The efficacy and safety of cetuximab plus 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin chemotherapy were evaluated as first-line treatment for patients with unresectable metastatic colorectal cancer.
Abstract
Background.
Triplet chemotherapy has demonstrated manageable toxicities and a favorable response rate. The addition of cetuximab to chemotherapy can increase treatment efficacy. We evaluated the efficacy and safety of cetuximab plus 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX), the ERBIRINOX regimen, as first-line treatment in patients with unresectable metastatic colorectal cancer (mCRC).
Patients and Methods.
In a phase II study, treatment consisted of weekly cetuximab plus biweekly. Treatment was continued for a maximum of 12 cycles and tumor response was evaluated every four cycles. The primary efficacy criterion was the complete response (CR) rate.
Results.
From April 2006 to April 2008, 42 patients were enrolled. The median age was 60 years (range, 32–76 years). The median duration of treatment was 5.2 months (range, 0.7–8.5 months), and a median of nine cycles was given per patient (range, 1–12 cycles). Five patients (11.9%) showed a CR, with a median duration of 23.1 months (95% confidence interval [CI], 10.8–39.7 months). The objective response rate was 80.9% (95% CI, 65.9%–91.4%). The median overall and progression-free survival times were 24.7 months (95% CI, 22.6 months to not reached) and 9.5 months (95% CI, 7.6–10.4 months), respectively. The most frequent grade 3–4 adverse events were diarrhea (52%), neutropenia (38%), and asthenia (32%).
Conclusion.
The ERBIRINOX regimen appears to be effective and feasible in first-line treatment of mCRC patients. These promising results led us to initiate a multicenter, randomized, phase II trial ([Research Partnership for Digestive Oncology] PRODIGE 14) in patients with potentially resectable mCRC.
Introduction
Colorectal cancer is the second leading cause of cancer-related death worldwide, accounting for >200,000 deaths per year in Europe alone [1]. Over half the patients with colorectal cancer develop metastatic disease, with a quarter having distant metastatic lesions at diagnosis [2]. Surgical resection of colorectal liver metastases is a potentially curative option; however, ∼80% of patients with colorectal liver metastases have unresectable disease at presentation, and the long-term survival rate remains low for these patients [3].
In the setting of unresectable metastatic colorectal cancer (mCRC), the best outcome is achieved in patients receiving fluoropyrimidines, oxaliplatin, and irinotecan in their disease course [4]. Over the last decade, several combinations of these three drugs significantly increased the response rate (RR) and overall survival (OS) time, with an RR of 40%–50% and a median OS duration up to 20 months [5]. However, in a sequential strategy, one third of patients are not able to receive second-line therapy. Many phase I–II studies demonstrated the feasibility and promising activity of upfront biweekly 5-fluorouracil (5-FU) infusion combined with oxaliplatin and irinotecan [6, 8]. A phase III study [9] comparing 5-FU, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) with 5-FU, leucovorin, and irinotecan (FOLFIRI) demonstrated that FOLFOXIRI produced manageable toxicities and led to a significantly higher RR (up to 60%), longer progression-free survival (PFS) time, and longer OS time. This regimen also resulted in a higher rate of secondary resection of liver metastases in patients with initially unresectable lesions [9, 10], but it did not lead to a higher complete response (CR) rate (<5%).
Recent advances have focused on targeting the epidermal growth factor receptor (EGFR). Currently, blocking this pathway presents great potential for cancer treatment. The monoclonal antibody cetuximab is an EGFR antagonist that is capable of activating internalization of the receptor and its degradation, leading to increased tumor cell apoptosis [11]. Cetuximab was initially approved for clinical use in patients with detectable EGFR mCRC who failed on first-line irinotecan therapy [12]. Recently, randomized studies [13, 14] showed that the addition of cetuximab to first-line chemotherapy (5-FU, leucovorin, and oxaliplatin [FOLFOX] or FOLFIRI) resulted in significantly better efficacy in patients with no activating tumor mutations in the KRAS gene, defined as wild-type KRAS.
Consequently, the combined use of cetuximab with FOLFIRINOX (ERBIRINOX) was a logical clinical research step for treating mCRC patients because both the FOLFIRINOX and cetuximab plus FOLFIRI or FOLFOX regimens have been proven to be highly efficacious with acceptable toxicities. This phase II trial was designed to evaluate the efficacy and safety of cetuximab in combination with FOLFIRINOX as first-line treatment in CRC patients who had definitively unresectable liver metastases. The impact of the chemotherapy plus a targeted agent combination alone was assessed in terms of the RR and survival time in that critical population of metastatic patients for whom conversion to resectability is not to be expected.
Methods
Patients
Patients were eligible if they had histologically confirmed unresectable mCRC with at least one radiologically measurable lesion. The criterion for nonresectability was the presence of extensive extrahepatic disease or, for patients with liver-only metastases, massive liver involvement with the remaining liver tissue expected to be insufficient for viable function. Additional inclusion criteria included: age 18–75 years; an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1; a life expectancy >3 months; and adequate renal, hepatic, and blood functions. Patients must not have received any previous chemotherapy for metastases and a rest period ≥4 weeks was necessary between the end of radiotherapy (or 8 weeks for large pelvic radiotherapy), any previous surgery, or adjuvant chemotherapy and the administration of study treatment. Patients were ineligible if they currently had or had a previous history of cancer other than colon cancer or had been treated for basal cell carcinoma within the last 5 years. Patients were also excluded if they had documented grade ≥2 peripheral neuropathy according to National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0 (NCI-CTCAE v 3.0); colon inflammation or intestinal resection; Crohn's disease; colorectal hemorrhage; another serious medical conditions such as unstable heart disease or a heart attack within the last 6 months; a history of a psychiatric or neurological illness; or an uncontrolled active infection. The study was approved by relevant ethics committees and was conducted in accordance with the Declaration of Helsinki. All patients provided written informed consent before study entry (ClinicalTrials.gov identifier, NCT 00556413).
Treatment Procedure
This was an open-label, single-arm, multicenter, phase II study. Cetuximab was administered weekly and before the chemotherapy. Cetuximab was delivered i.v. at a dose of 400 mg/m2 over 2 hours on day 1 of the first week. Subsequent administrations were performed at a dose of 250 mg/m2 over 1 hour. Antihistamine treatment was given before each cetuximab administration to reduce the risk for allergic reaction or hypersensitivity. The FOLFIRINOX regimen was given on day 1 of each 2-week cycle as follows: 85 mg/m2 oxaliplatin was administered as an i.v. infusion for 120 minutes, followed by 180 mg/m2 irinotecan as an i.v. infusion over 90 minutes and 200 mg/m2 leucovorin as an i.v. infusion over 120 minutes. 5-FU was given as a 400 mg/m2 bolus, followed by a 46-hour continuous infusion at 2,400 mg/m2. The treatment was administered for a maximum of 12 cycles (6 months) in the absence of disease progression, unacceptable toxicity, or patient refusal. Patients were monitored for potential adverse events before, during, and for 1 hour after the infusion. Prophylactic G-CSF was mandatory and was given s.c. on days 7–12 of the first cycle.
Assessment Criteria
All patients receiving at least four cycles of treatment were evaluable for efficacy, and the primary efficacy criterion was the CR rate according to the Response Evaluation Criteria in Solid Tumors, version 1.0. Secondary efficacy criteria were the objective RR (ORR) (including CRs and partial responses [PRs]), as well as the response duration, PFS time, OS time, and safety. Tumor response was evaluated at baseline, every 8 weeks (four cycles) during the treatment period, and every 3 months during follow-up by computed tomography or magnetic resonance imaging of the chest, abdomen, and pelvis. All imaging data were reviewed by an independent radiology committee. All patients receiving at least one cycle of treatment were considered evaluable for safety. Toxicity was evaluated according to the NCI-CTCAE v 3.0, except for neurotoxicity, which was evaluated using the modified Levi scale.
Severe toxicity was defined as follows: any grade 4 hematological toxicity (neutrophil count <0.5 × 109/L for ≥7 days, platelet count <25 times] 109/L), any febrile neutropenia (≥38.5°C) associated with grade 3–4 neutropenia, any infection with grade 3–4 neutropenia, any symptomatic thrombocytopenia (hemorrhage), any grade 4 diarrhea or any grade ≥2 diarrhea associated with grade 4 neutropenia, any grade 4 sensory peripheral neuropathy (for any grade 3, oxaliplatin was given as reported for 1 week then the dosage was reduced to 60 mg/m2 for subsequent cycles), any grade 4 toxicity (except vomiting in the absence of appropriate prophylaxis), and any toxicity requiring a cycle delay >15 days.
Analysis of EGFR Expression and KRAS Mutation
Paraffin-embedded tissue samples obtained by biopsy or after surgical treatment were used. Tumor DNA was isolated according to the manufacturer's recommendations from 10-μm thin sections using the QIAamp DNA FFPE Tissue Kit (Qiagen, Courtaboeuf, France). Mutational analysis of KRAS was achieved through high resolution melt (HRM) analysis and direct sequencing. For HRM screening an 80-base pair fragment from KRAS exon 2 was polymerase chain reaction (PCR) amplified using a Rotor-Gene 6000™ instrument (Qiagen) (primer sequences and cycling conditions available on request). All samples were tested in duplicate. HRM data were analyzed using the Rotor-Gene 6000 Software (version 1.7). For samples displaying a distinct melting curve compared with the wild-type allele, KRAS mutation was confirmed by bidirectional DNA sequencing of two seminested amplicons (PCR primer sequences and annealing temperatures available on request). Direct sequencing was carried out with a 3130 Genetic Analyzer (Applied Biosystems, Courtaboeuf, France) using the BigDye® Terminator version 1.1 cycle sequencing kit (Applied Biosystems, Courtaboeuf, France). Analysis of KRAS sequences was performed with Applied Biosystems SeqScape® software, version 2.5.
Statistical Analysis
The primary objective was the CR rate given with its confidence interval (CI). The sample size calculation was based on a two-stage Bryant and Day design with α = 10% (response and toxicity) and β = 15%. A first-stage analysis for efficacy and safety was performed after the inclusion of the first 14 patients. At least one CR and fewer than four cases of severe toxicity were required to continue recruiting patients. The probability of early stopping under the hypothesis of poor response and excessive toxicity was 73%. The planned sample size of 39 eligible patients (allowing for 5% ineligibility) then provided a maximum CI width of 90% for a CR rate of 25%.
Results
Patient Demographics
Forty-two patients were enrolled from four French centers in April 2006 to April 2008 (Fig. 1). Patient characteristics at inclusion are summarized in Table 1. The median age was 60 years (range, 32–76 years) and 79% of the patients had an ECOG performance status score of 0. Thirty-nine patients (93%) had liver metastases and 24 patients (57%) had more than one metastatic site. Twenty-three patients (55%) underwent previous surgical resection of the primary tumor, two patients (5%) received previous chemotherapy, and four patients (10%) had previous radiotherapy. Blood levels of carcinoembryonic antigen were abnormal in 90% of patients and 10 times more than the upper limit of normal in 43% of patients.
Figure 1.
Trial profile.
Table 1.
Patient characteristics at baseline
Abbreviations: ECOG, Eastern Cooperative Oncology Group; ULN, upper limit of normal.
Treatment Compliance
The median duration of treatment was 5.2 months (range, 0.7–8.5 months) and a median of nine cycles was given per patient (range, 1–12 cycles). Sixteen patients (38%) received all 12 planned cycles, two of them had a single dose reduction, and three others discontinued oxaliplatin and/or cetuximab. Thirty-two patients (76%) required at least one dose reduction and this was most commonly a result of nonhematological toxicity (40% of cases). The overall relative dose intensity for this chemotherapy treatment was >90% and the relative dose intensities for the individual drugs were 94% for cetuximab, 92% for 5-FU, 86% for irinotecan, and 85% for oxaliplatin.
Efficacy
Thirty-seven patients (88.1%) received at least four cycles of chemotherapy and were evaluable for efficacy. The results in the intent-to treat population are summarized in Table 2. The primary efficacy endpoint, which was the CR to chemotherapy alone (without surgery), was achieved in five patients (11.9%), and the median duration of CR was 23.1 months (95% CI, 10.8–39.7 months). Three patients were still in CR at the time of analysis (26.4, 27.6, and 39.6 months of follow-up) and the other two had a PFS interval of 10.8 months with lung and liver recurrence, respectively. Results of the secondary efficacy endpoints included an ORR of 80.9% (n = 34) and OS rates of 79% (95% CI, 63%–88%) at 1 year and 70% (95% CI, 53%–82%) at 18 months. The median OS duration was 24.7 months (95% CI, 22.6 months to not reached) (Fig. 2A). The median PFS interval was 9.5 months (95% CI, 7.6–10.4 months) (Fig. 2B) and the main sites of progression were the liver (58%) and the lungs (23%). Twenty-eight patients (67%) received second-line chemotherapy (in half of the cases, with FOLFIRI plus bevacizumab) and 13 patients (31%) received third-line chemotherapy (in half of the cases, with FOLFOX plus bevacizumab).
Table 2.
Efficacy in the intent-to-treat population
Abbreviations: CI, confidence interval; CR, complete response; NA, not available; NR, not reached; OS, overall survival; PFS, progression-free survival; PR, partial response; RECIST, Response Evaluation Criteria in Solid Tumors.
Figure 2.
Overall survival and progression-free survival. Shown are Kaplan–Meier curves for overall survival (A) and progression-free survival (B) in the study population.
Abbreviation: ERBIRINOX, cetuximab plus 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin.
Safety
All patients received at least one cycle of treatment and were therefore included in the safety evaluation. The maximum toxicity reached grade 3 in 28 patients and grade 4 in nine patients. All grade 3–4 adverse events are presented in Table 3. The most frequent events were diarrhea (52%), neutropenia (38%), and asthenia (32%). Grade 4 toxicity was observed only for neutropenia (19%), neuropathy (2.4%), and hemoglobin count (2.4%). Four patients ended all treatments because of toxicity. Treatment discontinuation resulted from one toxic death related to neutropenic septicemia in a patient who did not receive prophylactic G-CSF, one grade 3 asthenia and anorexia, one grade 3 vomiting and diarrhea, and one case of grade 3 general disorders. One patient stopped treatment because of disease progression that occurred after the first cycle. At the time of analysis, with a median follow-up of 18.1 months (range, 0.4–39.6 months), a total of 16 patients (38.1%) had died, for 15 of them because of disease progression and for one patient as a result of treatment toxicity.
Table 3.
Grade 3 or 4 adverse events
KRAS Analysis
KRAS retrospective analysis was available for 40 patients and showed mutated KRAS in 16 patients (40%) and wild-type KRAS in 24 patients (60%); two patients were not analyzable because of the absence of material. The efficacy of ERBIRINOX according to KRAS status is summarized in Table 2 and Figure 3. No significant difference was observed in terms of the RR according to the KRAS status. A CR was observed in two patients (12.5%) with mutated KRAS and in three patients (12.5%) with wild-type KRAS. The ORR was 81.3% (n = 13) in patients with mutated KRAS and 83.3% (n = 20) in patients with wild-type KRAS. No difference was observed in the toxicity profile between the two groups of patients. The median OS time was 23.1 months (95% CI, 12.2 months to not reached) for patients with mutated KRAS and was not reached for patients with wild-type KRAS (Fig. 4A). The median PFS time was slightly longer for patients with wild-type KRAS: 7.8 months (95% CI, 6.6–11.5 months) for patients with mutated KRAS versus 9.9 months (95% CI, 6.2–20.2 months) for patients with wild-type KRAS (Fig. 4B).
Figure 3.
Patient response rate according to KRAS status. Thirty-five patients were available for both KRAS status and tumor response evaluation. Red, mutated KRAS; blue, wild-type KRAS.
Figure 4.
Overall survival and progression-free survival according to KRAS status. Shown are Kaplan–Meier curves for overall survival (A) and progression-free survival (B) according to KRAS status.
Abbreviation: ERBIRINOX, cetuximab plus 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin.
Discussion
The first-line treatment of patients with unresectable mCRC is still a matter of debate. The results of this first phase II study evaluating the ERBIRINOX regimen in patients with unresectable mCRC demonstrate that this combination is both feasible and effective. The complete response rate of 11.9% seems to be interesting, compared with previous results with cetuximab plus doublet chemotherapy [13–18] or FOLFIRINOX alone [7, 9, 10]. This is comparable with the CR rate reported with bevacizumab plus FOLFOXIRI combination therapy [19]. The analysis of the secondary efficacy criteria is also encouraging and supports the effectiveness of this regimen. Indeed, the ORR of 80.9% is higher than the results obtained in all studies using cetuximab plus doublet chemotherapy in an unselected population.
The ERBIRINOX regimen had an acceptable safety profile, as illustrated by the occurrence of only the expected toxicities for each chemotherapy agent and no unexpected treatment interactions. The most frequent toxicity was diarrhea, with 52% of patients experiencing a grade 3 event, whereas no grade 4 event was observed. This relatively high diarrhea rate could be appropriately managed through symptomatic measures and reduction in the irinotecan dose to 150 mg/m2. This allowed a favorable outcome in most cases, leading us to recommend these practices in future studies using the same regimen. Grade 3–4 neutropenia was reported at similar levels in all studies testing cetuximab plus FOLFIRI or FOLFOX and FOLFIRINOX alone [7, 9, 10, 13–15], provided that prophylactic G-CSF is given with ERBIRINOX. In total, only four patients in our study needed to stop the treatment prematurely as a result of toxicity, although a large proportion of patients (76%) had at least one dose reduction.
Patients enrolled in this study were not selected by KRAS mutation status, which may have affected the RR to some degree because patients with mutated KRAS would not be expected to respond to cetuximab. An interaction between KRAS status and cetuximab response was demonstrated in several studies in mCRC patients with disease progression after failure of standard chemotherapy [20–24]. The predictive power of KRAS for response to cetuximab was also shown in the first-line treatment of mCRC patients with FOLFIRI with or without cetuximab (p = .03) [13]. Our study did not show any interaction between KRAS status and the RR. However, because the present original design did not include KRAS analysis, the statistical power required to detect an interaction between KRAS status and response to ERBIRINOX was not achieved.
One criticism that might be made regarding the ERBIRINOX regimen is the possible loss of efficacy or lesser feasibility of second-line treatment. In the case of FOLFOXIRI, the great majority of patients had been given a second chemotherapy regimen after progression, and it was shown in a recent study that the use of FOLFOXIRI as first-line treatment does not compromise the administration and the efficacy of second-line treatment [25, 26]. In our study as well, most patients (n = 28, 67%) had second-line therapy, whereas 13 patients (31%) had received third-line treatment at the time of analysis.
In conclusion, this study reports the first results of the ERBIRINOX regimen, and shows the best results described from a phase II study, especially in terms of the ORR in clearly nonresectable mCRC patients. Most patients who entered our trial had synchronous metastases (81%) or more than one metastatic site (58%), retaining a distinctly poor prognosis [27]. Even though the primary objective was not reached, and in spite of the limited number of patients, this study opens the field for further investigation of the ERBIRINOX regimen as first-line therapy. These data are consistent with the encouraging results we obtained from a multicenter phase II trial evaluating early response to three first-line intensified chemotherapy regimens (high-dose FOLFIRI, FOLFOX7, and FOLFIRINOX), compared with standard chemotherapy (FOLFIRI, FOLFOX4) in patients with initially unresectable or not optimally resectable liver metastases. The FOLFIRINOX regimen allowed us to achieve the best PR rate as well as the best conversion rate to resectability, with 67% of patients becoming eligible for liver resection after a median of eight cycles (range, 4–12 cycles) [10]. An R0 resection was possible in 45% of patients receiving FOLFIRINOX. With a median follow-up of 35.7 months (range, 1.1–55.4 months), the median PFS and OS times were shown to be superior in this treatment arm than in others. Based on these data, we have initiated a large, randomized, phase II trial in a selected population of unresectable mCRC patients to evaluate the efficacy of FOLFIRINOX combined with cetuximab (in patients with wild-type KRAS) or bevacizumab (in patients with mutated KRAS) for the treatment of mCRC patients with metastases confined to the liver, and with secondary resection as the main study objective in this target population ([Research Partnership for Digestive Oncology] PRODIGE 14 trial, [Concerted Actions for Colorectal and Digestive Cancers] ACCORD 21). The combination of triplet chemotherapy with targeted agents will be compared with doublet chemotherapy (FOLFIRI or FOLFOX) combined with the same targeted agents according to KRAS status.
Acknowledgments
The authors would like to thank Prof. David Azria and Vanessa Guillaumon for their editorial assistance.
This work was supported by funding from Merck Serono. The funding source had no role in the collection, analysis, and interpretation of data or study writing.
Footnotes
- (C/A)
- consulting/advisory relationship
- (RF)
- Research funding
- (E)
- Employment
- (H)
- Honoraria received
- (OI)
- Ownership interests
- (IP)
- Intellectual property rights/inventor/patent holder
Author Contributions
Conception/Design: Eric Assenat, Simon Thezenas, Andrew Kramar, Jean Pierre Bleuse, Marc Ychou
Provision of study material or patients: Eric Assenat, Francoise Desseigne, Frédéric Viret, Laurent Mineur, Emmanuelle Samalin, Fabienne Portales, Marc Ychou
Collection and/or assembly of data: Eric Assenat, Francoise Desseigne, Simon Thezenas, Frédéric Viret, Laurent Mineur, Andrew Kramar, Emmanuelle Samalin, Fabienne Portales, Frédric Bibeau, Evelyne Crapez-Lopez, Jean Pierre Bleuse, Marc Ychou
Data analysis and interpretation: Eric Assenat, Simon Thezenas, Andrew Kramar, Frédric Bibeau, Evelyne Crapez-Lopez, Jean Pierre Bleuse, Marc Ychou
Manuscript writing: Eric Assenat, Simon Thezenas, Andrew Kramar, Frédric Bibeau, Evelyne Crapez-Lopez, Jean Pierre Bleuse, Marc Ychou
Final approval of manuscript: Eric Assenat, Francoise Desseigne, Simon Thezenas, Frédéric Viret, Laurent Mineur, Andrew Kramar, Emmanuelle Samalin, Fabienne Portales, Frédric Bibeau, Evelyne Crapez-Lopez, Jean Pierre Bleuse, Marc Ychou
References
- 1.Boyle P, Ferlay J. Cancer incidence and mortality in Europe, 2004. Ann Oncol. 2005;16:481–488. doi: 10.1093/annonc/mdi098. [DOI] [PubMed] [Google Scholar]
- 2.O'Connell JB, Maggard MA, Ko CY. Colon cancer survival rates with the new American Joint Committee on Cancer sixth edition staging. J Natl Cancer Inst. 2004;96:1420–1425. doi: 10.1093/jnci/djh275. [DOI] [PubMed] [Google Scholar]
- 3.Adam R, Delvart V, Pascal G, et al. Rescue surgery for unresectable colorectal liver metastases downstaged by chemotherapy: A model to predict long-term survival. Ann Surg. 2004;240:644–657. doi: 10.1097/01.sla.0000141198.92114.f6. discussion 657–658. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.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. 2004;22:1209–1214. doi: 10.1200/JCO.2004.11.037. [DOI] [PubMed] [Google Scholar]
- 5.Tournigand C, André T, Achille E, et al. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: A randomized GERCOR study. J Clin Oncol. 2004;22:229–237. doi: 10.1200/JCO.2004.05.113. [DOI] [PubMed] [Google Scholar]
- 6.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. 2003;14:481–489. doi: 10.1093/annonc/mdg119. [DOI] [PubMed] [Google Scholar]
- 7.Ychou M, Viret F, Kramar A, et al. Tritherapy with fluorouracil/leucovorin, irinotecan and oxaliplatin (FOLFIRINOX): A phase II study in colorectal cancer patients with non-resectable liver metastases. Cancer Chemother Pharmacol. 2008;62:195–201. doi: 10.1007/s00280-007-0588-3. [DOI] [PubMed] [Google Scholar]
- 8.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 a phase II study with a simplified biweekly schedule. Ann Oncol. 2004;15:1766–1772. doi: 10.1093/annonc/mdh470. [DOI] [PubMed] [Google Scholar]
- 9.Falcone A, Ricci S, Brunetti I, et al. 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. J Clin Oncol. 2007;25:1670–1676. doi: 10.1200/JCO.2006.09.0928. [DOI] [PubMed] [Google Scholar]
- 10.Rivoire M, Thezenas C, Rebischung F, et al. Preliminary results of a randomized phase II trial comparing standard bi-therapy versus three intensified chemotherapy regimens as treatment for patients with non resectable liver metastases from colorectal cancer (LMCRC) (METHEP) J Clin Oncol. 2008;26(15 suppl) Abstract 4075. [Google Scholar]
- 11.Wu X, Fan Z, Masui H, et al. Apoptosis induced by an anti-epidermal growth factor receptor monoclonal antibody in a human colorectal carcinoma cell line and its delay by insulin. J Clin Invest. 1995;95:1897–1905. doi: 10.1172/JCI117871. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Cunningham D, Humblet Y, Siena S, et al. Ce-tuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med. 2004;351:337–345. doi: 10.1056/NEJMoa033025. [DOI] [PubMed] [Google Scholar]
- 13.Van Cutsem E, Köhne CH, Hitre E, et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med. 2009;360:1408–1417. doi: 10.1056/NEJMoa0805019. [DOI] [PubMed] [Google Scholar]
- 14.Bokemeyer C, Bondarenko I, Makhson A, et al. Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J Clin Oncol. 2009;27:663–671. doi: 10.1200/JCO.2008.20.8397. [DOI] [PubMed] [Google Scholar]
- 15.Tabernero J, Van Cutsem E, Déaz-Rubio E, et al. Phase II trial of cetuximab in combination with fluorouracil, leucovorin, and oxaliplatin in the first-line treatment of metastatic colorectal cancer. J Clin Oncol. 2007;25:5225–5232. doi: 10.1200/JCO.2007.13.2183. [DOI] [PubMed] [Google Scholar]
- 16.Arnold D, Höhler T, Dittrich C, et al. Cetuximab in combination with weekly 5-fluorouracil/folinic acid and oxaliplatin (FUFOX) in untreated patients with advanced colorectal cancer: A phase Ib/II study of the AIO GI Group. Ann Oncol. 2008;19:1442–1449. doi: 10.1093/annonc/mdn150. [DOI] [PubMed] [Google Scholar]
- 17.Folprecht G, Lutz MP, Schôffski P, et al. Cetuximab and irinotecan/5-fluorouracil/folinic acid is a safe combination for the first-line treatment of patients with epidermal growth factor receptor expressing metastatic colorectal carcinoma. Ann Oncol. 2006;17:450–456. doi: 10.1093/annonc/mdj084. [DOI] [PubMed] [Google Scholar]
- 18.Folprecht G, Gruenberger T, Bechstein WO, et al. Tumour response and secondary resectability ofcolorectal liver metastases following neoadjuvant chemotherapy with cetuximab: The CELIM randomised phase 2 trial. Lancet Oncol. 2010;11:38–47. doi: 10.1016/S1470-2045(09)70330-4. [DOI] [PubMed] [Google Scholar]
- 19.Masi G, Loupakis F, Salvatore L, et al. Bevacizumab with FOLFOXIRI (irinotecan, oxaliplatin, fluorouracil, and folinate) as first-line treatment for metastatic colorectal cancer: A phase 2 trial. Lancet Oncol. 2010;11:845–852. doi: 10.1016/S1470-2045(10)70175-3. [DOI] [PubMed] [Google Scholar]
- 20.De Roock W, Piessevaux H, De Schutter J, et al. KRAS wild-type state predicts survival and is associated to early radiological response in metastatic colorectal cancer treated with cetuximab. Ann Oncol. 2008;19:508–515. doi: 10.1093/annonc/mdm496. [DOI] [PubMed] [Google Scholar]
- 21.Di Fiore F, Blanchard F, Charbonnier F, et al. Clinical relevance of KRAS mutation detection in metastatic colorectal cancer treated by cetuximab plus chemotherapy. Br J Cancer. 2007;96:1166–1169. doi: 10.1038/sj.bjc.6603685. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Lièvre A, Bachet JB, Boige V, et al. KRAS mutations as an independent prognostic factor in patients with advanced colorectal cancer treated with cetuximab. J Clin Oncol. 2008;26:374–379. doi: 10.1200/JCO.2007.12.5906. [DOI] [PubMed] [Google Scholar]
- 23.Yen LC, Uen YH, Wu DC, et al. Activating KRAS mutations and overexpression of epidermal growth factor receptor as independent predictors in metastatic colorectal cancer patients treated with cetuximab. Ann Surg. 2010;251:254–260. doi: 10.1097/SLA.0b013e3181bc9d96. [DOI] [PubMed] [Google Scholar]
- 24.Normanno N, Tejpar S, Morgillo F, et al. Implications for KRAS status and EGFR-targeted therapies in metastatic CRC. Nat Rev Clin Oncol. 2009;6:519–527. doi: 10.1038/nrclinonc.2009.111. [DOI] [PubMed] [Google Scholar]
- 25.Masi G, Marcucci L, Loupakis F, et al. Firstline 5-fluorouracil/folinic acid, oxaliplatin and irinotecan (FOLFOXIRI) does not impair the feasibility and the activity of second line treatments in metastatic colorectal cancer. Ann Oncol. 2006;17:1249–1254. doi: 10.1093/annonc/mdl119. [DOI] [PubMed] [Google Scholar]
- 26.Masi G, Loupakis F, Pollina L, et al. Long-term outcome of initially unresectable metastatic colorectal cancer patients treated with 5-fluorouracil/leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) followed by radical surgery of metastases. Ann Surg. 2009;249:420–425. doi: 10.1097/SLA.0b013e31819a0486. [DOI] [PubMed] [Google Scholar]
- 27.Allen PJ, Kemeny N, Jarnagin W, et al. Importance of response to neoadjuvant chemotherapy in patients undergoing resection of synchronous colorectal liver metastases. J Gastrointest Surg. 2003;7:109–115. doi: 10.1016/S1091-255X(02)00121-X. discussion 116–117. [DOI] [PubMed] [Google Scholar]