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Annals of Oncology Advance Access originally published online on June 9, 2006
Annals of Oncology 2006 17(8):1249-1254; doi:10.1093/annonc/mdl119
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© 2006 European Society for Medical Oncology

First-line 5-fluorouracil/folinic acid, oxaliplatin and irinotecan (FOLFOXIRI) does not impair the feasibility and the activity of second line treatments in metastatic colorectal cancer

G. Masi1,*, L. Marcucci1, F. Loupakis1, E. Cerri1, C. Barbara1, S. Bursi1, G. Allegrini1, I. M. Brunetti2, R. Murr2, S. Ricci2, S. Cupini3, M. Andreuccetti1 and A. Falcone1,4

1 Division of Medical Oncology, Department of Oncology, Livorno; 2 Division of Medical Oncology, Department of Oncology, Pisa; 3 Division of Internal Medicine, Department of Oncology, Pontedera; 4 Cattedra di Oncologia Medica, University of Pisa, Italy

* Correspondence to: Dr G. Masi, U.O. Oncologia Medica, Presidio Ospedaliero, Viale Alfieri, 36, 57124 Livorno, Italy. Tel: +39 0586 223458; Fax: +39 0586 223457; E-mail: gl.masi{at}tin.it


   Abstract
Top
 Abstract
introduction
 patients and methods
 results
 discussion
 References
 
Background: We conducted two phase II trials evaluating the combination of 5-fluorouracil/folinic acid, oxaliplatin and irinotecan (FOLFOXIRI) as first-line treatment in 74 metastatic colorectal cancer patients. Results were very promising with an overall response rate of 71% and 72%, a median PFS of 10.4 and 10.8 months and an overall survival of 26.5 and 28.4 months, respectively. A concern about the use of all three active agents up-front is the possibility that this might limit, after progression, disease control with second-line treatments. Therefore, we conducted the present analysis to evaluate the outcome of second-line treatments in these 74 patients.

Methods: Among the 71 patients so far progressed 54 (76%) received second line chemotherapy (23: FOLFIRI, 17: FOLFOXIRI, five: 5-FU protracted infusion, three: FOLFOX, three: 5-FU+MMC, two: CPT-11, one: CPT-11+LOHP, one: raltitrexed). Seventeen patients (24%) did not receive second line treatments: 10 because of deterioration of performance status (PS), four because of patient refusal and three because of death. Patients' characteristics at the time of second-line treatment were: M/F 36 of 18 patients, median age 64 yrs (range 44–75), ECOG PS ≥ 1 21 (39%) patients, multiple sites of disease 33 (61%) patients.

Results: A median of 4.1 months of second-line chemotherapy per patient were administered (range 1–8). Overall response rate (52 out of 54 evaluable patients) was 33% and stable disease were 19 (37%). Median duration of response was 8.1 months. At a median follow up of 15.1 months from the start of salvage chemotherapy median PFS and overall survival were respectively 6.7 and 15.2 months.

Conclusions: First-line FOLFOXIRI does not impair the possibility to obtain objective responses and delay tumor progression with second line treatments containing the same agents used in first-line.

Key words: colorectal cancer, 5-fluorouracil, irinotecan, oxaliplatin, second-line


   introduction
Top
 Abstract
 introduction
patients and methods
 results
 discussion
 References
 
Colorectal cancer is the third most common cancer and the fourth most frequent cause of cancer deaths worldwide [1Go]. At the time of diagnosis, about a quarter of newly diagnosed patients will have metastatic disease and ultimately half of patients will develop metastatic disease [2Go]. The prognosis of metastatic colorectal cancer is poor and for more than four decades 5-fluorouracil (5FU) has represented the sole therapeutic choice available, achieving objective responses in 10–20% of patients and resulting in a median survival of about 10–12 months.

In recent years, the introduction in clinical practice of new active drugs such as irinotecan and oxaliplatin has deeply changed the therapeutic approach to metastatic colorectal cancer. In fact, several randomized trials demonstrated that a more active first-line combination chemotherapy is associated with a better outcome. In particular the combinations of 5FU and irinotecan [2Go–4Go] or 5FU with oxaliplatin [5Go, 6Go] are significantly more active and more efficacious than 5FU alone as first-line treatment of metastatic colorectal cancer patients and produced an overall survival of 16–19 months. Furthermore, the availability of active and not cross-resistant drugs has allowed a successful use of second-line chemotherapy after progression to first-line. Two studies demonstrated the role of an irinotecan-based second-line chemotherapy after the failure of a first-line 5FU-based regimen. In particular, irinotecan was superior in terms of survival and quality of life when compared to best supportive care alone or to an infusional 5FU-based treatment [7Go, 8Go]. The efficacy of a second-line therapy has afterwards been emphasized from a study by Rothenberg et al., where 436 patients pretreated with irinotecan and 5FU bolus (IFL) were randomized to receive as second-line treatment 5FU alone, oxaliplatin alone or oxaliplatin and infusional 5FU (FOLFOX). The results showed a statistically significant benefit for the combination both in terms of activity (responses: 0%, 1.3% and 9.9%, respectively) and of time to progression (2.7, 1.6 and 4.6 months respectively) [9Go]. More recently, Pitot et al. presented the data of a phase III trial in which 491 patients who progressed after a prior 5FU-based therapy were randomized to receive second-line chemotherapy with irinotecan versus the FOLFOX combination. Although no significant differences between the two arms were observed, the second-line treatments demonstrated notable efficacy with a median survival of 14.7 and 13.5 months, respectively [10Go]. Also the trial by Goldberg et al., that demonstrated the superiority of the FOLFOX-4 regimen over the IFL regimen as first-line treatment, supports the importance of the second-line therapy. In fact, the statistically significant difference in survival achieved (19.5 months versus 15.0 months) could be partially explained by the higher percentage of patients (60%) who received irinotecan in second-line in the FOLFOX-4 arm, compared to the modest amount of patients (24%) who received oxaliplatin in the IFL arm [11Go].

The French GERCOR group has evaluated in a phase III trial two different treatment strategies: first-line FOLFIRI followed by FOLFOX-6 after progression or the inverse sequence. Results did not demonstrate relevant differences between the two sequences. Of note, in both arms median survival exceeded 20 months, thus underlining one more time the value of the second-line therapy (performed in 82% of patients in one arm and 74% in the other) and the importance of the ‘exposure’ of patients to all the three most active agents even in different sequences [12Go]. Moreover, a recent pooled analysis of seven phase III trials in metastatic colorectal cancer demonstrates that survival is correlated with the rate of patients who received all the three active drugs in the course of their disease, but not with the rate of patients who received any second line therapy [13Go].

We have attempted, in the last few years, to develop a new and potentially more active and efficacious chemotherapy regimen in the treatment of metastatic colorectal cancer combining 5FU/LV with both irinotecan and oxaliplatin. We conducted a phase I–II study with a biweekly combination of irinotecan, oxaliplatin and infusional 5FU modulated by LV (FOLFOXIRI) [14Go] and a successive phase II study with a simplified schedule of FOLFOXIRI [15Go] respectively in 42 and 32 metastatic colorectal cancer patients with initially unresectable metastases. These studies demonstrated that such combinations are feasible with manageable toxicities. Of interest, these regimens were associated with very promising results with an overall response rate of 71% and 72%, a median PFS of 10.4 months and 10.8 months and an overall survival of 26.5 months and 28.4 months, respectively.

A possible concern about the use of all three main active agents up-front is, however, the possibility that this might limit, after progression, disease control with second line treatments. Therefore, we conducted the present analysis evaluating the outcome of second-line treatments in patients included in these phase II studies treated with a combination of irinotecan, oxaliplatin and 5FU/LV in first-line.


   patients and methods
Top
 Abstract
 introduction
 patients and methods
results
 discussion
 References
 
patients' selection
Main eligibility criteria in both phase II studies considered in this retrospective analysis included: histologically confirmed diagnosis of colorectal adenocarcinoma, age 18–75 years, Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2, measurable disease, adequate bone marrow, liver renal and cardiac functions and unresectable metastatic disease.

Exclusion criteria included: previous chemotherapy including irinotecan or oxaliplatin, symptomatic cardiac disease, myocardial infarction in the last 24 months, uncontrolled arrhythmia, active infections, inflammatory bowel disease, total colectomy. The studies were conducted in accordance with the Helsinki declaration and Good Clinical Practice guidelines. Written informed consent was required from all patients.

assessments
Pre-treatment evaluation before the start of second-line treatment, included history and physical examination, performance status assessment, complete blood cell with differential and platelet counts, complete blood profile, carcinoembryonic antigen (CEA), urine analysis, electrocardiogram, chest X-ray or computed tomography (CT) scan, abdominal CT scan and sonogram and any other appropriate diagnostic procedure to evaluate metastatic sites. During second-line treatment, a physical examination, a complete blood cell count, blood profile and urine analysis were performed every 2–3 weeks. Toxicities were scored according to the National Cancer Institute Common Toxicity Criteria, version 2. Sites of metastatic disease were evaluated at the onset of second-line chemotherapy and after every 8–9 weeks. For the evaluation of liver, lung or abdominal metastases an abdominal CT scan or MRI was required. Responses were evaluated according to WHO criteria and their duration was calculated from the day of treatment start.

survival analysis
Progression free survival was calculated as the period from the start of second-line chemotherapy to the first observation of disease progression or death from any cause. The overall survival time was calculated as the period from the start of second-line chemotherapy until death from any cause or until the date of the last follow up. Both progression free and overall survival times were estimated by the Kaplan-Meyer method.

chemotherapy
The first-line treatment planned in the first study (42 patients) consisted of: irinotecan 125 mg/m2 in the initial 3 patients, than 175 mg/m2 followed by oxaliplatin 100 mg/m2, l-Leucovorin 200 mg/m2 and 5FU 3800 mg/m2 administered as a 48-h chronomodulated continuous infusion (FOLFOXIRI) as previously reported. The first-line treatment planned in the later study (32 patients) consisted of: irinotecan 165 mg/m2 followed by oxaliplatin 85 mg/m2, l-Leucovorin 200 mg/m2 and 5FU 3200 mg/m2 administered as a 48-h flat continuous infusion (simplified FOLFOXIRI). Treatment schedules are outlined in Figure 1. Both regimens were repeated every 2 weeks. Treatments were administered biweekly until evidence of progression, unacceptable toxicity, patient refusal or for a maximum of 12 cycles.


Figure 1
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  		Figure 1. FOLFOXIRI schedules. CPT-11: irinotecan, LOHP: oxaliplatin, l-LV: leucovorin, 5-FU: 5-fluorouracil, IV: intravenous. FOLFOXIRI regimen consisted of: CPT-11 175 mg/m2 in 250 ml of NaCl 0.9% over 1 h immediately followed by LOHP 100 mg/m2 in 250 ml dextrose 5% and l-LV 200 mg/m2 in 250 ml dextrose 5% infused concomitantly over 2 h via a Y-connector, immediately followed by 5FU 3800 mg/m2 infused as a 48-h chronomodulated infusion. Simplified-FOLFOXIRI regimen consisted of: CPT-11 165 mg/m2 in 250 ml of NaCl 0.9% over 1 h immediately followed by LOHP 85 mg/m2 in 250 ml dextrose 5% and l-LV 200 mg/m2 in 250 ml dextrose 5% infused concomitantly over 2 h via a Y-connector, immediately followed by 5FU 3200 mg/m2 infused as a 48-h continuous infusion.

 
Second-line treatment was considered in all patients at the first evidence of progression. The second-line treatment regimen was not formally defined, but it was strongly suggested by the first-line treatment protocol and the choice followed pre-defined rules. In particular an irinotecan-based regimen was suggested in patients with persistent peripheral neurotoxicity, an oxaliplatin-based regimen was suggested in patients with impaired liver function and a re-treatment with a triple-drug combination (FOLFOXIRI) was suggested in patients achieving a ‘brilliant response’ to first-line treatment. Patients with a ‘brilliant response’ to first-line treatment were defined as the patients obtaining a complete response or a partial response and progressed more than 3 months after the end of first line chemotherapy.


   results
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 Abstract
 introduction
 patients and methods
 results
discussion
 References
 
patients
Between May 1999 and October 2002, 74 patients were enrolled into these two studies (Table 1). Among the 71 patients so far progressed 54 (76%) received second-line chemotherapy. Characteristics of these 54 patients are summarized in Table 2. The median number of first-line FOLFOXIRI cycles was 12 (range 2–15) and the median duration of first-line treatment was 6.2 months (range 2.3–8.5 months). The median time elapsed from the last first-line FOLFOXIRI infusion and the first infusion of second-line treatment was 6.0 months (range 0.7–27.4 months). Seventeen patients (24%) did not receive second line treatments: 10 because of deterioration of performance status (PS), four because of patient refusal and three because of death.


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  		Table 1. Characteristics of patients receiving first-line FOLFOXIRI

 

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  		Table 2. Characteristics of patients receiving second-line treatment after FOLFOXIRI

 
second-line treatments and toxicity
Second-line regimens used in these 54 patients were: FOLFIRI (23 patients), FOLFOXIRI (17 patients), 5-FU protracted infusion (five patients), FOLFOX-4 (three patients), 5-FU + Mytomicin-C (two patients), irinotecan (two patients), irinotecan + oxaliplatin (one patient), raltitrexed (one patient). A median of 4.1 months (range: 1.0–8.0 months) of second-line chemotherapy were administered. Most common toxicities were neutropenia, diarrhoea, nausea and vomiting, stomatitis, peripheral neurotoxicity, alopecia and thrombocytopenia. However, grade 3–4 toxicities were rare. Among all 54 patients five (9%) had grade 3 diarrhoea, two (4%) had grade 3 vomiting and one (2%) developed grade 3 stomatitis (Table 3). Three (6%) patients experienced at least one episode of grade 4 neutropenia, one (2%) had an episode of febrile neutropenia. Thirteen (24%) patients and 62 (16%) cycles required dose reductions of at least one drug and 20 (5%) cycles were delayed of more than one week. No patients were hospitalized because of toxicity and no toxic deaths have occurred.


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  		Table 3. Maximum toxicity per patient (54 patients)

 
activity and efficacy
With respect to the evaluation of antitumor activity, 52 patients were considered evaluable. Two patients were not evaluable because of not measurable disease (peritoneal carcinomatosis). Two (4%) and 15 (29%) patients respectively obtained a complete and a partial response for an objective response rate of 33% (95% confidence interval 20–47%). Responses lasted a median of 8.1 months (range 4.7–16.3). In the remaining patients we observed 19 (37%) disease stabilizations and 16 (30%) progressions.

After a median follow-up of 15.1 months, median progression-free survival was 6.7 months and median overall survival was and 15.2 months and the curves, estimated by the Kaplan-Meier method from the first day of second-line treatment, are reported in Figure 2.


Figure 2
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  		Figure 2. Actuarial progression-free and overall survival curves from the onset of second-line chemotherapy.

 
In particular among the 17 patients who achieved an objective response to second-line treatment median progression-free survival was 8.1 months and median overall survival was and 21.2 months. Characteristics of these responding patients were: duration of first-line treatment 6.2 months, time interval of end of first-line and beginning of second-line treatment 8.8 months, second-line regimen FOLFOXIRI (nine patients) and FOLFIRI (eight patients), duration of second line treatment 4.5 months. According to second-line regimen used among the 17 patients retreated with FOLFOXIRI response rate was 47%, median progression-free survival was 8.3 months and median overall survival was 15.2 months; among the 26 patients treated with a 5FU-based doublet (FOLFIRI or FOLFOX) response rate was 27%, median progression-free survival was 6.3 months and median overall survival was 15.2 months; among the remaining 11 patients (treated with a monotherapy) response rate was 18%, median progression-free survival was 4.6 months and median overall survival was 14.8 months. Patients' characteristics according to second-line regimen were (FOLFOXIRI/doublet/monotherapy): duration of first-line treatment 6.2/6.1/6.7 months, time interval of end of first-line and beginning of second-line treatment 6.4/5.4/8.4 months, duration of second line treatment 3.9/3.8/4.2 months. A subgroup analysis of potential characteristics correlated with the benefit of second-line treatment is reported in Table 4.


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  		Table 4. Subgroup analysis (54 patients)

 

   discussion
Top
 Abstract
 introduction
 patients and methods
 results
 discussion
References
 
The availability of active drugs not cross resistant with 5FU has profoundly changed the treatment of metastatic colorectal cancer and significantly improved both activity and efficacy of chemotherapy. Several data have suggested that the best outcome is achieved in patients who are ‘exposed’ to all the three main active agents (5FU, irinotecan, oxaliplatin) during the course of disease [12Go, 13Go], but that in a sequential strategy only 60 to 80% of patients are able to receive second-line treatments and therefore are exposed to all these three agents. These considerations supported our strategy to develop potentially more active first-line regimens combining 5FU with both irinotecan and oxaliplatin. We studied a three-drug combination including irinotecan, oxaliplatin and 5FU (FOLFOXIRI). In our initial phase I-II study [14Go] we demonstrated that biweekly irinotecan, oxaliplatin and infusional 5FU modulated by Leucovorin could be combined at significant doses of each single agent with acceptable toxicities. Of interest, this combination was associated with an high degree of antitumor activity with a response rate of 71.4% and a complete response-rate of 11.9%. Median progression-free and overall survivals (10.4 and 26.5 months, respectively) were also very promising.

On the basis of these results we studied a simplified FOLFOXIRI regimen which could be more easily feasible also in clinical practice as well as in multicenter settings [15Go]. This simplified regimen produced a lower incidence of both hematological and non hematological toxicities. Of interest results in terms of antitumor activity (overall response rate of 72%) and in terms of efficacy (median progression-free survival of 10.8 months and a median survival of 28.4 months) were similar with those previously reported and still very promising. Moreover, a combined analysis of these two studies showed that in 19 patients (26%) with initially unresectable metastatic colorectal cancer not selected for a neo-adjuvant approach and also with extra-hepatic disease a secondary, potentially curative surgical resection of metastases could be performed. Median overall survival of the operated patients was 36.8 months and the 4-year survival rate is 37% [16Go]. These promising results seems to be confirmed by the preliminary findings of a phase III randomized study comparing simplified FOLFOXIRI to FOLFIRI, conducted by the GONO group [17Go]. In fact, the response rate is significantly higher in the FOLFOXIRI arm (66% versus 41%, P = 0.0002) and this higher activity of FOLFOXIRI produced an increased rate of secondary R0 surgical resection of metastases compared to FOLFIRI (15% versus 6% of patients, P = 0.033). At a median follow-up of 15.2 months median progression free survival and overall survival are significantly longer in the FOLFOXIRI arm (9.8 versus 6.9 months, HR: 0.63, P = 0.0006 and 22.6 versus 16.7 months, HR:0.70, P = 0.032 respectively).

Several studies demonstrated a positive impact of second-line chemotherapy in metastatic colorectal cancer and using all the three active agents in the first-line might compromise the activity of second-line chemotherapy. Results of the present analysis indicate that the FOLFOXIRI regimen in first-line does not seem to weaken the benefit of second-line treatments. In fact 76% of patients could receive a treatment after progression and this rate compares well with the percentage of patients treated with second-line chemotherapy in other studies; in particular in the study conducted by the GERCOR, in which a second-line chemotherapy was planned by the protocol, treatment after progression was performed in 77% of patients. Moreover, FOLFOXIRI does not worsen the toxicity of second-line chemotherapy; in fact we observed a very low occurrence of grade 3–4 adverse events. Finally results obtained in term of responses (33%), time to progression (6.7 months) and median overall survival (15.2 months) are consistent with those observed in patients treated with ‘less aggressive’ first line chemotherapy such as 5FU alone [10Go] or IFL [9Go]. The subgroup analysis we conducted was unplanned and its significance is limited by the small study population. However, same consideration can be made, taking into account also the fact that no patient was treated with a targeted agent. First of all, the re-treatment with FOLFOXIRI seems to be the more active option also in second-line (response rate: 47%, progression free survival: 8.3 months), but, if FOLFOXIRI is not feasible, a 5FU-based doublet instead of a monotherapy should be considered. Moreover, the time elapsed from the end of first-line treatment and the start of second-line seems to be a very important prognostic indicator for the second-line treatment; in fact, no patients with an interval of less than 3 months responded, while the outcome of patients with an interval of more than 6 months was considerable. Finally, neither the Performance Status nor the age seems to have a great impact on the second-line outcome. Therefore, in patients with a progression free interval from the discontinuation of first-line FOLFOXIRI of at least 3 months a second-line treatment with combination chemotherapy (FOLFOXIRI, FOLFIRI or FOLFOX) if feasible, could achieve a substantial impact on the disease control and should always be considered.

More recently, some targeted agents have been introduced in the treatment of metastatic colorectal cancer. Cetuximab, an anti EGFR monoclonal antibody, and Bevacizumab, an anti VEGF monoclonal antibody demonstrated promising results in combination with chemotherapy and extended the therapeutic options of colorectal cancer. In particular, the BOND-1 study demonstrated that the combination of Cetuximab with irinotecan produced a response rate of 23% and a median time to progression of 4.1 months in a population of heavily pre-treated patients [18Go]. With regard to Bevacizumab, two large randomized studies demonstrated significant improvements with the addiction of Bevacizumab to first-line IFL [19Go] of second-line FOLFOX [20Go]. Therefore Cetuximab and Bevacizumab, in combination with chemotherapy, may represent two new therapeutic options with potential activity also in patients treated with FOLFOXIRI in first-line; data to this regard should soon be available from ongoing studies [17Go].

In conclusion, while first-line chemotherapy with the FOLFOXIRI regimen may represent a potentially more effective combination in metastatic colorectal cancer patients, it does not seem to impair the possibility to administer treatments after progression and to obtain objective responses and delay tumor progression with second-line chemotherapy containing the same agents used in first-line.


   Acknowledgements
 
The work was partially supported by Fondazione ARCO and Associazione Italiana per la Ricerca sul Cancro (AIRC).

Received for publication February 1, 2006. Revision received April 18, 2006. Accepted for publication April 19, 2006.


   References
Top
 Abstract
 introduction
 patients and methods
 results
 discussion
 References
 
1. Colorectal Cancer. In: Steward BW, Kleihues P (eds). World Cancer Report. Lyon: IACR Press 2003: 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 multicenter randomized trial. Lancet 2000; 355: 1041–1047.[CrossRef][Web of Science][Medline]

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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 2005; 23(22): 4856–4865.[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 2000; 181: 136–147.

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 2000; 18: 2938–2947.[Abstract/Free Full Text]

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

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

9. Rothenberg ML, Oza AM, Bigelow RH et al. Superiority of oxaliplatin and fluorouracil-leucovorin compared with either therapy alone in patients with progressive colorectal cancer after irinotecan and fluorouracil-leucovorin: interim results of a phase III trial. J Clin Oncol 2003; 21(11): 2059–2069.[Abstract/Free Full Text]

10. Pitot HC, Rowland KM, Sargent DJ et al. N9841: A randomized phase III equivalence trial of irinotecan (CPT-11) versus oxaliplatin/5-fluorouracil (5FU)/leucovorin (FOLFOX4) in patients (pts) with advanced colorectal cancer (CRC) previously treated with 5FU. Proc Am Soc Clin Oncol 2005; Abstract 3506.

11. Goldberg RM, Sargent DJ, Morton RF et al. A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 2004; 22: 23–30.[Abstract/Free Full Text]

12. 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 2004; 22: 229–237.[Abstract/Free Full Text]

13. 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.[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 2002; 20: 4006–4014.[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 a phase II study with a simplified biweekly schedule. Ann Oncol 2004; 15(12): 1766–1772.[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 2006; 13(1): 58–65.[Abstract/Free Full Text]

17. Falcone A, Masi G, Murr R et al. I Biweekly irinotecan, oxaliplatin and infusional 5FU/LV (FOLFOXIRI) versus FOLFIRI as first-line treatment of metastatic colorectal cancer (MCRC): results of a randomized phase III trial by the Gruppo Oncologico Nord Ovest (G.O.N.O.). Proceedings ASCO Gastro-Intestinal Symposium 2006; Abstract 599.

18. Cunningham D, Humblet Y, Siena S et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 2004; 22; 351(4): 337–345.[Abstract/Free Full Text]

19. Hurwitz H, Fehrenbacher L, Novotny W et al. Bevacizumab plus irinotecan, fluorouracil and leucovorin for metastatic colorectal cancer. N Engl J Med 2004; 350(23): 2335–2342.[Abstract/Free Full Text]

20. Giantonio BJ et al. High-dose bevacizumab improves survival when combined with FOLFOX4 in previously treated advanced colorectal cancer: Results from the Eastern Cooperative Oncology Group (ECOG) study E3200. Proc Am Soc Clin Oncol 2005; Abstract 2.


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