FOLFOXIRI (irinotecan, oxaliplatin, and infusional 5FU/LV) in combination with bevacizumab (BV) in the first-line treatment of metastatic colorectal cancer (mCRC): A phase II study by the G.O.N.O. group
Alfredo FalconeGianluca MasiFotios LoupakisEnrico VasileA. CiarloD. CavaciocchiD. AmorosoM. PuglisiElena FeaI. Brunetti
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4031Keywords:
First line treatment
FOLFIRI
4038 Background: The most commonly used treatment methods for metastatic colorectal cancer (mCRC)are systemic chemotherapy, molecular targeted therapy and local treatment. The main chemotherapy drugs for mCRC include Irinotecan, Oxaliplatin and 5-Fu. V308 Research shows that FOLFOX and FOLFIRI can be standard first or second-line of each other in the treatment of metastatic colorectal cancer. However if the first-line treatment regimen containing 5-FU fails, whether it is necessary to re-challenge 5-FU when Irinotecan is applied in the second line is unknown. There is no head-to-head comparative study to answer whether the FOLFIRI regimen is better than the Irinotecan monodrug. Therefore, it is necessary to carry out a comparative study of FOLFIRI Versus Irinotecan monodrug to observe whether adding 5-Fu on the basis of Irinotecan can improve the therapeutic effect. Methods: This was a randomized phase III trial. Patients from 5 centers in China with metastatic colorectal adenocarcinoma, for whom first-line of chemotherapy including oxaliplatin combined with fluorouracil drugs (combined or not combined with targeted therapy) had failed, were enrolled. 172 patients with mCRC were randomly treated with FOLFIRI or Irinotecan monodrug were included in this study. FOLFIRI group: Irinotecan 180mg/m 2 ; Lecovorin 400mg/m 2 ; 5-Fu 400mg/m 2 ; 5-Fu 2400mg/m 2 CIV 46h. Irinotecan monodrug group 180mg/m 2 , The regimen was repeated every 2 weeks. The primary endpoint is PFS, and this clinical trail is a superiority trial. Results: ITT (Intention-To-Treat) analysis: Among 172 patients, 10 had PR, 93 had SD, and 63 had PD, 6 patients have not received efficacy evaluation yet. The ORR was 5.68% VS. 5.95%, and the DCR was 61.36% and 54.76% in FOLFIRI group and Irinotecan monodrug group, respectively. Adverse reactions included neutropenia, stomatitis, diarrhea, fatigue, abnormal liver enzymes, pyrexia, arrhythmia, nausea and most of these were grade 1-2. The dose reduction rate induced by drug tocixity of was 13.64% and 7.14% in FOLFIRI group and Irinotecan monodrug group, respectively. Conclusions: These data show that Irinotecan monodrug has the similar ORR and DCR with FOLFIRI regimen in second-line treatment of mCRC. Irinotecan monodrug has lower adverse effect. Clinical trial information: NCT02935764 .
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FOLFIRI
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Irinotecan, in combination with 5-fluorouracil (5-FU) and a high dose of leucovorin (LV), known as FOLFIRI regimen, has shown activity in recurrent or metastatic colorectal cancer. Therefore, we evaluated the efficacy and safety of irinotecan, 5-FU and a low dose of LV (modified FOLFIRI) as a first line of therapy for patients with relapsed or metastatic colorectal cancer.Between January 2002 and October 2004, 44 patients with histologically confirmed recurrent or metastatic colorectal cancer were enrolled. The chemotherapy regimen schedule consisted of 180 mg/m2 of irinotecan being administered intravenously (i.v) on Day 1, 400 mg/m2 of 5-FU via i.v bolus with 600 mg/m2 of continuous infusion for 22 hrs on both Day 1 and 2, and 20 mg/m2 of leucovorin on both Day 1 and 2 , repeated every two weeks.The overall response rate was 47.8%. Of the 40 evaluated patients, one had CR (2.3%) and 20 had PR (46.5%). Toxicities were mild and easily manageable. Three patients experienced 23 episodes of Grade 3/4 leukopenia., Only one patient developed Grade 3/4 diarrhea. None experienced Grade 3/4 thrombocytopenia.Modified FOLFIRI with a low dose of LV is an effective and tolerable regimen for patients with recurrent or metastatic colorectal cancer.
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505 Background: Although Irinotecan prolongs survival, it causes severe diarrhea and neutropenia. Recent pharmacogenetic studies on irinotecan have revealed significant associations of UDP-glucuronosyltransferase 1A1 (UGT1A1) polymorphisms *28 and *6, the latter being specifically detected in East Asians resulting in severe toxicity. It is necessary that the dose-finding trial that decided the optimal dose according to the gene polymorphism to draw out the maximum therapeutic effect while evading the side effect. Previously, we showed UGT1A1 polymorphisms in Japanese patients (2011 ASCO-GI). Here, we present the interim report of prospective trial of the safety about FOLFIRI therapy according to each gene type of UGT1A1 for Japanese patients with advanced CRC. Methods: From 2008, 250 Japanese patients in TOKUSHIMA University were enrolled in this study. Homo group (*6/*6 and *28/*28 or a both hetero types), hetero group (It was *28 and either *6 was hetero type), and wild group (*28 and *6 were wild types) were defined. On the 30 patients with advanced CRC treated with FOLFIRI after standard chemotherapy, wild and homo groups were administered 150mg/m 2 irinotecan, and homo group was 100mg/m 2 . The incidences of severe toxicities in each gene type of UGT1A1 and the response rate in FOLFIRI therapy were investigated. Results: In Japanese people, UGT1A1*6 polymorphisms were higher than *28 (*6 homo 3%, hetero 27% vs *28 homo 0.5%, hetero 13%). On the 30 patients with advanced CRC treated with FOLFIRI, the genotypes of UGT1A1*28 were homozygous in 1 (3%) and heterozygous in 6 (20%), *6 were homozygous in 0 and heterozygous in 8 (27%). In *6 heterozygous patients, severe toxicities (grade 3 or more) were found (38%). In *28 heterozygous patients, 1 patient (17%) showed severe toxicities. There was no decrease of irinotecan doses in each group. The number of course to PD was 7.6 (1-23). Regarding the response rate, PR, SD, PD was observed in 2 (7%), 6 (20%) and 18 patients (60%), respectively. Conclusions: In our interim report, the dosages of irinotecan based on UGT1A1 polymorphisms are safety in FOLFIRI therapy.
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Although several evidences have demonstrated a synergistic activity of 5-fluorouracil with irinotecan and oxaliplatin, thus explaining the use of this drug combination in the first-line treatment of advanced colorectal cancer, the need for the reintroduction of 5-FU in the second-line setting is more questionable.We retrospectively evaluated the outcome of patients developing progressive disease while on an infusional 5-FU-based front-line chemotherapy and subsequently treated with one of the four following chemotherapy regimens: irinotecan, oxaliplatin and irinotecan or oxaliplatin both combined with the de Gramont schedule (LV5-FU2).225 patients (137 males and 88 females), were eligible for analysis. Second-line chemotherapy consisted of irinotecan in 79 patients (35%, group A), oxaliplatin in 47 patients (21%, group B), irinotecan with LV5-FU2 in 53 patients (24%, group C) and oxaliplatin with LV5-FU2 in the remaining 46 cases (20%, group D). The response rate to second-line chemotherapy was obtained in 6/79 patients (8%) in group A, in 4/47 patients (9%) in group B, in 11/53 patients (21%) in group C and in 10/46 patients (22%) in group D (p = 0.04).These data suggest that reintroduction of 5-FU could increase irinotecan and oxaliplatin activity in patients progressing during a 5-FU-based first-line chemotherapy.
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Purpose:To investigate the efficacy of combined chemotherapy based on Oxaliplatin(OXA),Irinotecan(CPT-11)and fluorouracil(5-Fu),for treatment of relapse and metastatic colorectal cancer and its side-effects. Methods:25 cases of relapse and metastatic colorectal cancer by interventional arterial chemotherapy and iv drip,based on Oxaliplatin,Irinotecan and 5-Fu,CF,then after 2 cycles of treatment,the efficacy and clinical symptoms were evaluated. Results:After treatment,the terventional arterial group 1/15 achieved CR,9/15 achieved PR,the response rate was 66.7%. In the iv drip group 4/10 achieved PR,response rate was 40.0%,there was no significant difference between the two groups(P0.05),the overall response rate was 56.0% .Symptoms(18/25) related to cancer improved and side-reactions were tolerable. Conclusions:Treatment of relapse and metastatic colorectal cancer with combined chemotherapy based on oxaliplatin,irinotecan and 5-Fu by arterial intervention and iv drip is safe and effective,with only slight side-effects. This treatment can improve the symptoms and life quality of patients.
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Purpose: Five-fluorouracil (5-FU) is the basement drug of chemotherapy in patients with colorectal cancer. Recently, 5-FU and oxaliplatin or irinotecan is to be used by merging. This study investigated the chemosensitivity of 5-FU in patients with colorectal cancer, the additional effects of oxaliplatin or irinotecan to chemosensitivity when they are combined, and the effects of clinicopathologic factors to chemosensitivity. Methods: We performed in vitro chemosensitivity test for the fresh tumor tissue of 48 patients of colorectal cancer and evaluated the chemosensitivity to standard drugs (5-FU, 5-FU plus oxaliplatin: FOx, and 5-FU plus irinotecan: FIri) by using Histoculture drug response assay. Results: The average chemosensitiviy of FOx and FIri were significantly higher than that of 5-FU (32.3% and 36.0% vs. 21.8%, P<0.001). The chemosensitivity of FOx in the lymph node (LN) negative group was higher than LN positive group (35.3% vs. 19.3%, P=0.008). The group of under 70-year-old and the group of negative distant metastasis showed the trends of increased sensitivity to FOx (P=0.052, respectively). The chemosensitivity to FIri in the well or moderately differentiated group was significantly higher than the poorly differentiated goup (35.2% vs. 15.0%, P=0.038). Ki-67 positive group showed significantly increased chemosensitivity to FIri (P=0.021). Conclusion: This study demonstrates that combination of oxaliplatin or irinotecan to 5-FU can be more effective than 5-FU on in vitro chemosensitivity assay in colorectal cancer tissues. Oxaliplatin might be effective in LN negative group, and irinotecan might be effective in well differentiated group and Ki-67 positive group. Keywords: Anticancer drug sensitivity tests, Colorectal neoplasm, Fluorouracil, Oxaliplatin, Irinotecan
Chemosensitivity assay
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