M. Andreuccetti

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

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.

Bevacizumab with FOLFOXIRI (irinotecan, oxaliplatin, fluorouracil, and folinate) as first-line treatment for metastatic colorectal cancer: a phase 2 trial

BACKGROUND The FOLFOXIRI (irinotecan, oxaliplatin, fluorouracil, and folinate) regimen has been shown to be better than FOLFIRI (fluorouracil, folinate, and irinotecan) in a phase 3 trial in patients with metastatic colorectal cancer. Results of various studies have shown that the addition of bevacizumab to chemotherapy increases treatment efficacy. We therefore assessed the safety and activity of the combination of FOLFOXIRI plus bevacizumab in patients with colorectal cancer. METHODS In a phase 2 study, patients (aged 18-75 years) with colorectal cancer, which was judged to be unresectable for metastatic disease, were given the combination of intravenous bevacizumab (5 mg/kg on day 1) and intravenous FOLFOXIRI (irinotecan 165 mg/m(2) on day 1, oxaliplatin 85 mg/m(2) on day 1, folinate 200 mg/m(2) on day 1, and fluorouracil 3200 mg/m(2) for 48 h continuous infusion starting on day 1 and repeated every 2 weeks) as first-line treatment in seven centres in Italy. Induction treatment (FOLFOXIRI and bevacizumab) was administered for a maximum of 6 months, followed by maintenance treatment with bevacizumab (5 mg/kg intravenously on day 1, repeated every 2 weeks). The primary endpoint was progression-free survival (PFS) at 10 months from study entry in the intention-to-treat population. This study has been completed and is registered with ClinicalTrials.gov, number NCT01163396. FINDINGS From July 2, 2007, to April 1, 2008, 57 patients were enrolled; all patients were assessed for safety and efficacy. Median follow-up time was 28.8 months (95% CI 24.9-32.5). PFS at 10 months was 74% (95% CI 62-85). Main grade 3 or 4 adverse events during induction treatment were neutropenia (n=28 [49%], including one case of febrile neutropenia), diarrhoea (n=8 [14%]), stomatitis (n=2 [4%]), neurotoxicity (n=1 [2%]), deep-vein thrombosis (n=4 [7%]), and hypertension (n=6 [11%]). No treatment-related deaths occurred. Six serious adverse events occurred during the induction treatment: febrile neutropenia (n=1 [2%]), grade 3 diarrhoea with dehydration (n=2 [4%]), grade 4 stomatitis (n=1 [2%]), grade 4 hypertension (n=1 [2%]), and fluorouracil-related cardiac ischaemia (n=1 [2%]). The most common grade 3 or 4 adverse events noted in the 37 patients who received maintenance treatment were hypertension (n=5 [14%]) and neurotoxicity (n=3 [8%]). One case of acute myocardial infarction due to coronary thrombosis was noted during the maintenance treatment. INTERPRETATION Bevacizumab can be safely used with FOLFOXIRI without causing unforeseen adverse events. Treatment achieved promising results in terms of PFS. A phase 3 study for the comparison of FOLFOXIRI plus bevacizumab with FOLFIRI plus bevacizumab is in progress. FUNDING Gruppo Oncologico Nord Ovest, ARCO Foundation, and Roche.

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.

Objective/Background:The GONO-FOLFOXIRI regimen improved the rate of R0 secondary resection of metastases in initially unresectable metastatic colorectal cancer. The objective of this study was to evaluate the long-term outcome of resected patients and the impact of FOLFOXIRI on perioperative morbidities, mortality, and chemotherapy induced hepatotoxicity. Patients and Methods:Overall, 196 patients with initially unresectable metastatic colorectal cancer were treated with FOLFOXIRI in 2 phase II and 1 phase III trial. This regimen was associated with an elevated response rate (70.4%) and 37 patients (19%) could undergo a secondary R0 surgery on metastases. This study was registered with the Australian New Zealand Clinical Trials Registry Database at http://www.anzctr.org.au/Statistics.aspx and has ID number ACTRN12608000615381. Results:Main characteristics of the 37 radically resected patients were: median age 64 years (45–73), Eastern Cooperative Oncology Group Performance Status (ECOG) PS ≥1 in 30%, synchronous metastases in 65%, multiple sites of disease in 22%, and metastases confined to the liver in 68%. Preoperative FOLFOXIRI was administered for a median of 5.5 months. There was no perioperative mortality and all morbidities (27% of patients) resolved without sequelae. After a median follow up of 67 months, 5-year and 8-year survival are 42% and 33% respectively. At 5 years, 29% of patients are free of disease. The analysis of treatment-induced liver injury showed neither G3 vascular toxicity nor G4 steatosis, and steato-hepatitis in only 5% of patients. Conclusions:The GONO-FOLFOXIRI regimen allow an R0 surgery in approximately 1 out of 5 unselected patients with initially unresectable metastatic colorectal cancer, and the long-term survival of resected patients is considerable. Neoadjuvant FOLFOXIRI for 3-6 months is safe and not associated with severe liver injury.

Randomized Trial of Two Induction Chemotherapy Regimens in Metastatic Colorectal Cancer: An Updated Analysis

BACKGROUND In a randomized trial with a median follow-up of 18.4 months, 6 months of induction chemotherapy with a three-drug regimen comprising 5-fluorouracil (by continuous infusion)-leucovorin, irinotecan, and oxaliplatin (FOLFOXIRI) demonstrated statistically significant improvements in response rate, radical surgical resection of metastases, progression-free survival, and overall survival compared with 6 months of induction chemotherapy with fluorouracil-leucovorin and irinotecan (FOLFIRI). METHODS From November 14, 2001, to April 22, 2005, we enrolled 244 patients with metastatic colorectal cancer. To evaluate if the superiority of FOLFOXIRI is maintained in the long term, we updated the overall and progression-free survival data to include events that occurred up to February 12, 2009, with a median follow-up of 60.6 months. We performed a subgroup and a risk-stratified analysis to examine whether outcomes differed in specific patient subgroups, and we analyzed the results of treatment after progression. Survival curves were estimated by the Kaplan-Meier method. Multivariable Cox regression models were fit to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). All statistical tests were two-sided. RESULTS FOLFOXIRI demonstrated statistically significant improvements in median progression-free survival (9.8 vs 6.8 months, HR for progression = 0.59, 95% CI = 0.45 to 0.76, P < .001) and median overall survival (23.4 vs 16.7 months, HR for death = 0.74, 95% CI = 0.56 to 0.96, P = .026) with a 5-year survival rate of 15% (95% CI = 9% to 23%) vs 8% (95% CI = 4% to 14%). The improvements in progression-free survival and, to a lesser extent, in overall survival were evident even when the analysis excluded patients who received radical resection of metastases. With regard to the risk-stratified analysis, FOLFOXIRI results in longer progression-free survival and overall survival than FOLFIRI in all risk subgroups. CONCLUSIONS Six months of induction chemotherapy with FOLFOXIRI is associated with a clinically significant improvement in the long-term outcome compared with FOLFIRI with an absolute benefit in survival at 5 years of 7%.

A multicenter phase II study of the combination of oxaliplatin, irinotecan and capecitabine in the first-line treatment of metastatic colorectal cancer

The triple drug combination consisting of irinotecan, oxaliplatin and 5-fluorouracil (FOLFOXIRI) has demonstrated higher activity and efficacy compared to the doublet FOLFIRI. 5-Fluorouracil could be substituted in FOLFOXIRI regimen by capecitabine, an oral fluoropyrimidine with similar efficacy. Recently, a dose-finding trial has demonstrated the feasibility of the combination of irinotecan, oxaliplatin and capecitabine (XELOXIRI) and established their recommended doses. The aim of this study was to evaluate the activity of XELOXIRI. A total of 36 patients with unresectable metastatic colorectal cancer received irinotecan 165 mg m−2 and oxaliplatin 85 mg m−2 on day 1 plus capecitabine 2000 mg m−2 per day orally in two doses from day 1 to day 7, every 2 weeks. Grade 3–4 toxicities were infrequent, expect for neutropenia and diarrhoea, which were each observed in 30% of patients. Two complete and twenty-two partial responses were obtained, corresponding to an overall response rate of 67% (95% CI 51.4–82%). After a median follow-up of 17.7 months, the median progression-free and overall survival were 10.1 and 17.9 months, respectively.The substitution of 5-fluorouracil with capecitabine, in combination with irinotecan and oxaliplatin, is feasible and does not impair the activity of the regimen. However, the XELOXIRI combination is associated with a high incidence of diarrhoea and, therefore, should be considered as a not preferable alternative to FOLFOXIRI.

Azidothymidine in combination with 5-fluorouracil in human colorectal cell lines: In vitro synergistic cytotoxicity and dna-induced strand-breaks

The in vitro cytotoxicity of the combination of azidothymidine (AZT) and 5-fluorouracil (5-FU) against the human colorectal cancer cells SW-480, SW-620 and COLO-320DM was evaluated. The cytotoxic effects of 5-FU and AZT were determined by the assay using 2,3-bis(2-methoxy-4-nitro-5-sulfophenil)-2H-tetrazolium-5-carbo xanilide inner salt (XXT), while drug-induced DNA strand-breaks were measured using a fluorometric analysis of DNA unwinding. After an exposure of 72 h, 5-FU and AZT induced a dose-dependent cytotoxicity against each cell line. The addition of 3, 10 and 30 microM AZT to various concentrations of 5-FU, as well as the addition of 0.5, 1 and 3 microns 5-FU to various concentrations of AZT, resulted in an enhanced cytotoxic effect. Isobologram analysis and the combination index (CI) method demonstrated that the interaction between 5-FU and AZT was clearly synergistic in each cell line, except for the 30% level of effect in SW-620, where borderline synergism was observed. The evaluation of DNA strand-breaks after an exposure of 16 h to 5-FU, AZT or 5-FU + AZT demonstrated that the 5-FU + AZT combination produced the greatest DNA damage, and that this interaction was synergistic in each cell line. In conclusion, our study supports the evidence that the potential antitumour activity of AZT can be modulated by combining it with agents which inhibit thymidylate (dTMP) formation, such as 5-FU, and that the increased cytotoxicity is related to enhanced DNA damage. These findings should encourage further experimental and clinical studies of the potential use of AZT in combination with inhibitors of de novo dTMP synthesis.

Maximum tolerable doses of intravenous zidovudine in combination with 5-fluorouracil and leucovorin in metastatic colorectal cancer patients Clinical evidence of significant antitumor activity and enhancement of zidovudine-induced DNA single strand breaks in peripheral nuclear blood cells

BACKGROUND Experimental studies have demonstrated that 5-fluorouracil (5-FU) enhances zidovudine (AZT)-induced DNA strand breaks and cytotoxicity. Phase I studies have demonstrated that the maximum tolerable dose (MTD) of AZT is 8000 mg/sqm when administered i.v. over two hours after weekly 5-FU + l-leucovorin (LV), and that this combination has promising antitumor activity. The purpose of this study was therefore to evaluate the antitumor activity of weekly bolus 5-FU + LV + AZT, administered at its MTD, and to determine whether 5-FU enhances AZT-induced DNA strand breaks in blood nuclear cells. PATIENTS AND METHODS Twenty-nine chemotherapy-naïve metastatic colorectal cancer patients with measurable disease entered the study to evaluate the activity of a weekly 5-FU 500 mg/m2 i.v. bolus + LV 250 mg/m2 i.v. two-hour infusion + AZT 8000 mg/m2 i.v. two-hour infusion. In 10 different patients, who during three different weeks received 5-FU + LV, AZT and 5-FU + LV + AZT, DNA strand breaks in blood nuclear cells were determined by a fluorescent analysis of DNA unwinding. RESULTS Treatment was generally well tolerated and WHO grades III-IV toxicities, consisting mostly of diarrhea (17%), were uncommon. One patient died of severe diarrhea with consequent hypokalemia and cardiac arrhythmia. All patients were considered evaluable for response, and 3 (10%) complete and 10 (35%) partial responses were observed, for an objective response rate of 45% (95% confidence limit interval 26%-64%). Both 5-FU + LV and AZT decreased the percentage of double stranded DNA in nuclear blood cells. The greatest effect was observed with 5-FU + LV + AZT, which reduced the percentage of double stranded DNA to 50% and 36% after 24 and 48 hours, respectively, and this interaction between 5-FU + LV and AZT was found to be cumulative. CONCLUSIONS These studies demonstrate that the present dose and schedule of AZT in combination with 5-FU + LV has significant activity in metastatic colorectal cancer and that the combination of 5-FU + LV with AZT increases the amount of DNA damage. Therefore, AZT in combination with 5-FU + LV warrants further study in colorectal cancer.

Second-line Treatment for Non–Small-Cell Lung Cancer: One Size Does Not Fit All

After progression following first-line treatment, many patients with advanced non-small-cell lung cancer (NSCLC) still have a good performance status and can be considered for further treatments. Based on 2 randomized phase III trials, docetaxel was the first approved second-line therapy associated with longer survival and better quality of life compared with best supportive care alone and vinorelbine or ifosfamide. Since then, other agents have been approved for the second-line treatment of NSCLC (ie, pemetrexed, erlotinib, and gefitinib). Recently, new molecular-targeted agents are being increasingly considered in this setting, above all, bevacizumab and vandetanib. The discovery and validation of predictive markers of efficacy for both chemotherapy drugs and the new targeted therapies is of primary importance for the selection of second-line treatment for all patients with advanced NSCLC.

First line chemotherapy with planned sequential administration of gemcitabine followed by docetaxel in elderly advanced non-small-cell lung cancer patients: a multicenter phase II study

This multicenter phase II study evaluated, in chemonaive patients with stage IIIB–IV NSCLC, age ⩾70 and with a performance status 0–2, the activity, efficacy and tolerability of planned sequential administration of gemcitabine 1200 mg m−2 on days 1 and 8 every 3 weeks for three courses followed by three cycles of docetaxel 37.5 mg m−2 on days 1 and 8 every 3 weeks, provided there was no evidence of disease progression. A total of 56 patients entered the study. According to intention-to-treat analysis, the objective response rate was 16.0% (95% CI 7.6–28.3%); 23 patients (41.0%) had stable disease and 24 patients (43%) had progressive disease. Five patients who had a stable disease after three courses of gemcitabine obtained a conversion to partial response by docetaxel. Median time to progression was 4.8 months (95% CI 3.6–6.0 months) and median duration of survival was 8.0 months (95% CI 5.6–10.5 months). The 1-year survival rate was 34%. No grade 4 haematological toxicity was observed and grade 3 neutropenia and thrombocytopenia were reported in 5.4 and 3.6% of the patients, respectively. Grade 3/4 mucositis and grade 3 diarrhoea, both occurred in 3.6% of the patients and grade 3 asthenia was observed in 9% of patients. One patient reported a grade 4 skin toxicity. No treatment-related deaths occurred. Sequential gemcitabine and docetaxel is a well-tolerated and effective regimen in elderly advanced NSCLC patients.

Phase II study of sequential chemotherapy with docetaxel–estramustine followed by mitoxantrone–prednisone in patients with advanced hormone-refractory prostate cancer

Sequential chemotherapy may improve treatment efficacy avoiding the additive toxicity associated with concomitant polichemotherapy in hormone-refractory prostate cancer (HRPC). Forty patients received docetaxel 30 mg m−2 intravenous (i.v.), weekly, plus estramustine 280 mg twice daily for 12 weeks. After 2 weeks rest, patients with a decline or stable PSA were treated with mitoxantrone 12 mg m−2 i.v. every 3 weeks plus prednisone 5 mg twice daily for 12 cycles. Forty patients were assessable for toxicity after docetaxel/estramustine. Main toxicities were grade 3–4 AST/ALT or bilirubin increase in seven patients (17.5%) and deep venous thrombosis (DVT) in four patients (10%). Twenty-seven patients received mitoxantrone/prednisone. Main toxicities included DVT in one patient (3.7%) and congestive heart failure in two patients (7%). Thirty-nine patients were assessable for PSA response. Twenty-nine patients (72.5%; 95% CI 63–82%) obtained a ⩾50% PSA decline with 15 patients (37.5%; 95% CI 20–50%) that demonstrated a ⩾90% decrease. Median progression-free and overall survival were respectively 7.0 (95% CI 5.8–8.2 months) and 19.2 months (95% CI 13.9–24.3 months). In conclusion, although this regimen demonstrated a favourable toxicity profile, sequential administration of mitoxantrone is not able to improve docetaxel activity in patients with HRPC.