scholarly journals Plasma deoxyuridine as a surrogate marker for toxicity and early clinical response in patients with metastatic colorectal cancer after 5-FU-based therapy in combination with arfolitixorin

2020 ◽  
Author(s):  
Helena Taflin ◽  
Elisabeth Odin ◽  
Göran Carlsson ◽  
Roger Tell ◽  
Bengt Gustavsson ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Clinical Response ◽  
Plasma Concentrations ◽  
Haematological Toxicity ◽  
Surrogate Marker ◽  
Explanatory Variables ◽  
Gender And Age ◽  
Toxicity Scores ◽  
Dose Levels

Abstract Purpose The aim was to explore the correlation between increasing doses of [6R]-5,10-methylenetetrahydrofolate (arfolitixorin) and plasma concentrations of deoxyuridine (dUr) in patients with metastatic colorectal cancer (mCRC), subjected to 5-fluorouracil (5-FU)-based chemotherapy. The aim was further to investigate the possibility to predict toxicity and clinical response during treatment using gender, age, and plasma dUr as explanatory variables. Methods Thirty-three patients from the ISO-CC-005 phase I/IIa study, which investigated safety and tolerability of arfolitixorin at four dose levels, were included. Toxicity and clinical response were evaluated after 4 cycles of chemotherapy. Plasma dUr was quantified before (0 h) and 24 h after 5-FU administration at the first (C1) and fourth (C4) cycle using LC–MS/MS. Fit modelling was used to predict toxicity and clinical response. Results The dUr levels increased with increasing arfolitixorin dose. Females had higher total and haematological toxicity scores (p = 0.0004 and 0.0089, respectively), and needed dose reduction more often than males (p = 0.012). Fit modeling showed that gender and the dUr levels at C1-0 h and C4-24 h predicted total toxicity (p = 0.0011), whereas dUr C4-0 h alone was associated with gastrointestinal toxicity (p = 0.026). Haematological toxicity was predicted by gender and age (p = 0.0071). The haematological toxicity score in combination with the dUr levels at C1-24 h and C4-24 h predicted early clinical response (p = 0.018). Conclusion The dUr level before and during administration of 5-FU and arfolitixorin was predictive for toxicity and early clinical response and could be a potential surrogate marker for thymidylate synthase inhibition in patients with mCRC. Trial registration NCT02244632, first posted on ClinicalTrials.gov on September 19, 2014

Safety, efficacy, and time to clinical response with bevacizumab plus FOLFIRI regimen in metastatic colorectal cancer

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e15138-e15138
Author(s):  
S. Tomao ◽  
G. Spinelli ◽  
L. Rossi ◽  
G. Pasciuti ◽  
G. Arcangeli ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Clinical Response ◽  
Median Time ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Clinical Activity ◽  
Efficacy And Safety ◽  
First Line ◽  
Ecog Ps

e15138 Background: Bevacizumab (BEV) has shown clinical activity in metastatic colorectal cancer patients (mCRC)and randomised phase III trials have demonstrated that this agent significantly improves overall and/or progression-free survival when added to first-line irinotecan based chemotherapy (CT) regimens. We evaluated the efficacy and safety of BEV plus FOLFIRI (irinotecan, 5- fluorouracil, and leucovorin) as first line treatment in 27 consecutive metastatic colorectal cancer cases, with the primary end point to calculate the median time to clinical response with this chemotherapeutic schedule. Methods: Between October 2007 and January 2008 we collected the data on 27 patients with mCRC treated with first line chemotherapy with BEV plus FOLFIRI. Elegibility criteria had to be: mCRC; no prior CT for metastatic disease; ECOG PS 0/1, adequate organ function; no CNS metastases. The treatment consisted of a minimum of six cycles of irinotecan plus infusional 5-FU/LV according to the classical FOLFIRI schedule; BEV (5mg/kg) was given on day 1 with CT and then every 2 weeks until disease progression. Safety and response were assessed at the time of first CT and every 4 weeks thereafter. Results: 27 pts were evaluable (male 18; median age 61 years (range 45–77), ECOG PS 0: 52%, PS 1: 48%. The sites of metastases were: liver (15 pts), lung (5 pts), liver and lung (5 pts), peritoneal wall (2 pts).Median follow-up was 18 weeks. Two patients had complete response(CR) and 13 pts partial response (PR), with an overall response rate of 57.7%. Five patients had stable disease and 6 patients showed progressive disease. A clinical benefit was demonstrated in 77 % of pts. We observed a median time to clinical response of 11 weeks, evaluated with tumor markers and with CT/NMR/US examinations. A grade 3 or 4 neutropenia was detected in 39% of pts and grade 2 or 3 hypertension in 9%. We did’nt observe cases of thrombosis, bleeding and gastrointestinal perforation, sometimes related to the use of BEV. Conclusions: In this little experience the efficacy and safety of BEV associated with FOLFIRI schedule, a first line therapy in mCRC,is consistent with results from other previous studies, showing moreover a short time to clinical response with this association. No significant financial relationships to disclose.

A triplet combination with irinotecan, oxaliplatin, continuous infusion 5-fluorouracil and leucovorin (FOLFOXIRI) plus cetuximab as first-line treatment in RAS wild-type, metastatic colorectal cancer: A phase 1 dose finding study.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 856-856 ◽  
Author(s):  
Shigenori Kadowaki ◽  
Toshiki Masuishi ◽  
Takashi Ura ◽  
Seiichiro Mitani ◽  
Yukiya Narita ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Continuous Infusion ◽  
Response Rate ◽  
Group Performance ◽  
Phase 1 ◽  
Eastern Cooperative Oncology Group ◽  
Fixed Dose ◽  
Wild Type ◽  
Dose Levels

856 Background: The FOLFOXIRI regimen (irinotecan, oxaliplatin, 5-fluorouracil and leucovorin) improves the response rate and overall survival compared to FOLFIRI in pts with metastatic colorectal cancer (mCRC), and addition of cetuximab to chemotherapy increases efficacy in pts with RAS wild-type mCRC. We conducted a phase 1 study of FOLFOXIRI plus cetuximab to determine the maximum-tolerated dose (MTD) and recommended dose (RD) and to assess its safety and efficacy in Japanese pts with RAS wild-type mCRC. Methods: Main eligibility criteria were: histologically confirmed colorectal adenocarcinoma; KRAS and NRAS wild-type status; measurable metastatic disease according to Response Evaluation Criteria in Solid Tumors version 1.1; age 20-74 years; Eastern Cooperative Oncology Group performance status 0 or 1. Pts with UDP-glucuronosyltransferase 1A1*6/*6, *28/*28 and *6/*28 genotypes were excluded. Pts received an escalating dose of intravenous irinotecan (100, 120, and 150 mg/m2 in the dose levels 0, 1, and 2, respectively) and a fixed dose of intravenous oxaliplatin (85 mg/m2), continuous infusion 5-fluorouracil (2400 mg/m2) plus l-leucovorin (200 mg/m2), and cetuximab (an initial dose of 400 mg/m2 followed by 250 mg/m2 per week). Results: A total of 9 Japanese pts were treated (3 and 9 in the dose levels 1 and 2, respectively). No patients experienced a dose-limiting toxicity (the MTD was not reached), and the dose level 2 (irinotecan 150 mg/m2) was established as the RD. With a median 8 cycles per patient, the most common grade 3 or 4 adverse events included neutropenia (44%), paronychia (22%), and acne-like rash (11%). No febrile neutropenia and treatment-related death were observed. Among 9 pts, 1 pt had complete response, 7 pts had partial response, and 1 pt had progressive disease, for an overall response rate of 89%. As of September 24, 2017, median progression free survival was 14.0 (95% CI 7.2-20.7) months. Conclusions: The combination of cetuximab and FOLFOXIRI has shown a favorable toxicity profile and promising antitumor activity in pts with RAS wild-type mCRC. Clinical trial information: UMIN000018217.

scholarly journals Circulating tumor cells as a surrogate marker for determining response to chemotherapy in Japanese patients with metastatic colorectal cancer

2011 ◽  
Vol 102 (6) ◽  
pp. 1188-1192 ◽  
Author(s):  
Satoshi Matsusaka ◽  
Mitsukuni Suenaga ◽  
Yuji Mishima ◽  
Ryoko Kuniyoshi ◽  
Koichi Takagi ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Surrogate Marker ◽  
Japanese Patients ◽  
Response To Chemotherapy

scholarly journals Clinical Response to Sorafenib in a Patient with Metastatic Colorectal Cancer and FLT3 Amplification

2015 ◽  
Vol 8 (1) ◽  
pp. 83-87 ◽  
Author(s):  
Raphael Brandão Moreira ◽  
Renata D''Alpino Peixoto ◽  
Marcelo Rocha de Sousa Cruz
Keyword(s):  
Colorectal Cancer ◽  
Targeted Therapy ◽  
Metastatic Colorectal Cancer ◽  
Clinical Response ◽  
Performance Status ◽  
Colorectal Tumor ◽  
Sorafenib Treatment ◽  
Flt3 Mutation ◽  
Number Of Patients

Background: A considerable number of patients with metastatic colorectal cancer progress after exhausting all approved standard therapies but maintain an adequate performance status and could be candidates for further treatment. We aim at reviewing our experience with sorafenib treatment of a patient with FLT3 mutation in refractory metastatic colorectal cancer. Methods: Treatment with sorafenib of a patient with metastatic colorectal cancer and FLT3 translocation who had previously been heavily treated. Results: The patient with metastatic colorectal cancer, aged 51 years, showed significant symptomatic and laboratory improvement with sorafenib treatment (400 mg twice daily). Conclusion: The presented case illustrates how an aggressive and refractory colorectal tumor may respond well to targeted therapy.

Panitumumab as a single agent in 269 metastatic colorectal cancer patients in the real practice: A post EMA approval study.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e14148-e14148
Author(s):  
Francoise Grude ◽  
Jean François Ramée ◽  
Laurent Guivarch ◽  
Sophie Rochard ◽  
Olivier Dupuis ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Clinical Response ◽  
Median Duration ◽  
Primary Tumor ◽  
Real Life ◽  
Published Data ◽  
Health Politics ◽  
The Real ◽  
End Of Treatment

e14148 Background: Metastatic colorectal cancer (mCRC) management has been improved by targeted therapies. The evaluation of the use of panitumumab (PANI), after approval, in the real life is strategic to assess health politics. Clinical trials concern usually patients younger and with better health status. Little is known about elderly people (over 70 years old). The observatory of Cancer Bretagne - Pays de Loire is a network of private and public cancer centers. Methods: Patients with wild-type KRAS, EGFR-expressing, mCRC progressing after fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy , received PANI,6 mg/kg biweekly. Sex, age, primary tumor, line of treatment, toxicity, reason of discontinuation, response, progression free survival (PFS) and overall survival (OS) were collected. Results: 269 patients (183 men and 86 women) treated between second half of 2008 and end of 2010 have been included. Median age: 67 years [36-90] (Amado et al, 2008 : 62.5 years [29-82]). Primary tumor was : colon (74%), rectum (24%) and double site (2%). PANI was used mostly at line 2 (19%), 3 (31%) or 4 (29%). Discontinuation of treatment was due to disease progression: 53%, death: 12% and toxicities: 5% (skin toxicities 3.5%). Clinical response was evaluated for the first 201 patients: partial response (PR): 20%, stable disease (SD): 19% and progression (P): 60% (Amado et al, 2008 PR : 17%, SD : 34%, P : 49%). Median duration of treatment was 2.3 months [0.26-17.52]. Median of OS was 6.71 months which is lower than previously described (Amado : 8.1 months). Median duration between end of treatment and death when death is the cause of end of treatment was 17 days [4-57] (n=24). From our data of 269 patients, a comparison between 123 patients over 70 and 146 patients under 69 will be shown at the meeting. Conclusions: Analysis of patients treated with PANI for a mCRC allows assessing the proper, per label use, in the real life. Complete results on clinical response, PFS, OS and safety as well as previously published data will be shown at the meeting.

Circulating tumor cells as a surrogate marker for determining response to chemotherapy in Japanese patients with metastatic colorectal cancer.

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 486-486 ◽  
Author(s):  
Satoshi Matsusaka ◽  
Mitsukuni Suenaga ◽  
Yuji Mishima ◽  
Yasuhito Terui ◽  
Eiji Shinozaki ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Surrogate Marker ◽  
Progression Free Survival ◽  
Japanese Patients ◽  
Rank Test ◽  
Treatment Benefit ◽  
Response To Chemotherapy

486 Background: The purpose of this study was to investigate the potential of circulating tumor cells (CTCs) as a surrogate marker of clinical outcome in metastatic colorectal cancer (mCRC) patients in order to identify Japanese patients responsive to oxaliplatin-based chemotherapy. Methods: The treatment regimen was oxaliplatin-based chemotherapy. Collection of CTCs from whole blood was performed at baseline and at 2 and 8-12 weeks after initiation of chemotherapy. Isolation and enumeration of CTCs was performed using immunomagnetics. Results: Between January 2007 and April 2008, 64 patients with mCRC were enrolled in this prospective study.Patients with ≥3 CTCs at baseline and at 2 and 8-12 weeks had a shorter median progression-free survival (8.5, 7.3, and 1.9 months, respectively) than those with <3 CTCs (9.7, 10.4 and 9.1 months, respectively) (log-rank test: p=0.047, p<0.001, and p<0.001, respectively). Patients with ≥3 CTCs at 2 and 8-12 weeks had a shorter median overall survival (10.2 and 4.1 months, respectively) than those with <3 CTCs (29.1 and 29.1 months, respectively) (p<0.001 and p=0.001, respectively). A spurious early rise in CEA level was observed in 11 patients showing a partial response. On the other hand, no rise in early CTC level was observed among responders. Conclusions: The clinical utility of CTC enumeration in improving our ability to accurately assess treatment benefit and in expediting the identification of effective treatment regimens for individual Japanese patients.

Biopsy-driven study to identify biomarkers predictive of clinical response to second-line regorafenib in patients with metastatic colorectal cancer.

2014 ◽  
Vol 32 (15_suppl) ◽  
pp. TPS3656-TPS3656
Author(s):  
Petr Kavan ◽  
Caroline Rousseau ◽  
Francine Aubin ◽  
Adrian Langleben ◽  
Adrian Gologan ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Clinical Response ◽  
Second Line

scholarly journals Genotype-Driven Phase I Study of Irinotecan Administered in Combination With Fluorouracil/Leucovorin in Patients With Metastatic Colorectal Cancer

2010 ◽  
Vol 28 (5) ◽  
pp. 866-871 ◽  
Author(s):  
Giuseppe Toffoli ◽  
Erika Cecchin ◽  
Giampiero Gasparini ◽  
Mario D'Andrea ◽  
Giuseppe Azzarello ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Maximum Tolerated Dose ◽  
Pharmacokinetic Data ◽  
Patients With Cancer ◽  
Starting Dose ◽  
Common Grade ◽  
Grade 3 ◽  
Dose Levels ◽  
Higher Doses

PurposeWe aimed to identify the maximum-tolerated dose (MTD) of irinotecan in patients with cancer with UGT1A1*1/*1 and *1/*28 genotypes. We hypothesize that the patients without the *28/*28 genotype tolerate higher doses of irinotecan.Patients and MethodsPatients undergoing first-line treatment for metastatic colorectal cancer (CRC) eligible for treatment with irinotecan plus infusional fluorouracil/leucovorin (FOLFIRI) were screened for the UGT1A1*28/*28 genotype and excluded from the study. Fifty-nine white patients with either the *1/*1 or the *1/*28 genotype were eligible for dose escalation of irinotecan. The starting dose of biweekly irinotecan was 215 mg/m2for both genotype groups, whereas the dose of infusional fluorouracil was fixed. Pharmacokinetic data of irinotecan and metabolites were also obtained.ResultsThe dose of irinotecan was escalated to 370 mg/m2in patients with the *1/*28 genotype and to 420 mg/m2in those with the *1/*1 genotype. Dose-limiting toxicities (DLTs) were observed in two of four of *1/*28 patients at 370 mg/m2and in two of three of *1/*1 patients at 420 mg/m2. No DLTs were observed in 10 *1/*28 patients at 310 mg/m2and in 10 *1/*1 patients at 370 mg/m2; hence these dose levels were the MTD for each genotype group. The most common grade 3 to 4 toxicities were neutropenia and diarrhea. The pharmacokinetics of irinotecan and SN-38 exhibit linear kinetics.ConclusionThe recommended dose of 180 mg/m2for irinotecan in FOLFIRI is considerably lower than the dose that can be tolerated when patients with the UGT1A1*28/*28 genotype are excluded. Prospective genotype-driven studies should test the efficacy of higher irinotecan doses in the FOLFIRI schedule.

scholarly journals Modified two‐dimensional response as surrogate marker of overall survival in patients with metastatic colorectal cancer

2016 ◽  
Vol 107 (10) ◽  
pp. 1492-1498 ◽  
Author(s):  
Goro Nakayama ◽  
Tsutomu Fujii ◽  
Kenta Murotani ◽  
Keisuke Uehara ◽  
Norifumi Hattori ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
Metastatic Colorectal Cancer ◽  
Surrogate Marker ◽  
Two Dimensional
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