Gianluca Masi

Bio: Gianluca Masi is an academic researcher from University of Pisa. The author has contributed to research in topics: Colorectal cancer & FOLFOXIRI. The author has an hindex of 44, co-authored 262 publications receiving 10681 citations.

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

Abstract: Purpose The Gruppo Oncologico Nord Ovest (GONO) conducted a phase III study comparing fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI [irinotecan 165 mg/m 2 day 1, oxaliplatin 85 mg/m 2 day 1, leucovorin 200 mg/m 2 day 1, fluorouracil 3,200 mg/m 2 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. J Clin Oncol 25:1670-1676. © 2007 by American Society of Clinical Oncology

Initial Therapy with FOLFOXIRI and Bevacizumab for Metastatic Colorectal Cancer

Abstract: BackgroundA 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. MethodsWe 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. ResultsThe median progression-free survival was 12.1 months in the experimental group, as compared...

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

Abstract: RAS and RAF proteins play a key role in the control of cellular growth, proliferation and differentiation (Bos, 1989; Wickenden et al, 2008) KRAS-activating mutations reduce or abolish intrinsic GTPase activity of the protein, leading to its constitutive activation (Conlin et al, 2005) Similarly BRAF V600E mutation induces structural changes in RAF protein which increase its kinase activity (Wan et al, 2004) Activated RAS and RAF are responsible for the disregulation of RAS/RAF/MAPKs signalling pathway. KRAS codons 12 and 13 activating mutations are widely recognised as predictors of resistance to the treatment with anti-EGFR monoclonal antibodies (moAbs) in metastatic colorectal cancer (mCRC) patients (Karapetis et al, 2008; Amado et al, 2008). Based on retrospectively collected data and post hoc analyses of large phase III studies, the European Medicines Agency has restricted the use of cetuximab to the treatment of patients with KRAS codons 12 and 13 wild-type disease (about the 60% of the overall population; EMEA, 2008) and the American Society of Clinical Oncology has similarly recommended in a recent provisional clinic opinion not to administer anti-EGFR moAbs to patients with KRAS codons 12 or 13 mutated tumours (Allegra et al, 2009). Nevertheless, in a systematic review and meta-analysis, Linardou et al reported a very high specificity (0.93, (0.83–0.97)) and a much lower sensitivity (0.47, (0.43–0.52)) of KRAS analysis in predicting resistance to anti-EGFR moAbs in mCRC, thus underlining the need for additional predictive markers to be combined with KRAS codons 12 and 13 evaluation, for a more accurate patients' selection (Linardou et al, 2008). A recently published experience found a correlation between BRAF V600E-activating mutation, mutually exclusive with KRAS ones, and resistance to the treatment with cetuximab and panitumumab administered alone or in combination with chemotherapy (Di Nicolantonio et al, 2008). On the basis of the above-mentioned evidences, around 50% of candidate patients would be excluded from receiving anti-EGFR moAbs, with a significant improvement of the treatment's cost effectiveness. However, as cetuximab or panitumumab monotherapies determine a response rate of about 10% regardless of the line of treatment and no more than 23% of patients respond to the combination of cetuximab and irinotecan (Cunningham et al, 2004; Van Cutsem et al, 2007; Jonker et al, 2007) it is plausible that the selection of candidate patients to receive an anti-EGFR moAb might be further slightly refined. Additional KRAS-activating mutations, involving codons 61 and 146 (Edkins et al, 2006) occur with frequencies ranging from 1 to 4% in CRCs. These relatively rare mutations, as well as codons 12 and 13 mutations, are responsible for the oncogenic constitutive activation (Buhrman et al, 2007; Feig and Cooper, 1988) of RAS/RAF/MAPKs pathway and they might account for up to a 10% of resistant patients bearing KRAS codons 12 and 13 and BRAF wild-type tumours. To optimise the selection of patients who are more likely to benefit from anti-EGFR we investigated in a cohort of patients treated with the combination of cetuximab and irinotecan and bearing KRAS codons 12 and 13 wild-type tumours, the association of KRAS codons 61 and 146 mutations and BRAF V600E mutation with clinical outcomes.

KRAS codon 61, 146 and BRAF V600E mutations predict resistance to cetuximab plus irinotecan in KRAS codon 12 and 13 wild-type metastatic colorectal cancer

Abstract: 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.

Detection of Circulating Tumor DNA in Early- and Late-Stage Human Malignancies

Abstract: The development of noninvasive methods to detect and monitor tumors continues to be a major challenge in oncology. We used digital polymerase chain reaction-based technologies to evaluate the ability of circulating tumor DNA (ctDNA) to detect tumors in 640 patients with various cancer types. We found that ctDNA was detectable in >75% of patients with advanced pancreatic, ovarian, colorectal, bladder, gastroesophageal, breast, melanoma, hepatocellular, and head and neck cancers, but in less than 50% of primary brain, renal, prostate, or thyroid cancers. In patients with localized tumors, ctDNA was detected in 73, 57, 48, and 50% of patients with colorectal cancer, gastroesophageal cancer, pancreatic cancer, and breast adenocarcinoma, respectively. ctDNA was often present in patients without detectable circulating tumor cells, suggesting that these two biomarkers are distinct entities. In a separate panel of 206 patients with metastatic colorectal cancers, we showed that the sensitivity of ctDNA for detection of clinically relevant KRAS gene mutations was 87.2% and its specificity was 99.2%. Finally, we assessed whether ctDNA could provide clues into the mechanisms underlying resistance to epidermal growth factor receptor blockade in 24 patients who objectively responded to therapy but subsequently relapsed. Twenty-three (96%) of these patients developed one or more mutations in genes involved in the mitogen-activated protein kinase pathway. Together, these data suggest that ctDNA is a broadly applicable, sensitive, and specific biomarker that can be used for a variety of clinical and research purposes in patients with multiple different types of cancer.

Multiple Imputation for Nonresponse in Surveys

Abstract: 25. Multiple Imputation for Nonresponse in Surveys. By D. B. Rubin. ISBN 0 471 08705 X. Wiley, Chichester, 1987. 258 pp. £30.25.