scholarly journals Oncological Outcomes of Patients with Peritoneal Metastasis–only Colorectal Cancer Treated with First-line Bevacizumab and FOLFIRI through Irinotecan Dose Escalation According to UGT1A1 Polymorphism: Compared to Liver Metastasis–only, and Lung Metastasis–only

2021 ◽  
Author(s):  
Ching-Chun Li ◽  
Tsung-Kun Chang ◽  
Yen-Cheng Chen ◽  
Hsiang-Lin Tsai ◽  
Ching-Wen Huang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Liver Metastasis ◽  
Lung Metastasis ◽  
Dose Escalation ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
First Line ◽  
Mutation Status ◽  
Therapy Regimen ◽  
Irinotecan Dose

Abstract Background:The prognosis of metastatic colorectal cancer (mCRC) depends on the metastatic site and systemic therapy regimen. Peritoneal metastases are associated with a relatively unfavorable prognosis among patients with mCRC. In this article, we present the treatment outcomes of patients with peritoneal carcinomatosis (PC)–only, liver metastasis (LiM)–only, and lung metastasis (LuM)–only CRC.Methods:Overall, 206 mCRC patients with single-site metastasis and who had received treatment from January 2014 to December 2018 were recruited. Among 206 patients with mCRC, 15 had PC-only mCRC, 145 had LiM-only mCRC, and 46 had LuM-only mCRC. They attended regular follow-ups until November 2020, and the median follow-up period was 24.7 months (5.1–41.3 months). Patients’ characteristics, including clinical data, gene mutation profiles, and clinical outcomes, were evaluated. All patients with PC-only CRC were treated with first-line bevacizumab and FOLFIRI, and the irinotecan dose escalation depended on UGT1A1 polymorphism.Results:Of the 206 patients, no statistical difference was observed between the PC-only, LiM-only, and LuM-only groups in terms of age, primary tumor location, RAS mutation status, BRAF mutation status, and epidermal growth factor receptor overexpression (all P > 0.05). KRAS mutations were detected in two (16.7%) patients with PC-only CRC, 39 (36.4%) patients with LiM-only CRC, and 12 (36.4%) patients with LuM-only CRC. NRAS mutations were detected in one (8.3%) patient with PC-only CRC, six (7.3%) patients with LiM-only CRC, and two (7.1%) patients with LuM-only CRC. BRAF mutations were detected in two (15.4%) patients with PC-only CRC, seven (6.9%) patients with LiM-only CRC, and one (2.9%) patient with LuM-only CRC. Patients with PC-only CRC had a median progression-free survival (mPFS) of 18.0 months and a median overall survival (mOS) of 24.6 months. Patients with LiM-only or LuM-only CRC had mPFS of 18.2 and 26.6 months and mOS of 25.0 and 44.5 months, respectively. No significant differences regarding PFS and OS (both P > 0.05) between the three groups of patients with mCRC were observed.Conclusions:A PC-only status is considered to be a challenge in the treatment of patients with mCRC. Our study revealed that in patients with PC-only mCRC had a higher incidence of BRAF mutations, and treatment of first-line bevacizumab and FOLFIRI through irinotecan dose escalation according to UGT1A1 polymorphism could confer such patients with comparable outcomes to that of patients with LiM-only and LuM-only mCRC. However, further prospective randomized trials on patients with peritoneal metastatic mCRC should be conducted to verify the findings of this retrospective study.

Prospective analysis of UGT1A1 promoter polymorphism for irinotecan dose escalation in metastatic colorectal cancer patients treated with bevacizumab combined with FOLFIRI as the first-line setting.

2013 ◽  
Vol 31 (4_suppl) ◽  
pp. 491-491
Author(s):  
Yung-Sung Yeh ◽  
Meng-Lin Huang ◽  
Chien-Yu Lu ◽  
Jaw-Yuan Wang
Keyword(s):  
Colorectal Cancer ◽  
Disease Control ◽  
Metastatic Colorectal Cancer ◽  
Dose Escalation ◽  
Promoter Polymorphism ◽  
Line Treatment ◽  
First Line ◽  
Line Setting ◽  
Irinotecan Dose ◽  
First Line Treatment

491 Background: Infusional fluorouracil/leucovorin plus irinotecan-based regimen (FOLFIRI) with bevacizumab has been widely used as first-line treatment for patients with metastatic colorectal cancer (mCRC). We prospectively analyzed the influence of uridine diphosphate glucuronosyl transferase 1A1 (UGT1A1) genotyping for irinotecan dose escalation in mCRC patients treated with combination of FOLFIRI and bevacizumab as the first-line setting. Methods: A total of 65 mCRC patients undergoing first-line treatment with FOLFIRI combined with bevacizumab were analyzed. Genotypes were performed by analyzing the sequence of TATA box of UGT1A1 of genomic DNA from the patients. Genotype and clinical parameters were compared by univariate analysis. The irinotecan dose is escalating form 180 mg/m2 to 260 mg/m2 in UGT1A1 6/6 or 6/7, and from 120 mg/m2 to 210 mg/m2 in UGT1A17/7. Results: The response rate was observed in 44 of 60 UGT1A1 6/6 or 6/7 (73.3%) in comparison to 1 of 5 UGT1A1 7/7 (20%) patients (p=0.013). The grade III-IV adverse events (AE) was observed in 4 of 60 UGT1A1 6/6 or 6/7 (6.7%) in comparison to 3 of 5 UGT1A1 7/7 (60%) patients (p<0.001), but it was not different between age of ≥ 70 and < 70 (p=0.559). Fifteen of 60 (20%) patients with UGT1A1 6/6 or 6/7 could be performed with liver or lung metastaectomy in comparison to none of 5 patients with UGT1A1 7/7. In addition, the disease control rate was significantly higher in irinotecan dose of ≥ 210 mg/m2 than irinotecan dose of < 210 mg/m2(p=0.015). Conclusions: UGT1A1 promoter polymorphism was found to be predictive of toxicity and efficacy in mCRC patients with first-line treatment of FOLFIRI combined with bevacizumab. The higher dose of irinotecan (≥ 210 mg/m2) may achieve a better disease control rate but do not increase the incidence of GR III-IV AE in mCRC patients of age ≥ 70 years.

A prospective, multicenter, randomized clinical trial of UGT1A1 promoter polymorphism for irinotecan dose escalation in metastatic colorectal cancer patients treated with bevacizumab plus FOLFIRI as the first-line setting (PURE FIST).

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. 625-625
Author(s):  
Jaw-Yuan Wang
Keyword(s):  
Colorectal Cancer ◽  
Clinical Trial ◽  
Metastatic Colorectal Cancer ◽  
Dose Escalation ◽  
Control Group ◽  
Study Group ◽  
First Line ◽  
Line Setting ◽  
And Control ◽  
Irinotecan Dose

625 Background: The polymorphisms of genes encoding drug-metabolizing enzymes can play a crucial role in the increased susceptibility of patients to chemotherapy. This study is a prospective, multicenter, randomized clinical trial to compare the clinical outcomes and adverse events in metastatic colorectal cancer (mCRC) patients treated with bevacizumab plus 5-fluorouracil/leucovorin/irinotecan (FOLFIRI) with or without UGT1A1genotyping and irinotecan dose escalation as the first-line setting (NCT02256800). Methods: The enrolled patients were randomly assigned to one of two groups on the basis of receiving UGT1A1 genotyping or not. The study group receives a biweekly FOLFIRI plus bevacizumab, with irinotecan dose escalation based on UGT1A1 genotyping; whereas the control group receives the conventional biweekly FOLFIRI plus bevacizumab without UGT1A1 genotyping. The primary endpoint was the overall response rate (ORR), and the second endpoint was progression-free survival (PFS), overall survival (OS) and toxicities between the two groups. Results: BetweenAugust 2013 and May 2016, eighty-eight mCRC patients were enrolled, including 45 patients in the study group and 43 patients in the control group. With a median follow up time of 12.5 months (range, 5-30), the ORR was 71.4% vs. 44.2% ( P = 0.011). The PFS was 14.04 ± 1.44 vs. 9.08 ± 0.58 months in study group and control group ( P = 0.195), OS was 19.12 ± 1.24 vs. 14.16 ± 1.04 months ( P = 0.098), and ≥ Gr. III anemia was 2.2% vs. 23.3% ( P= 0.002) in study group and control group, respectively. However, there were no significant differences in ≥ Gr. III leukopenia or diarrhea even though the 1.36 fold relative dose intensity (RDI) in the study group. Conclusions: In the current study, patients with mCRC undergoing UGT1A1 genotyping may receive escalated doses of irinotecan for a potentially more favorable clinical response and outcome, in addition to acceptable toxicities. Such a personalized medicine based on genotyping may be feasible for potentially clinical practice. Clinical trial information: NCT02256800.

scholarly journals Amphiregulin can predict treatment resistance to palliative first-line cetuximab plus FOLFIRI chemotherapy in patients with RAS wild-type metastatic colorectal cancer

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Sang-A Kim ◽  
Hyejoo Park ◽  
Kui-Jin Kim ◽  
Ji-Won Kim ◽  
Ji Hea Sung ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Growth Factor Receptor ◽  
Treatment Resistance ◽  
Progression Free Survival ◽  
Clinical Findings ◽  
Wild Type ◽  
First Line ◽  
Potential Biomarker

AbstractAmphiregulin (AREG) is an epidermal growth factor receptor (EGFR) ligand. The aim of this study was to investigate the effects of baseline plasma AREG levels in KRAS, NRAS, and BRAF wild-type metastatic colorectal cancer (CRC) on treatment outcome with palliative first-line cetuximab + FOLFIRI chemotherapy. Chemotherapy outcomes were analyzed based on baseline plasma AREG levels. The clinical findings were further validated using an in vitro model of CRC. Among 35 patients, the progression-free survival (PFS) was significantly inferior in patients with high AREG than in those with low AREG levels: 10.9 vs. 24.2 months, respectively (p = 0.008). However, after failure of first-line chemotherapy, AREG levels were associated with neither PFS (4.8 vs. 11.6 months; p = 0.215) nor overall survival (8.4 vs. 13.3 months; p = 0.975). In SNU-C4 and Caco-2 cells which were relatively sensitive to cetuximab among the seven CRC cell lines tested, AREG significantly decreased the anti-proliferative effect of cetuximab (p < 0.05) via AKT and ERK activation. However, after acquiring cetuximab resistance with gradual exposure for more than 6 months, AREG neither increased colony formation nor activated AKT and ERK after cetuximab treatment. Our results suggest that plasma AREG is a potential biomarker to predict clinical outcomes after cetuximab-based chemotherapy.

scholarly journals The efficacy of anti-EGFR therapy in treating metastatic colorectal cancer differs between the middle/low rectum and the left-sided colon

2021 ◽  
Author(s):  
Kun-Han Lee ◽  
Wei-Shone Chen ◽  
Jeng-Kai Jiang ◽  
Shung-Haur Yang ◽  
Huann-Sheng Wang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Rectal Cancer ◽  
Colon Cancer ◽  
Metastatic Colorectal Cancer ◽  
Primary Tumour ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
The Cancer Genome Atlas ◽  
First Line ◽  
Cancer Data

Abstract Background Clinically, metastatic rectal cancer has been considered a subset of left-sided colon cancer. However, heterogeneity has been proposed to exist between high and middle/low rectal cancers. We aimed to examine the efficacy of anti-epidermal growth factor receptor (EGFR) treatment for middle/low rectal and left-sided colon cancers. Methods This study enrolled 609 patients with metastatic colorectal cancer who were treated with anti-EGFR therapy. They were divided into groups based on primary tumour locations: the right-sided colon, the left-sided colon or the middle/low rectum. The efficacy of first-line and non-first-line anti-EGFR treatment was analysed. Genomic differences in colorectal cancer data from The Cancer Genome Atlas (TCGA) were investigated and visualised with OncoPrint and a clustered heatmap. Results On first-line anti-EGFR treatment, patients with middle/low rectal tumours had significantly lower progression-free survival, overall survival, and overall response rates (6.8 months, 27.8 months and 43%, respectively) than those with left-sided colon cancer (10.1 months, 38.3 months and 66%, respectively). Similar outcomes were also identified on non-first-line anti-EGFR treatment. In TCGA analysis, rectal tumours displayed genetic heterogeneity and shared features with both left- and right-sided colon cancer. Conclusions Anti-EGFR treatment has lower efficacy in metastatic middle/low rectal cancer than in left-sided colon cancer.

Examining progression-free survival in first- and second-line treatment for BRAF-mutant metastatic colorectal cancer (CRC).

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. 728-728
Author(s):  
Belinda Lee ◽  
Angelyn Anton ◽  
Margaret Lee ◽  
Rachel Wong ◽  
Phillip Parente ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Treatment Strategies ◽  
Progression Free Survival ◽  
Rank Test ◽  
Second Line ◽  
First Line ◽  
Mutation Status ◽  
Kaplan Meier ◽  
The Impact ◽  
Line Chemotherapy

728 Background: BRAF mutated (BRAFm) CRC represents ~10% of all CRC and is associated with significantly poorer prognosis. However, responses to chemotherapy do still occur. Some data suggest that the poor prognosis associated with BRAFm CRC is dominated by substantially poorer second line PFS (PFS2), whereas first line PFS (PFS1) was similar for both BRAFm and BRAF wildtype (BRAFwt) CRC. Using a large multicenter dataset, our study aimed to examine PFS1 and PFS2 in BRAFm versus BRAFwt CRC. Methods: Prospectively collected data from the Treatment of Recurrent and Advanced Colorectal Cancer (TRACC) database was interrogated. PFS was calculated and compared in patients with BRAFm versus BRAFwt CRC. Median survival was determined by the Kaplan-Meier method and compared using the log rank test. Results: TRACC identified 523 CRC patients with known BRAF mutation status, who received first-line chemotherapy: 53 (10%) were BRAFm, while 470 (90%) were BRAFwt. At the time of data analysis, only 231 (44%) CRC patients had received second-line chemotherapy, of which 21 (9%) were BRAFm and 210 (91%) were BRAFwt. PFS1 analyses demonstrated significantly poorer survival in the BRAFm population (Median 7.8mo versus 11.5mo, HR 1.72, p = 0.0026). PFS2 analyses revealed similar findings for the BRAFm population, albeit non-significant due to smaller numbers (Median 5.5mo versus 7.7mo, HR1.26, p = 0.44). Conclusions: Our study demonstrated that BRAFm CRC was associated with poorer PFS in both first- and second-line settings. Additional analyses will be performed to examine the impact of different treatment strategies and other clinicopathological features.

scholarly journals UGT1A1 Polymorphism for Irinotecan Dose Escalation in Patients with BRAF-Mutated Metastatic Colorectal Cancer Treated with First-Line Bevacizumab and FOLFIRI

2021 ◽  
Vol 2021 ◽  
pp. 1-9
Author(s):  
Yi-Chien Hsieh ◽  
Tsung-Kun Chang ◽  
Wei-Chih Su ◽  
Ching-Wen Huang ◽  
Hsiang-Lin Tsai ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Disease Control ◽  
Metastatic Colorectal Cancer ◽  
Dose Escalation ◽  
Braf V600e ◽  
First Line ◽  
Oncological Outcomes ◽  
Ugt1a1 Polymorphism ◽  
Line Therapy ◽  
Irinotecan Dose

Background. Patients with metastatic colorectal cancer (mCRC) and BRAF V600E mutation have a poor prognosis, with a median progression-free survival (PFS) of only 5–7 months after initial therapy. The current standard first-line chemotherapy for these patients includes FOLFOX or FOLFIRI plus bevacizumab. In this study, we explored the effects and oncological outcomes of UGT1A1 polymorphism for irinotecan escalation in patients with BRAF-mutated mCRC. Patients and Methods. This retrospective study included 17 patients with BRAF-mutated mCRC between April 2016 and December 2019. UGT1A1 genotyping was performed on all patients prior to initiating bevacizumab plus FOLFIRI chemotherapy. The primary endpoint was PFS, and the secondary endpoints were toxicity, response rate, disease control rate, and overall survival (OS). Results. Fifteen and two patients had UGT1A1 1∗/1∗ and 1∗/28∗, respectively. Eight underwent irinotecan dose escalation with tolerable adverse effects (AEs), and nine maintained an irinotecan dose of 180 mg/m2 or required deescalation to 150 mg/m2 due to intolerable AEs. After a median follow-up period of 15.7 (range, 3–54) months, the median PFS and OS were 9.4 and 15.7 months, respectively. Grade 3/4 AEs were observed in three (6%) patients. The disease control and partial response rates were 64.7% and 11.8%, respectively, indicating that most patients (14, 82.3%) could maintain this as a first-line line therapy with stable disease or proceed to second-line therapy if disease progression occurred, thereby maintaining acceptable performance status. Conclusions. The oncological outcomes of patients with BRAF-mutated mCRC treated using FOLFIRI plus bevacizumab with irinotecan dose escalation as a first-line therapy are acceptable with tolerable AEs; this may be a feasible treatment option in such patients. Pretherapeutic UGT1A1 genotyping-guided dose adjustment can achieve favorable outcomes.

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