Classification by a gene expression profile can help to select oxaliplatin- or irinotecan-based regimen for first-line treatment of metastatic colorectal cancer: Translational research of the TRICOLORE study
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE147571 | GEO | 2020/03/27
REPOSITORIES: GEO
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Project description:Oxaliplatin (OX) and irinotecan (IRI) are used as key drugs for the first-line treatment of metastatic colorectal cancer (mCRC). However, no biomarkers have been identified to decide which of the drugs is initially used. In this translational research (TR) of the TRICOLORE trial, the advanced colorectal cancer subtype (aCRCS) was analyzed as a potential biomarker for the selection of OX or IRI. We collected 335 (68.8%) formalin-fixed, paraffin-embedded (FFPE) primary tumor specimens from 487 patients registered in the TRICOLORE trial and performed direct sequencing and immunohistochemical staining of CRC-related genes, comprehensive gene-expression analysis, and genome-wide methylation analysis. The progression-free survival (PFS) of the IRI group was significantly better compared with the OX group in BRAF wild-type (WT), PTEN-positive, and aCRCS A1 patients. Among the molecular factors, aCRCS were only associated with the PFS of OX and IRI groups. The PFS of the IRI group was significantly better compared with the OX group in aCRCS A1 + B1 (hazard ratio [HR] = 0.58; 95% confidence interval [CI] = 0.41-0.82; P = .0023). In contrast, the OX group had better PFS compared with the IRI group in aCRCS B2, although this was not statistically significant (HR = 1.66; 95% CI = 0.94-2.96; P = .083). Nearly half of patients with mCRC (46.8%, aCRCS A1 + B1) respond well to IRI, while only about 18.5% (aCRCS B2) of patients with mCRC responded well to OX. In conclusion, the aCRCS might be a predictive factor for the clinical outcomes of OX-based and IRI-based therapies.
| S-EPMC8019218 | biostudies-literature
Project description:Classification by a gene expression profile can help to select oxaliplatin- or irinotecan-based regimen for first-line treatment of metastatic colorectal cancer: Translational research of the TRICOLORE study
| PRJNA615619 | ENA
Project description:Interventions: Step1: Confirmation of dosage of each drug (Oxaliplatin and Irinotecan)
i)Induction treatment
The following drugs will be administered in 3week/cycle for 6cycles (maximum 8cycle, if investigator required). With regard to determination of oxaliplatin (OX) and Irinotecan (IRI) dosage, initial 3patients (pts) will be enrolled of level0. After finishing initial enrollment, Steering committee (SC) will evaluate safety of 3pts at the time of starting of cycle2 and will decide whether the proceeding same level (add 3 pts) or other level (level+1 or level-0.5). Final decision of Recommended Dose (RD) of OX and IRI will be required 6pts of safety evaluation in same level and will be endorsed by SC and Independent Data monitoring committee (IDMC).
1) Each drug dosage of CAPOXIRI+Bevacizumab
Bevacizumab (BEV: 7.5 mg/kg, i.v., 90, 60, 30 min, Day 1)
Irinotecan (IRI: 130 mg/m2, i.v., 90 min, Day 1)
Oxaliplatin (OX: 200 mg/m2, i.v., 120 min, Day 1)
Capecitabine (CAP: 800 mg/m2 p.o., twice daily, 14 days consecutively)
2) OX and IRI dose level
Level +1: IRI: 200 mg/m2, OX:130mg/m2
Level 0: IRI: 200 mg/m2, OX:100mg/m2
Level -0.5: IRI: 180 mg/m2, OX:100mg/m2
Level -1: IRI: 150 mg/m2, OX:100mg/m2
ii)Maintenance treatment
After finishing the induction treatment, investigator will select 1) 5-FU/LV+BEV (2weeks cycle) or 2) CAP+BEV treatment (3weeks/cycle).
1)5-FU/LV+BEV treatment
The following drugs will be administered in 2week/cycle until meeting discontinuation criteria.
- Each drug dosage of 5-FU/LV+BEV -
Bevacizumab (BEV: 5.0 mg/kg, i.v., 90, 60, 30 min, Day 1)
Leucovorin (LV: 200 mg/m2, i.v., 120 min, Day 1)
5-FU (3200 mg/m2, c.i.v., 48 hours, Day 1-3)
2)CAP+BEV treatment
The following drugs will be administered in 2week/cycle until meeting discontinuation criteria.
- Each
Primary outcome(s): Progression-free survival (PFS)
Study Design: randomized controlled trial, open(masking not used), active control, parallel assignment, treatment purpose
| 2614949 | ecrin-mdr-crc
Project description:BackgroundFive-fluorouracil, folinic acid, oxaliplatin and irinotecan (FOLFOXIRI) regimen is used as the first-line treatment for metastatic colorectal cancer (mCRC). The use of capecitabine, an oral fluoropyrimidine pro-drug, is feasible and safe; hence, it provides an interesting alternative to 5-fluorouracil in the abovementioned regimen. This study aimed to evaluate the efficacy and safety of capecitabine, oxaliplatin, and irinotecan (XELOXIRI) regimen use with or without targeted drugs in Chinese patients with mCRC.MethodsWe conducted a retrospective, longitudinal cohort study of patients with mCRC who received XELOXIRI regimen with or without targeted drugs (bevacizumab or cetuximab) every 2 weeks between January 2017 and November 2019 at the National Cancer Center/Cancer Hospital, the Chinese Academy of Medical Sciences, and Peking Union Medical College. Treatment efficacy was assessed by investigators by evaluating the objective response rate (ORR) and disease control rate (DCR). Overall survival (OS) was assessed using Cox proportional hazards models. The adverse events were also analyzed.ResultsSixty-one consecutive patients were examined and followed up for survival. As of November 8, 2021, the median follow-up time was 35.4 months. Disease progression and death occurred in 50 (82%) and 38 (62%) patients, respectively. The median treatment duration of XELOXIRI with or without bevacizumab or cetuximab was 10 cycles (range, 1-12 cycles). The median OS and PFS were 32.2 months (95%CI [24.8-39.6]) and 9.3 months (95% CI [8.1-10.5]), respectively. The ORR of 48 patients with measurable lesions was 70.8%, and the DCR was 89.6%. RAS/BRAF wild-type (HR 0.39; 95% CI [0.16-0.96], p = 0.04) and metastatic organs > 2 (HR 3.25; 95% CI [1.34-7.87], p = 0.009) were independent prognostic factors for OS. The incidence of any grade of adverse events (AEs) was 96.7% (59/61). Grade ≥ 3 AEs included neutropenia (19.7%), leukopenia (9.8%), diarrhea (3.3%), vomiting (3.3%), febrile neutropenia (1.6%), and thrombocytopenia (1.6%). No treatment-related death occurred.ConclusionThe use of the XELOXIRI regimen with or without a targeted drug was effective, with a manageable toxicity profile in Chinese patients with mCRC.
| S-EPMC9306070 | biostudies-literature
Project description:The tolerance and efficacy of oxaliplatin and irinotecan for metastatic colorectal cancer are unknown in elderly patients. Methods. All consecutive patients over 74 years treated with oxaliplatin or irinotecan for metastatic colorectal cancer were enrolled. The tumour response was assessed every 2-3 months and toxicity was collected at each cycle according to World Health Organisation criteria. A total of 66 patients were enrolled from 12 centres. The median age was 78 years (range, 75-88 years); 39 patients had no severe comorbidity according to the Charlson score. In total, 44 and 22 patients received oxaliplatin or irinotecan, respectively, in combination with 5-fluororuracil+/-folinic acid or raltitrexed in 64 patients. A total of 545 chemotherapy cycles were administered in first (41%), second (51%) or third line (8%). A dose reduction occurred in 190 cycles (35%). Complete response, partial response and stabilisation occurred in 1.5, 20 and 47% of patients, respectively. The median time to progression and overall survival were 6.8 and 11.2 months in first line and 6.3 and 11.6 months in second line, respectively. Grade 3 and 4 toxicity occurred in 42% of patients: neutropenia 17%, diarrhoea 15%, neuropathy 11%, nausea and vomiting 8% and thrombopenia 6%. There was no treatment-related death. In selected elderly patients, chemotherapy with oxaliplatin or irinotecan is feasible with manageable toxicity.
| S-EPMC2394343 | biostudies-other
Project description:BackgroundLimited second-line therapeutic options are available for metastasis pancreatic cancer (mPC). We aimed to explore the efficacy and safety of oxaliplatin plus irinotecan (IROX) in mPC patients.MethodsThis is an open-label, Phase 2, randomized study of mPC patients (aged 18-75 years) who failed when using gemcitabine plus S-1 as first-line therapy. Block randomization with a block size of four was used to randomly assign patients (1:1) between October 2015 and December 2017 to receive either IROX (oxaliplatin 85 mg/m2 and irinotecan 160 mg/m2) or irinotecan monotherapy (irinotecan 180 mg/m2) until disease progression, unacceptable adverse events, or consent withdrawal. The primary end point was overall survival, and the secondary end points were progression-free survival, overall response rate, and adverse event rate.ResultsA total of 74 patients were enrolled in this study, including 44 males and 30 females, with an average age of 61 years. The median overall survival was 10.2 and 6.7 months (adjusted hazard ratio [HR], 0.7; 95% confidence interval [CI], 0.4-1.2; P = 0.20) and the median progression-free survival was 5.1 and 2.3 months (adjusted HR, 0.4; 95% CI, 0.2-0.6; P < 0.01) in the IROX group and irinotecan group, respectively. The overall response rates were 18.4% (7/38) in the IROX group and 5.5% (2/36) in the irinotecan group (P = 0.06). Grade 3-4 adverse events occurred in 34% (13/38) of patients in the IROX group and 19% (7/36) of patients in the irinotecan group (P = 0.15).ConclusionsIROX had no significant survival benefit over irinotecan monotherapy in our study. However, IROX reduced the risk of disease progression by 60%, with acceptable toxicity.
| S-EPMC9897170 | biostudies-literature
Project description:The care of metastatic colorectal cancers is based on combination chemotherapies including 5-fluorouracil, oxaliplatin, irinotecan, and monoclonal antibodies targeting the epidermal growth factor receptor or vascular endothelial growth factor. The regimen is determined based on the patient's molecular biology and general condition. Irinotecan bifractionation showed efficacy in chemorefractory patients in a previous study, FOLFIRI-3, but a desynchronized triplet has never been tested. The aim of bFOLFIRINOX-3 is to determine the safety, tolerance, and efficacy of a new regimen (FOLFIRINOX-3 bevacizumab) in chemorefractory patients. The aim of this study was to evaluate the safety and efficacy of FOLFIRINOX-3 bevacizumab in chemorefractory metastatic colorectal cancer (mCRC). A standard phase I, "3 + 3" design study was performed. The standard protocol comprised simplified FOLFOX 4 (folinic acid 400 mg/m2), 5-fluorouracil (a 400 mg/m2 bolus followed by 2400 mg/m2 for 46 h), oxaliplatin (85 mg/m2) and irinotecan (administered before and after 5-fluorouracil infusion), plus bevacizumab (5 mg/kg). In a "3 + 3" design, three different doses of irinotecan were tested: 60, 70 and 90 mg/m2. The primary endpoint was the maximum tolerable dose (MTD) of irinotecan. The secondary endpoints included the objective response (at 8 and 16 weeks) according to the RECIST 1.1 criteria and progression free survival. Thirteen patients were enrolled, and twelve patients were finally evaluated for dose-limiting toxicity (DLT). The dose level defined was 70 mg/m2 irinotecan. A total of three DLTs were observed (grade 3 diarrhea): two DLTs at the 90 mg/m2 dose level and one at the 70 mg/m2 dose level. The most frequently described adverse events were asthenia (93%), diarrhea (77%), nausea (62%) and peripheral sensory neuropathy (46%). The most frequent biological event was thrombopenia (54%). Regarding efficacy, among the 11 evaluable patients, no progression was observed at 8 weeks, and the partial response rate was 18.2%. At 16 weeks, a partial response rate of 27.3% was observed, and five patients had a stable disease. The new regimen of bFOLFIRINOX-3 with irinotecan at 70 mg/m2 was well tolerated. In chemorefractory patients, this protocol shows a high response rate.
| S-EPMC8582415 | biostudies-literature
Project description:A total of 41 metastatic colorectal cancer (CRC) patients received tegafur/uracil (UFT)+leucovorin (LV)+oxaliplatin alternated with UFT/LV+irinotecan. The overall response rate was 58.5% (95% confidence interval, 42.2-73.3%), and the median progression-free survival was 8.8 months. There were no grade 4 toxicities; 12 patients (29%) experienced grade 3 diarrhoea. There were no cases of hand-foot syndrome. This alternating regimen seems to be effective and well tolerated in the first-line treatment of patients with metastatic CRC.
| S-EPMC2409570 | biostudies-other
Project description:Environmental stability of perovskite solar cells (PSCs) has been improved by trial-and-error exploration of thin low-dimensional (LD) perovskite deposited on top of the perovskite absorber, called the capping layer. In this study, a machine-learning framework is presented to optimize this layer. We featurize 21 organic halide salts, apply them as capping layers onto methylammonium lead iodide (MAPbI3) films, age them under accelerated conditions, and determine features governing stability using supervised machine learning and Shapley values. We find that organic molecules' low number of hydrogen-bonding donors and small topological polar surface area correlate with increased MAPbI3 film stability. The top performing organic halide, phenyltriethylammonium iodide (PTEAI), successfully extends the MAPbI3 stability lifetime by 4 ± 2 times over bare MAPbI3 and 1.3 ± 0.3 times over state-of-the-art octylammonium bromide (OABr). Through characterization, we find that this capping layer stabilizes the photoactive layer by changing the surface chemistry and suppressing methylammonium loss.
| S-EPMC7441172 | biostudies-literature
Project description:AimsTriplet chemotherapy with fluoropyrimidines, oxaliplatin and irinotecan is a standard therapy for metastatic colorectal cancer (CRC). Single nucleotide polymorphisms (SNPs) in DPYD and UGT1A1 influence fluoropyrimdines and irinotecan adverse events (AEs). Low frequency DPYD variants (c.1905 + 1G > A, c.1679 T > G, c.2846A > T) are validated but more frequent ones (c.496A > G, c.1129-5923C > G and c.1896 T > C) are not. rs895819 T > C polymorphism in hsa-mir-27a is associated with reduced DPD activity. In this study, we evaluated the clinical usefulness of a pharmacogenetic panel for patients receiving triplet combinations.MethodsGermline DNA was available from 64 CRC patients enrolled between 2008 and 2013 in two phase II trials of capecitabine, oxaliplatin and irinotecan plus bevacizumab or cetuximab. SNPs were determined by Real-Time PCR. We evaluated the functional variants in DPYD (rare: c.1905 + 1G > A, c.1679 T > G, c.2846A > T; most common: c.496A > G, c.1129-5923C > G, c.1896 T > C), hsa-mir-27a (rs895819) and UGT1A1 (*28) genes to assess their association with grade 3-4 AEs.ResultsNone of the patients carried rare DPYD variants. We found DPYD c.496A > G, c.1129-5923C > G, c.1896 T > C in heterozygosity in 19%, 5% and 8%, respectively, homozygous rs895819 in hsa-mir-27a in 9% and homozygous UGT1A1*28 in 8%. Grade 3-4 AEs were observed in 36% patients and were associated with DPYD c.496A > G (odds ratio (OR) 4.93, 95% CI 1.29, 18.87; P = 0.021) and homozygous rs895819 in hsa-mir-27a (OR 11.11, 95% CI 1.21, 102.09; P = 0.020). Carriers of DPYD c.1896 T > C and homozygous UGT1A1*28 showed an OR of 8.42 (95% CI 0.88, 80.56; P = 0.052). Multivariate analysis confirmed an independent value for DPYD c.496A > G and c.1896 T > C.ConclusionsConcomitant assessment of DPYD variants and the UGT1A1*28 allele is a promising strategy needing further validation for dose personalization.
| S-EPMC4574842 | biostudies-literature