 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, 2003[Abstract/Free Full Text]

22. Calvo E, Cortes J, Rodriguez J, et al: Irinotecan, oxaliplatin, and 5-fluorouracil/leucovorin combination chemotherapy in advanced colorectal carcinoma: A phase II study. Clin Colorectal Cancer 2:104-110, 2002[Medline]

23. Garufi C, Bria E, Vanni B, et al: A phase II study of irinotecan plus chronomodulated oxaliplatin, 5-fluorouracil and folinic acid in advanced colorectal cancer patients. Br J Cancer 89:1870-1875, 2003[CrossRef][Medline]

24. Comella P, Casaretti R, De Rosa V, et al: Oxaliplatin plus irinotecan and leucovorin-modulated 5-fluorouracil triplet regimen every other week: A dose-finding study in patients with advanced gastrointestinal malignancies. Ann Oncol 13:1874-1881, 2002[Abstract/Free Full Text]

25. Goetz MP, Erlichman C, Windebank AJ, et al: Phase I and pharmacokinetic study of two different schedules of oxaliplatin, irinotecan, Fluorouracil, and leucovorin in patients with solid tumors. J Clin Oncol 21:3761-3769, 2003[Abstract/Free Full Text]

26. Colucci G, Gebbia V, Paoletti G, et al: Phase III randomized trial of FOLFIRI versus FOLFOX4 in the treatment of advanced colorectal cancer: A multicenter study of the Gruppo Oncologico Dell'Italia Meridionale. J Clin Oncol 23:4866-4875, 2005[Abstract/Free Full Text]

27. Seymour MT: Fluorouracil, Oxaliplatin and CPT-11 (irinotecan), Use and Sequencing (MRC FOCUS): A 2135-patient randomized trial in advanced colorectal cancer (ACRC). J Clin Oncol 23:16S (suppl; abstr 3518)

28. Labianca R, Floriani I, Cortesi E, et al: Alternating versus continuous "FOLFIRI" in advanced colorectal cancer (ACC): A randomized "GISCAD" trial. J Clin Oncol 24:18S (suppl; abstr 3505)

29. Souglakos J, Androulakis N, Syrigos K, et al: FOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin and irinotecan) vs FOLFIRI (folinic acid, 5-fluorouracil and irinotecan) as first-line treatment in metastatic colorectal cancer (MCC): a multicentre randomised phase III trial from the Hellenic Oncology Research Group (HORG). Br J Cancer 94:798-805, 2006[CrossRef][Medline]

Submitted September 17, 2006; accepted January 30, 2007.

This article has been cited by other articles:

				E. Aranda, M. Valladares, M. Martinez-Villacampa, M. Benavides, A. Gomez, B. Massutti, E. Marcuello, M. Constenla, J. C. Camara, A. Carrato, et al. Randomized study of weekly irinotecan plus high-dose 5-fluorouracil (FUIRI) versus biweekly irinotecan plus 5-fluorouracil/leucovorin (FOLFIRI) as first-line chemotherapy for patients with metastatic colorectal cancer: a Spanish Cooperative Group for the Treatment of Digestive Tumors Study Ann. Onc., August 20, 2008; (2008) mdn557v1. [Abstract] [Full Text] [PDF]

				B. Gruenberger, D. Tamandl, J. Schueller, W. Scheithauer, C. Zielinski, F. Herbst, and T. Gruenberger Bevacizumab, Capecitabine, and Oxaliplatin As Neoadjuvant Therapy for Patients With Potentially Curable Metastatic Colorectal Cancer J. Clin. Oncol., April 10, 2008; 26(11): 1830 - 1835. [Abstract] [Full Text] [PDF]

				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]

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 Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Falcone, A. Articles by Masi, G. Search for Related Content PubMed PubMed Citation Articles by Falcone, A. Articles by Masi, G.