scholarly journals Inflammatory biomarkers in metastatic colorectal cancer: prognostic and predictive role beyond the first line setting

Oncotarget ◽  
2017 ◽  
Vol 8 (56) ◽  
pp. 96048-96061 ◽  
Author(s):  
Jakob Michael Riedl ◽  
Florian Posch ◽  
Florian Moik ◽  
Angelika Bezan ◽  
Joanna Szkandera ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Inflammatory Biomarkers ◽  
First Line ◽  
Predictive Role ◽  
Line Setting

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.

Predicting resistance to first-line FOLFOX plus bevacizumab in metastatic colorectal cancer: Final results of the multicenter, international PERMAD trial.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 115-115
Author(s):  
Thomas Seufferlein ◽  
Thomas Jens Ettrich ◽  
Alexander Stein ◽  
Dirk Arnold ◽  
Gerald W. Prager ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Random Forest ◽  
Metastatic Colorectal Cancer ◽  
Treatment Resistance ◽  
Antiangiogenic Agents ◽  
Learning Approaches ◽  
First Line ◽  
Marker Combination ◽  
Treatment Naïve ◽  
Line Setting

115 Background: Antiangiogenic agents, in particular monoclonal antibodies (mAbs) against VEGF, a major driver of tumor angiogenesis, are widely used in cancer therapy including metastatic colorectal cancer (mCRC). However, some patients do not profit from antiangiogenic treatments (AT), other patients benefit initially, but subsequently develop resistance not only to chemotherapy but also to AT. So far, no biomarkers are available to predict resistance to AT. Having an accurate assessment of imminent resistance to an AT may e.g. enable to respond by treating the patient with a more broadly acting antiangiogenic agent and thereby further delay resistance to the treatment and at the same time avoid employing a not anymore efficacious treatment. We hypothesized that repeated analysis of multiple cytokines related to angiogenesis together with machine learning approaches may enable an accurate prediction of anti-VEGF resistance during first-line treatment of mCRC patients with FOLFOX plus bevacizumab. The PERMAD trial aimed at establishing a CAF marker combination that enables the prediction of treatment resistance of patients with mCRC receiving Bevacizumab plus mFOLFOX6 in a palliative first-line setting about three months prior to radiological progress using an omics approach and bioinformatics. Methods: A phase I/II biomarker trial was conducted, including 15 centers in Germany and Austria. All mCRC patients included were treatment naïve and received FOLFOX plus Bevacizumab treatment. 102 different, preselected CAFs were prospectively collected and centrally analyzed in plasma samples (n = 647) obtained prior to treatment and biweekly until radiological progress determined by CT scan every 2 months. The values of CAFs affected in a similar fashion by both chemotherapy and disease progress were excluded. Using the remaining CAFs we employed a random forest predictor to define a combination of 5 CAF (CAF marker combination) whose change in values/pattern correlated with subsequent progress 3 months prior to radiological progress according to RECIST 1.1. Results: Using the samples described above and a random forest predictor we established a CAF marker combination comprising 5 CAF whose specific change in value/pattern over time indicated treatment resistance 3 months prior to radiological progress. The model allowed to differentiate timepoints without progress from timepoints predicting progress 100 days before radiological progress with an accuracy of 83%, a sensitivity of 76% and specificity of 88%. Conclusions: Using advanced bioinformatics, we identified a CAF marker combination that points out treatment resistance to FOLFOX plus Bevacizumab in patients with mCRC 3 months prior to radiological progress. Clinical trial information: NCT02331927.

Tumor bulk to predict clinical outcomes of anti-EGFR therapy in treatment refractory metastatic colorectal cancer independent of sidedness.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 795-795
Author(s):  
Jeremy D. Kratz ◽  
Noelle K. LoConte ◽  
Sam Joseph Lubner ◽  
Daniel Mulkerin ◽  
Nataliya Volodymyrivna Uboha ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Clinical Outcomes ◽  
Tumor Biology ◽  
First Line ◽  
Bulky Disease ◽  
Treatment Refractory ◽  
Line Setting ◽  
The Right ◽  
The Impact

795 Background: Epidermal growth factor receptor (EGFR) antibodies, cetuximab (C) and panitumumab (P) have shown improvement in clinical outcomes for distinct molecular profiles in metastatic colorectal cancer (mCRC). In the first line setting, EGFR targeting of left-sided tumors has shown favorable clinical outcomes when compared to right-sided tumors. Here we examined the efficacy of EGFR therapy in the treatment refractory setting as well as the impact of tumor bulk on clinical outcomes. Methods: A retrospective cohort of 72 patients (pts) with KRAS wild-type mCRC were identified who received either C or P in the late-line setting. Tumor measurements were performed per RECIST v1.1. Disease bulk was defined as single lesion with longest diameter or lymph node with short axis > 3.5 cm. Right colon primary was defined proximal to splenic flexure. Results: In pts with treatment refractory right-sided disease the response rate (RR) was 16.7%, progression free survival (PFS) was 3.7 months (mo), and overall survival (OS) was 14.0 mo. This was compared to left sided disease with RR of 26.0%, PFS 6.2 mo (p < 0.05), and OS 15.0 mo. In the non-bulky cohort the RR was 32.4%, PFS 7.9 mo, and OS 18.4 mo. In the bulky cohort the RR was 5.3% (p < 0.01), PFS 4.0 mo (p < 0.02), and OS 6.6 mo. In the right-sided non-bulky cohort there was a RR of 33% v. 0% in the right-sided bulky cohort. In the left-sided non-bulky cohort there was a RR of 32.3% v. 7.7% in the bulky cohort (p < 0.05). Conclusions: These data indicate that tumor bulk can predict clinical outcomes for anti-EGFR targeting. In the late line setting, pts with left-sided cancers overall trended towards improvements in clinical outcomes, consistent with prior understanding in first line setting. Despite a limited cohort size, response was observed in pts with non-bulky right-sided disease. There was limited-to-no benefit of anti-EGFR targeting with right-sided bulky disease. Left-sided non-bulky patient received the greatest benefit from anti-EGFR targeting. Future prospective studies of targeted therapeutics should incorporate tumor bulk and sidedness when assessing clinical outcomes and tumor biology.

scholarly journals P-0241 A Comparison of Xeliri Plus Bevacizumab with Folfiri Plus Bevacizumab as First-Line Setting in Patients with Metastatic Colorectal Cancer

2012 ◽  
Vol 23 ◽  
pp. iv98-iv99
Author(s):  
Bilici Ahmet ◽  
Kazim Uygun ◽  
Serap Kaya ◽  
Bala Basak Oven Ustaalioglu ◽  
Ramazan Yildiz ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
First Line ◽  
Line Setting
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