scholarly journals Effect of oxaliplatin plus 5-fluorouracil or capecitabine on circulating and imaging biomarkers in patients with metastatic colorectal cancer: a prospective biomarker study

2020 ◽  
Author(s):  
Reem Mahmood ◽  
Danielle Shaw ◽  
Tine Descamps ◽  
Cong Zhou ◽  
Robert D. Morgan ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Liver Metastases ◽  
Metastatic Colorectal Cancer ◽  
Targeted Therapies ◽  
Cytotoxic Chemotherapy ◽  
Imaging Biomarker ◽  
Imaging Biomarkers ◽  
Study Results ◽  
Pre Treatment ◽  
The Impact

Abstract Background: Patients with metastatic colorectal cancer are treated with cytotoxic chemotherapy supplemented by molecularly targeted therapies. There is a critical need to define biomarkers that can optimise the use of these therapies to maximise efficacy and avoid unnecessary toxicity. However, it is important to firstly define the changes in potential biomarkers following cytotoxic chemotherapy alone. This study reports the impact of standard cytotoxic chemotherapy across a range of circulating and imaging biomarkers.Methods: A single-centre, prospective, biomarker-driven study. Eligible patients included those diagnosed with colorectal cancer with liver metastases that were planned to receive first line oxaliplatin plus 5-fluorouracil or capecitabine. Patients underwent paired blood sampling and magnetic resonance imaging (MRI), and biomarkers were associated with progression-free survival (PFS) and overall survival (OS).Results: 20 patients were recruited to the study. Results showed that chemotherapy significantly reduced the number of circulating tumour cells as well as the circulating concentrations of Ang1, Ang2, VEGF-A, VEGF-C and VEGF-D from pre-treatment to cycle 2 day 2. The changes in circulating concentrations were not associated with PFS or OS. Across all patients, the MRI perfusion parameter, Ktrans, increased in response to cytotoxic chemotherapy from pre-treatment to cycle 2 day 2 and this increase was associated with worse OS (HR 1.099, 95%CI 1.01-1.20, p=0.025).Conclusions: In patients diagnosed with colorectal cancer with liver metastases, treatment with standard chemotherapy changes cell- and protein-based biomarkers, although these changes are not associated with survival outcomes. In contrast, the imaging biomarker, Ktrans, offers promise to direct molecular targeted therapies such as anti-angiogenic agents.

scholarly journals Effect of oxaliplatin plus 5-fluorouracil or capecitabine on circulating and imaging biomarkers in patients with metastatic colorectal cancer: a prospective biomarker study

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Reem D. Mahmood ◽  
Danielle Shaw ◽  
Tine Descamps ◽  
Cong Zhou ◽  
Robert D. Morgan ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Liver Metastases ◽  
Metastatic Colorectal Cancer ◽  
Targeted Therapies ◽  
Progression Free Survival ◽  
Cytotoxic Chemotherapy ◽  
Imaging Biomarker ◽  
Imaging Biomarkers ◽  
Pre Treatment ◽  
The Impact

Abstract Background Patients with metastatic colorectal cancer are treated with cytotoxic chemotherapy supplemented by molecularly targeted therapies. There is a critical need to define biomarkers that can optimise the use of these therapies to maximise efficacy and avoid unnecessary toxicity. However, it is important to first define the changes in potential biomarkers following cytotoxic chemotherapy alone. This study reports the impact of standard cytotoxic chemotherapy across a range of circulating and imaging biomarkers. Methods A single-centre, prospective, biomarker-driven study. Eligible patients included those diagnosed with colorectal cancer with liver metastases that were planned to receive first line oxaliplatin plus 5-fluorouracil or capecitabine. Patients underwent paired blood sampling and magnetic resonance imaging (MRI), and biomarkers were associated with progression-free survival (PFS) and overall survival (OS). Results Twenty patients were recruited to the study. Data showed that chemotherapy significantly reduced the number of circulating tumour cells as well as the circulating concentrations of Ang1, Ang2, VEGF-A, VEGF-C and VEGF-D from pre-treatment to cycle 2 day 2. The changes in circulating concentrations were not associated with PFS or OS. On average, the MRI perfusion/permeability parameter, Ktrans, increased in response to cytotoxic chemotherapy from pre-treatment to cycle 2 day 2 and this increase was associated with worse OS (HR 1.099, 95%CI 1.01–1.20, p = 0.025). Conclusions In patients diagnosed with colorectal cancer with liver metastases, treatment with standard chemotherapy changes cell- and protein-based biomarkers, although these changes are not associated with survival outcomes. In contrast, the imaging biomarker, Ktrans, offers promise to direct molecularly targeted therapies such as anti-angiogenic agents.

scholarly journals Effect of oxaliplatin plus 5-fluorouracil or capecitabine on circulating and imaging biomarkers in patients with metastatic colorectal cancer: a prospective biomarker study

2020 ◽  
Author(s):  
Reem Mahmood ◽  
Danielle Shaw ◽  
Tine Descamps ◽  
Cong Zhou ◽  
Robert D. Morgan ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Liver Metastases ◽  
Metastatic Colorectal Cancer ◽  
Targeted Therapies ◽  
Progression Free Survival ◽  
Cytotoxic Chemotherapy ◽  
Imaging Biomarker ◽  
Imaging Biomarkers ◽  
Pre Treatment ◽  
The Impact

Abstract Background: Patients with metastatic colorectal cancer are treated with cytotoxic chemotherapy supplemented by molecularly targeted therapies. There is a critical need to define biomarkers that can optimise the use of these therapies to maximise efficacy and avoid unnecessary toxicity. However, it is important to first define the changes in potential biomarkers following cytotoxic chemotherapy alone. This study reports the impact of standard cytotoxic chemotherapy across a range of circulating and imaging biomarkers.Methods: A single-centre, prospective, biomarker-driven study. Eligible patients included those diagnosed with colorectal cancer with liver metastases that were planned to receive first line oxaliplatin plus 5-fluorouracil or capecitabine. Patients underwent paired blood sampling and magnetic resonance imaging (MRI), and biomarkers were associated with progression-free survival (PFS) and overall survival (OS).Results: 20 patients were recruited to the study. Data showed that chemotherapy significantly reduced the number of circulating tumour cells as well as the circulating concentrations of Ang1, Ang2, VEGF-A, VEGF-C and VEGF-D from pre-treatment to cycle 2 day 2. The changes in circulating concentrations were not associated with PFS or OS. On average, the MRI perfusion/permeability parameter, Ktrans, increased in response to cytotoxic chemotherapy from pre-treatment to cycle 2 day 2 and this increase was associated with worse OS (HR 1.099, 95%CI 1.01-1.20, p=0.025).Conclusions: In patients diagnosed with colorectal cancer with liver metastases, treatment with standard chemotherapy changes cell- and protein-based biomarkers, although these changes are not associated with survival outcomes. In contrast, the imaging biomarker, Ktrans, offers promise to direct molecularly targeted therapies such as anti-angiogenic agents.

Use and impact of bevacizumab in patients undergoing liver resection for metastatic colorectal cancer in routine clinical practice.

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 698-698
Author(s):  
Edmond Michael Kwan ◽  
Belinda Lee ◽  
Hui-Li Wong ◽  
Margaret Lee ◽  
Rachel Wong ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Liver Resection ◽  
Liver Metastases ◽  
Metastatic Colorectal Cancer ◽  
Survival Outcomes ◽  
Perioperative Chemotherapy ◽  
Palliative Intent ◽  
Clinical Dilemma ◽  
The Impact ◽  
Proven Benefit

698 Background: In metastatic colorectal cancer (mCRC) patients with isolated liver metastases, surgical resection offers the greatest likelihood of cure. Whilst for mCRC patients treated with palliative intent the addition of bevacizumab to the chemotherapy backbone is of proven benefit, whether to use bevacizumab in the resectable or potentially resectable population is a clinical dilemma. Methods: Consecutive patients who underwent resection of liver metastases were identified from a prospective Australian mCRC registry that captures comprehensive data on patient and tumor characteristics (including resectability), treatment and outcome. The use of bevacizumab in this setting was examined and the impact on outcomes was explored. Results: From a total mCRC population of 1,700 patients, 543 patients with liver-only mCRC were identified, of which 217 patients (40%) underwent liver resection. Perioperative chemotherapy was administered to 185 patients (85.3%), with bevacizumab added to chemotherapy in 73 (39.5%) patients. There was a trend for bevacizumab treated patients to be younger (median age 60.4 vs 65.1 years, p = 0.07) and fitter (mean Charlson score 2.22 vs 2.64, p = 0.054). Patients that received bevacizumab with perioperative chemotherapy were considerably less likely to have disease regarded as resectable at diagnosis (39 of 73 (53.4%) vs 95 of 112 (84.8%), p =<.01). At 5 years, overall survival was similar for bevacizumab treated and non-treated patients (61.4% vs. 59.2%, HR 0.83, p=0.52). There were no deaths within 30 days of surgery in any patients. Conclusions: Despite limited evidence to support the use of bevacizumab in patients with resectable or potentially resectable liver-only mCRC, clinicians are not infrequently utilising this approach, particularly in younger and fitter patients and those not considered to have resectable disease at diagnosis. The addition of bevacizumab did not appear to impact survival outcomes. A multivariate analysis is underway to better define the impact of bevacizumab on survival outcomes.

scholarly journals Image Contrast, Image Pre-Processing, and T1 Mapping Affect MRI Radiomic Feature Repeatability in Patients with Colorectal Cancer Liver Metastases

Cancers ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 240
Author(s):  
Damien J. McHugh ◽  
Nuria Porta ◽  
Ross A. Little ◽  
Susan Cheung ◽  
Yvonne Watson ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Liver Metastases ◽  
Intraclass Correlation ◽  
Imaging Biomarkers ◽  
Sequence Comparisons ◽  
Colorectal Cancer Liver Metastases ◽  
T1 And T2 ◽  
Non Gaussian ◽  
The Impact ◽  
T2 Weighted Images

Imaging biomarkers require technical, biological, and clinical validation to be translated into robust tools in research or clinical settings. This study contributes to the technical validation of radiomic features from magnetic resonance imaging (MRI) by evaluating the repeatability of features from four MR sequences: pre-contrast T1- and T2-weighted images, pre-contrast quantitative T1 maps (qT1), and contrast-enhanced T1-weighted images. Fifty-one patients with colorectal cancer liver metastases were scanned twice, up to 7 days apart. Repeatability was quantified using the intraclass correlation coefficient (ICC) and repeatability coefficient (RC), and the impact of non-Gaussian feature distributions and image normalisation was evaluated. Most radiomic features had non-Gaussian distributions, but Box–Cox transformations enabled ICCs and RCs to be calculated appropriately for an average of 97% of features across sequences. ICCs ranged from 0.30 to 0.99, with volume and other shape features tending to be most repeatable; volume ICC > 0.98 for all sequences. 19% of features from non-normalised images exhibited significantly different ICCs in pair-wise sequence comparisons. Normalisation tended to increase ICCs for pre-contrast T1- and T2-weighted images, and decrease ICCs for qT1 maps. RCs tended to vary more between sequences than ICCs, showing that evaluations of feature performance depend on the chosen metric. This work suggests that feature-specific repeatability, from specific combinations of MR sequence and pre-processing steps, should be evaluated to select robust radiomic features as biomarkers in specific studies. In addition, as different repeatability metrics can provide different insights into a specific feature, consideration of the appropriate metric should be taken in a study-specific context.

RAS mutational status and CEA production at initial presentation in metastatic colorectal cancer.

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 542-542
Author(s):  
May Thet Cho ◽  
Leanne Goldstein ◽  
Chie Akiba ◽  
S. Cecilia Lau ◽  
Milhan Telatar ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Liver Metastases ◽  
Metastatic Colorectal Cancer ◽  
Metastatic Disease ◽  
Hepatic Metastases ◽  
Small Sample ◽  
Eligibility Criteria ◽  
Mutational Status ◽  
Ras Status ◽  
The Impact

542 Background: Serial CEA testing is recommended in the surveillance of patients with resected stage II-IV colorectal cancer. However, the sensitivity of CEA in identifying metastatic disease has not been evaluated in the settings of RAS mutant (MT) and RAS/BRAF wild-type tumors (WT). In order to evaluate the impact of RAS mutational status on CEA production, we retrospectively evaluated a single-institute metastatic colorectal cancer (mCRC) population. Methods: We retrospectively reviewed, in a single center, all cases with mCRC with known RAS mutational status based on next generation sequencing (ONCO44 and ONCO48). These assays identify clinically relevant mutations in BRAF, KRAS, and NRAS. Additional eligibility criteria included the availability of CEA levels and imaging studies at first diagnosis of mCRC. Patient demographics, primary tumor location and sites of metastatic disease at 1st diagnosis were captured. CEA levels were stratified as normal or elevated based on a cut point of 5ng/ml. Results: 139 mCRC patients satisfied the eligibility criteria (75 RAS-MT, 59 RAS/BRAF-WT, and 5 BRAF-MT). BRAF-MT patients were excluded from the analysis due to their small sample size. Patients with RAS/BRAF-WT tumors were more likely to present with metastatic disease to the liver, but this did not reach statistical significance (p = 0.056). There was no difference in the incidence of normal CEA at presentation in RAS-MT (30%) and RAS/BRAF-WT (28%) cohorts. CEA production was dependent on the pattern of metastatic disease. Elevated CEA was associated with the presence of liver metastases versus no metastases among RAS-MT (92% vs 47% p <.0001) and RAS/BRAF-WT patients (82% vs 50% p = 0.0101). RAS status did not impact the likelihood of CEA production within the hepatic metastases and non-hepatic metastases groups. Conclusions: RAS status does not appear to influence CEA production in patients with mCRC. CEA elevations are highly associated with liver metastases and are less prevalent in patients without hepatic involvement. These findings confirm the limited predictive value of CEA for non-hepatic recurrence, irrespective of RAS status.

scholarly journals The Evolutionary Landscape of Treatment for BRAFV600E Mutant Metastatic Colorectal Cancer

Cancers ◽  
2021 ◽  
Vol 13 (1) ◽  
pp. 137
Author(s):  
Gianluca Mauri ◽  
Erica Bonazzina ◽  
Alessio Amatu ◽  
Federica Tosi ◽  
Katia Bencardino ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Checkpoint Inhibitors ◽  
Mapk Pathway ◽  
Treatment Options ◽  
Braf Inhibitor ◽  
Current Treatment ◽  
Cytotoxic Chemotherapy ◽  
Cytotoxic Agents ◽  
Poor Prognostic Factor

The BRAFV600E mutation is found in 8–10% of metastatic colorectal cancer (mCRC) patients and it is recognized as a poor prognostic factor with a median overall survival inferior to 20 months. At present, besides immune checkpoint inhibitors (CPIs) for those tumors with concomitant MSI-H status, recommended treatment options include cytotoxic chemotherapy + anti-VEGF in the first line setting, and a combination of EGFR and a BRAF inhibitor (cetuximab plus encorafenib) in second line. However, even with the latter targeted approach, acquired resistance limits the possibility of more than an incremental benefit and survival is still dismal. In this review, we discuss current treatment options for this subset of patients and perform a systematic review of ongoing clinical trials. Overall, we identified six emerging strategies: targeting MAPK pathway (monotherapy or combinations), targeting MAPK pathway combined with cytotoxic agents, intensive cytotoxic regimen combinations, targeted agents combined with CPIs, oxidative stress induction, and cytotoxic agents combined with antiangiogenic drugs and CPIs. In the future, the integration of new therapeutic strategies targeting key players in the BRAFV600E oncogenic pathways with current treatment approach based on cytotoxic chemotherapy and surgery is likely to redefine the treatment landscape of these CRC patients.

Lonsurf (trifluridine/tipiracil): Assessing the impact of dose related toxicities and progression free survival in (refractory) metastatic colorectal cancer

2021 ◽  
pp. 107815522110179
Author(s):  
Olivia R Court
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Dose Reduction ◽  
Progression Free Survival ◽  
Electronic Patient Records ◽  
Free Survival ◽  
Length Of Treatment ◽  
Common Grade ◽  
Grade 3 ◽  
The Impact

In the RECOURSE trial which lead to its accreditation, Lonsurf (trifluridine/tipiracil) was shown to extend progression free survival (PFS) by 1.8 months in metastatic colorectal cancer. This Trust audit aims to assess the average quantity of cycles of Lonsurf received by participants and the length of time it extends PFS. Similarly, to identify how many participants required a dose-reduction or experienced toxicities which necessitated supportive therapies. Quantitative data was collected retrospectively from all participants who had received ≥1 cycle of Lonsurf from The Clatterbridge Cancer Centre (CCC) from 2016 until June 2020. Participant electronic patient records were accessed to identify toxicity grading, length of treatment received, the date progression was identified, if dose reductions were applied and if supportive therapies were administered. Lonsurf extends PFS in patients with metastatic colorectal cancer at CCC by 3.0 months (95% CI: 2.73–3.27) and average treatment length was 2.4 months. However, 78 participants (41.5%) received a dose reduction due to toxicities. A total of 955 toxicities were recorded by participants; the most commonly reported toxicities irrespective of grade were fatigue (33.8%), diarrhoea (13.8%) and nausea (12.3%). The most common grade ≥3 toxicities were constipation and infection. The most frequently utilised supportive therapies were loperamide (49.6%) and domperidone (49.1%). Granulocyte colony stimulating factor (GCSF) was required by patients on 5 occasions (0.3%) in total. Lonsurf extends median PFS in patients with metastatic colorectal cancer by 3.0 months. The most common grade ≥3 toxicities which necessitated supportive therapies or a dose reduction were gastrointestinal and infection.

scholarly journals Treatment with Antiangiogenic Drugs in Multiple Lines in Patients with Metastatic Colorectal Cancer: Meta-Analysis of Randomized Trials

2016 ◽  
Vol 2016 ◽  
pp. 1-9 ◽  
Author(s):  
R.-D. Hofheinz ◽  
U. Ronellenfitsch ◽  
S. Kubicka ◽  
A. Falcone ◽  
I. Burkholder ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Kinase Inhibitors ◽  
Meta Analysis ◽  
Progression Free Survival ◽  
Optimal Sequence ◽  
Primary Endpoints ◽  
Disease Stabilization ◽  
Antiangiogenic Drugs ◽  
The Impact

Background. In metastatic colorectal cancer (mCRC), continuing antiangiogenic drugs beyond progression might provide clinical benefit. We synthesized the available evidence in a meta-analysis.Patients and Methods. We conducted a meta-analysis of studies investigating the use of antiangiogenic drugs beyond progression. Eligible studies were randomized phase II/III trials. Primary endpoints were overall survival (OS) and progression-free survival (PFS). Secondary endpoints were the impact of continuing antiangiogenic drugs (i) in subgroups, (ii) in different types of compounds targeting the VEGF-axis (monoclonal antibodies versus tyrosine kinase inhibitors), and (iii) on remission rates and prevention of progression.Results. Eight studies (3,668 patients) were included. Continuing antiangiogenic treatment beyond progression significantly improved PFS (HR 0.64; 95%-CI, 0.55–0.75) and OS (HR 0.83; 95%-CI, 0.76–0.89). PFS was significantly improved in all subgroups with comparable HR. OS was improved in all subgroups stratified by age, gender, and ECOG status. The rate of patients achieving at least stable disease was improved with an OR of 2.25 (95%-CI, 1.41–3.58).Conclusions. This analysis shows a significant PFS and OS benefit as well as a benefit regarding disease stabilization when using antiangiogenic drugs beyond progression in mCRC. Future studies should focus on the optimal sequence of administering antiangiogenic drugs.

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