Gianluca Masi

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.

KRAS codon 61, 146 and BRAF mutations predict resistance to cetuximab plus irinotecan in KRAS codon 12 and 13 wild-type metastatic colorectal cancer

Background:KRAS codons 12 and 13 mutations predict resistance to anti-EGFR monoclonal antibodies (moAbs) in metastatic colorectal cancer. Also, BRAF V600E mutation has been associated with resistance. Additional KRAS mutations are described in CRC.Methods:We investigated the role of KRAS codons 61 and 146 and BRAF V600E mutations in predicting resistance to cetuximab plus irinotecan in a cohort of KRAS codons 12 and 13 wild-type patients.Results:Among 87 KRAS codons 12 and 13 wild-type patients, KRAS codons 61 and 146 were mutated in 7 and 1 case, respectively. None of mutated patients responded vs 22 of 68 wild type (P=0.096). Eleven patients were not evaluable. KRAS mutations were associated with shorter progression-free survival (PFS, HR: 0.46, P=0.028). None of 13 BRAF-mutated patients responded vs 24 of 74 BRAF wild type (P=0.016). BRAF mutation was associated with a trend towards shorter PFS (HR: 0.59, P=0.073). In the subgroup of BRAF wild-type patients, KRAS codons 61/146 mutations determined a lower response rate (0 vs 37%, P=0.047) and worse PFS (HR: 0.45, P=0.023). Patients bearing KRAS or BRAF mutations had poorer response rate (0 vs 37%, P=0.0005) and PFS (HR: 0.51, P=0.006) compared with KRAS and BRAF wild-type patients.Conclusion:Assessing KRAS codons 61/146 and BRAF V600E mutations might help optimising the selection of the candidate patients to receive anti-EGFR moAbs.

PTEN Expression and KRAS Mutations on Primary Tumors and Metastases in the Prediction of Benefit From Cetuximab Plus Irinotecan for Patients With Metastatic Colorectal Cancer

PURPOSE PTEN, AKT, and KRAS are epidermal growth factor receptor (EGFR) downstream regulators. KRAS mutations confer resistance to cetuximab. This retrospective study investigated the role of PTEN loss, AKT phosphorylation, and KRAS mutations on the activity of cetuximab plus irinotecan in patients with metastatic colorectal cancer (mCRC). PATIENTS AND METHODS A cohort of patients with irinotecan-refractory mCRC who were treated with cetuximab plus irinotecan was tested for PTEN immunoreactivity (ie, immunohistochemistry; IHC), pAKT IHC, and KRAS mutations. Analyses were performed both on primary tumors and on related metastases, and the association among IHC, mutational results, and treatment outcomes was investigated. RESULTS One-hundred two patients were eligible. Ninety-six primary tumors, 59 metastases, and 53 paired samples were available. Forty-nine primary tumors (58% of assessable samples) had a preserved PTEN expression (PTEN-positive), whereas 35 (40% of assessable samples) were pAKT-positive. Levels of concordance between primary tumors and metastases were 60%, 68%, and 95% for PTEN, pAKT, and KRAS, respectively. PTEN status on primary tumors and pAKT status both on primary tumors and on metastases did not predict response or progression-free survival (PFS). On metastases, 12 (36%) of 33 patients with PTEN-positive tumors were responders compared with one (5%) of 22 who had PTEN-negative tumors (P = .007). The median PFS of patients with PTEN-positive metastases was 4.7 months compared with 3.3 months for those with PTEN-negative metastases (hazard ratio [HR], 0.49; P = .005). Patients with PTEN-positive metastases and KRAS wild type had longer PFS compared with other patients (5.5 months v 3.8 months; HR, 0.42; P = .001). CONCLUSION PTEN loss in metastases may be predictive of resistance to cetuximab plus irinotecan. The combination of PTEN IHC and KRAS mutational analyses could help to identify a subgroup of patients with mCRC who have higher chances of benefiting from EGFR inhibition.

Initial Therapy with FOLFOXIRI and Bevacizumab for Metastatic Colorectal Cancer

BACKGROUND A fluoropyrimidine plus irinotecan or oxaliplatin, combined with bevacizumab (a monoclonal antibody against vascular endothelial growth factor), is standard first-line treatment for metastatic colorectal cancer. Before the introduction of bevacizumab, chemotherapy with fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) showed superior efficacy as compared with fluorouracil, leucovorin, and irinotecan (FOLFIRI). In a phase 2 study, FOLFOXIRI plus bevacizumab showed promising activity and an acceptable rate of adverse effects. METHODS We randomly assigned 508 patients with untreated metastatic colorectal cancer to receive either FOLFIRI plus bevacizumab (control group) or FOLFOXIRI plus bevacizumab (experimental group). Up to 12 cycles of treatment were administered, followed by fluorouracil plus bevacizumab until disease progression. The primary end point was progression-free survival. RESULTS The median progression-free survival was 12.1 months in the experimental group, as compared with 9.7 months in the control group (hazard ratio for progression, 0.75; 95% confidence interval [CI], 0.62 to 0.90; P=0.003). The objective response rate was 65% in the experimental group and 53% in the control group (P=0.006). Overall survival was longer, but not significantly so, in the experimental group (31.0 vs. 25.8 months; hazard ratio for death, 0.79; 95% CI, 0.63 to 1.00; P=0.054). The incidences of grade 3 or 4 neurotoxicity, stomatitis, diarrhea, and neutropenia were significantly higher in the experimental group. CONCLUSIONS FOLFOXIRI plus bevacizumab, as compared with FOLFIRI plus bevacizumab, improved the outcome in patients with metastatic colorectal cancer and increased the incidence of some adverse events. (Funded by the Gruppo Oncologico Nord Ovest and others; ClinicalTrials.gov number, NCT00719797.).

Pharmacogenetic Profiling in Patients With Advanced Colorectal Cancer Treated With First-Line FOLFOX-4 Chemotherapy

PURPOSE The objective is to investigate whether polymorphisms with putative influence on fluorouracil/oxaliplatin activity are associated with clinical outcomes of patients with advanced colorectal cancer treated with first-line oxaliplatin, folinic acid, and fluorouracil palliative chemotherapy. MATERIALS AND METHODS Consecutive patients were prospectively enrolled onto medical oncology units in Central Italy. Patients were required to have cytologically/histologically confirmed metastatic disease with at least one measurable lesion. Peripheral blood samples were used for genotyping 12 polymorphisms in thymidylate synthase, methylenetetrahydrofolate reductase, xeroderma pigmentosum group D (XPD), excision repair cross complementing group 1 (ERCC1), x-ray cross complementing group 1, x-ray cross complementing protein 3, glutathione S-transferases (GSTs) genes. The primary end point of the study was to investigate the association between genotypes and progression-free survival (PFS). RESULTS In 166 patients, ERCC1-118 T/T, XPD-751 A/C, and XPD-751 C/C genotypes were independently associated with adverse PFS. The presence of two risk genotypes (ERCC1-118 T/T combined with either XPD-751 A/C or XPD-751 C/C) occurred in 50 patients (31%). This profiling showed an independent role for unfavorable PFS with a hazard ratio of 2.84% and 95% CI of 1.47 to 5.45 (P = .002). Neurotoxicity was significantly associated with GSTP1-105 A/G. Carriers of the GSTP1-105 G/G genotype were more prone to suffer from grade 3 neurotoxicity than carriers of GSTP1-105 A/G and GSTP1-105 A/A genotypes. CONCLUSION A pharmacogenetic approach may be an innovative strategy for optimizing palliative chemotherapy in patients with advanced colorectal cancer. These findings deserve confirmation in additional prospective studies.

High concordance of KRAS status between primary colorectal tumors and related metastatic sites: implications for clinical practice.

PURPOSE Several studies have suggested that KRAS somatic mutations may predict resistance to cetuximab- and panitumumab-based treatments in metastatic colorectal cancer (CRC) patients. Nevertheless, most experiences were conducted on samples from primaries. The aim of this study was to evaluate the grade of concordance in terms of KRAS status between primaries and related metastases. PATIENTS AND METHODS We analyzed KRAS codon 12 and 13 mutations from formalin-fixed sections of 107 CRC primaries and related metastases. Eight pairs were excluded from the analysis because of the low amount of tumor tissue in the available samples. The main characteristics were: 50 men, 49 women; median age at diagnosis, 71 years (range, 41-84). The metastatic sites analyzed were the liver in 80 patients (80.8%), lung in seven patients (7.1%), and other sites in 12 patients (12.1%). RESULTS A KRAS mutation was found in 38 (38.4%) primary tumors and in 36 (36.4%) related metastases. The rate of concordance was 96.0% (95% confidence interval, 90.0%-98.9%). Discordance was observed in only four (4%) patients. CONCLUSIONS Our results indicate that the detection of KRAS mutations in either primary or metastatic tumors from patients with CRC is concordant and this assessment could be used to predict response to targeted therapies such as cetuximab and panitumumab.

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.

Treatment with 5-Fluorouracil/Folinic Acid, Oxaliplatin, and Irinotecan Enables Surgical Resection of Metastases in Patients With Initially Unresectable Metastatic Colorectal Cancer

BackgroundThe prognosis of unresectable metastatic colorectal cancer might be improved if a radical surgical resection of metastases could be performed after a response to chemotherapy.MethodsWe treated 74 patients with unresectable metastatic colorectal cancer (not selected for a neoadjuvant approach) with irinotecan, oxaliplatin, and 5-fluorouracil/leucovorin (FOLFOXIRI and simplified FOLFOXIRI). Because of the high activity of these regimens (response rate, 72%), a secondary curative operation could be performed in 19 patients (26%).ResultsFour patients underwent an extended hepatectomy, nine patients underwent a right hepatectomy, three patients underwent a left hepatectomy, and three patients had a segmental resection. In five patients, surgical removal of extrahepatic disease was also performed. In seven patients, surgical resection was combined with intraoperative radiofrequency ablation. The median overall survival of the 19 patients who underwent operation is 36.8 months, and the 4-year survival rate is 37%. The median overall survival of the 34 patients who were responsive to chemotherapy, but who did not undergo operation, is 22.2 months (P = .0114).ConclusionsThe FOLFOXIRI regimens we studied have significant antitumor activity and allow a radical surgical resection of metastases in patients with initially unresectable metastatic colorectal cancer not selected for a neoadjuvant approach and also those with extrahepatic disease. The median survival of patients with resected disease is promising.

Biweekly Chemotherapy With Oxaliplatin, Irinotecan, Infusional Fluorouracil, and Leucovorin: A Pilot Study in Patients With Metastatic Colorectal Cancer

PURPOSE To determine the feasibility, recommended doses, plasma pharmacokinetics, and antitumor activity of a biweekly chemotherapy regimen with oxaliplatin (L-OHP), irinotecan (CPT-11), infusional fluorouracil (5-FU), and leucovorin (LV) in metastatic colorectal cancer patients. PATIENTS AND METHODS Patients received CPT-11 followed by L-OHP and LV 200 mg/m(2) and followed by 5-FU 3,800 mg/m(2) as a 48-hour infusion, repeated every 2 weeks. In the first part of the study, an escalation of CPT-11 dose and/or a decrease of the L-OHP dose were planned. Once the recommended doses of CPT-11 and L-OHP were determined, all subsequent patients were treated at the recommended doses. RESULTS Forty-two patients entered the study. CPT-11 175 mg/m(2) and L-OHP 100 mg/m(2) in combination with LV 200 mg/m(2) and 5-FU 3,800 mg/m(2) could be administered with acceptable toxicities; 39 patients were treated at these dose levels. The pharmacokinetics parameters of the agents used and their metabolites did not seem to be influenced by the concomitant use of the other drugs. The most relevant toxicities were diarrhea and neutropenia, with 14% of patients experiencing one episode of febrile neutropenia. In five patients (11.9%) a complete and in 25 (59.5%) a partial response was demonstrated, for an objective response rate of 71.4% (95% confidence interval, 47% to 83%). In 11 patients (26%), a surgical resection of residual disease could be performed. Median progression-free and overall survival times were 10.4 and 26.5 months, respectively. CONCLUSION This biweekly regimen is feasible and has acceptable and manageable toxicities and no apparent relevant pharmacokinetics interactions. This combination is associated with a promising antitumor activity, time to progression, and survival. A phase III randomized trial in Italy planned by the Gruppo Oncologico Nord Ovest has just started.