Bevacizumab-based Chemotherapy Research Articles

Evaluation of serum mid-infrared spectroscopy as new prognostic marker for first-line bevacizumab-based chemotherapy in metastatic colorectal cancer

Background and aimsBevacizumab-based chemotherapy is a recommended first-line treatment for metastatic colorectal cancer (mCRC). Robust biomarkers with clinical practice applicability have not been identified for patients with this treatment. We aimed to evaluate the prognostic yield of serum mid-infrared spectroscopy (MIRS) on patients receiving first-line bevacizumab-based chemotherapy for mCRC. MethodsWe conducted an ancillary analysis from a multicentre prospective study (NCT00489697). All baseline serums were screened by attenuated total reflection method. Principal component analysis and unsupervised k-mean partitioning methods were performed blinded to all patients’ data. Endpoints were progression-free survival (PFS) and overall survival (OS). ResultsFrom the 108 included patients, MIRS discriminated two prognostic groups. First group patients had significantly lower body mass index (p = 0.026) and albumin levels (p < 0.001), and higher levels of angiogenic markers, lactate dehydrogenase and carcinoembryonic antigen (p < 0.001). In univariate analysis, their OS and PFS were shorter with respective medians: 17.6 vs 27.9 months (p = 0.02) and 8.7 vs 11.3 months (p = 0.03). In multivariate analysis, PFS was significantly shorter (HR = 1.74, p = 0.025) with a similar trend for OS (HR = 1.69, p = 0.061). ConclusionBy metabolomic fingerprinting, MIRS proves to be a promising prognostic tool for patients receiving first-line bevacizumab-based chemotherapy for mCRC.

Prognostic value of the tumor-to-liver density ratio in patients with metastatic colorectal cancer treated with bevacizumab-based chemotherapy. A post-hoc study of the STIC-AVASTIN trial

BackgroundThe Response Evaluation Criteria in Solid Tumors (RECIST) are often inadequate for the early assessment of the response to cancer therapy, particularly bevacizumab-based chemotherapy. In a first cohort of patients with colorectal cancer liver metastases (CRLM), we showed that variations of the tumor-to-liver density (TTLD) ratio and modified size-based criteria determined using computed tomography (CT) data at the first restaging were better prognostic criteria than the RECIST. The aims of this study were to confirm the relevance of these radiological biomarkers as early predictors of the long-term clinical outcome and to assess their correlation with contrast-enhanced ultrasound (CEUS) parameters in a new patient cohort.MethodsIn this post-hoc study of the multicenter STIC-AVASTIN trial, we retrospectively reviewed CT data of patients with CRLM treated with bevacizumab-based regimens. We determined the size, density and TTLD ratio of target liver lesions at baseline and at the first restaging and also performed a morphologic evaluation according to the MD Anderson criteria. We assessed the correlation of these parameters with progression-free survival (PFS) and overall survival (OS) using the log-rank test and a Cox proportional hazard model. We also examined the association between TTLD ratio and quantitative CEUS parameters.ResultsThis analysis concerned 79 of the 137 patients included in the STIC-AVASTIN trial. PFS and OS were significantly longer in patients with tumor size reduction > 15% at first restaging, but were not correlated with TTLD ratio variations. However, PFS was longer in patients with TTLD ratio > 0.6 at baseline and first restaging than in those who did not reach this threshold. In the multivariate analysis, only baseline TTLD ratio > 0.6 was a significant survival predictor. TTLD ratio > 0.6 was associated with improved perfusion parameters.ConclusionsAlthough TTLD ratio variations did not correlate with the long-term clinical outcomes, TTLD absolute values remained a good predictor of survival at baseline and first restaging, and may reflect tumor microvascular features that might influence bevacizumab-based treatment efficiency.Trial registrationNCT00489697, registration number of the STIC-AVASTIN trial.

Forecasting Survival Rates in Metastatic Colorectal Cancer Patients Undergoing Bevacizumab-Based Chemotherapy: A Machine Learning Approach

Background: Antibiotics can play a pivotal role in the treatment of colorectal cancer (CRC) at various stages of the disease, both directly and indirectly. Identifying novel patterns of antibiotic effects or responses in CRC within extensive medical data poses a significant challenge that can be addressed through algorithmic approaches. Machine Learning (ML) emerges as a promising solution for predicting clinical outcomes using clinical and heterogeneous cancer data. In the pursuit of our objective, we employed ML techniques for predicting CRC mortality and antibiotic influence. Methods: We utilized a dataset to examine the accuracy of death prediction in metastatic colorectal cancer. In addition, we analyzed the association between antibiotic exposure and mortality in metastatic colorectal cancer. The dataset comprised 147 patients, nineteen independent variables, and one dependent variable. Our analysis involved testing different classification-supervised ML, including an oversampling pool for classification models, Logistic Regression, Decision Trees, Naive Bayes, Support Vector Machine, Random Forest, XGBboost Classifier, a consensus of all models, and a consensus of top models (meta models). Results: The consensus of the top models’ classifier exhibited the highest accuracy among the algorithms tested (93%). This model met the standards for good accuracy, surpassing the 90% threshold considered useful in ML applications. Consistent with the accuracy results, other metrics are also good, including precision (0.96), recall (0.93), F-Beta (0.94), and AUC (0.93). Hazard ratio analysis suggests that there is no discernible difference between patients who received antibiotics and those who did not. Conclusions: Our modelling approach provides an alternative for analyzing and predicting the relationship between antibiotics and mortality in metastatic colorectal cancer patients treated with bevacizumab, complementing classic statistical methods. This methodology lays the groundwork for future use of datasets in cancer treatment research and highlights the advantages of meta models.

Identification and validation of basic fibroblast growth factor as a prognostic biomarker for the response of lung adenocarcinoma patients to bevacizumab treatment

Basic fibroblast growth factor (bFGF) stimulates angiogenesis, influencing the proliferation, migration, and survival of tumour cells, which have pivotal roles in tumour progression. This study investigated the prognostic significance of bFGF expression in lung adenocarcinoma treated with bevacizumab. The expression levels of bFGF were assessed in bevacizumab-treated patients with lung adenocarcinoma using immunohistochemistry. Propensity score matching (PSM) analysis was performed to evaluate prognostic potential. bFGF expression was also investigated in another independent cohort of patients with lung adenocarcinoma treated with routinechemotherapy. We also compared the PSM value of bFGF expression levels independently and in combination with epidermal growth factor receptor and vascularendothelial growth factor expression levels. A high bFGF expression level was found to be an independent prognostic factor for disease-free survival in patients receiving bevacizumab-based chemotherapy. Similar results were not observed in patients who underwent routinechemotherapy. In conclusion, the bFGF expression level may be a clinically feasible prognostic marker and bFGF is a potential therapeutic target for patients with lung adenocarcinoma receiving routinechemotherapy.

FOLFOXIRI Plus Cetuximab or Bevacizumab as First-Line Treatment of BRAFV600E-Mutant Metastatic Colorectal Cancer: The Randomized Phase II FIRE-4.5 (AIO KRK0116) Study.

BRAFV600E mutation is associated with a poor outcome in metastatic colorectal cancer (mCRC). This clinical trial investigated the efficacy of triplet chemotherapy (fluorouracil, folinic acid, oxaliplatin, and irinotecan) combined with either cetuximab or bevacizumab in patients with previously untreated BRAFV600E-mutant mCRC. In this controlled, randomized, open-label phase II trial, 109 patients were randomly assigned, 107 of whom were included into the full analysis set (FAS). Patients were randomly assigned in a 2:1 ratio to receive either FOLFOXIRI plus cetuximab in the experimental arm (n = 72) or FOLFOXIRI plus bevacizumab in the control arm (n = 35). The primary end point was objective response rate (ORR) according to RECIST 1.1., evaluated in patients treated according to protocol (ATP population). Progression-free survival (PFS), overall survival (OS), toxicity, and feasibility were analyzed as secondary end points. Eighteen patients discontinued study treatment before the first tumor assessment, thus resulting in the ATP population of 89 patients. In these patients, ORR was 51% (30/59) in the cetuximab-based experimental arm and 67% (20/30) in the bevacizumab-based control arm (odds ratio, 1.93; 80% CI, 1.06 to 3.52; P = .92 [one-sided]). In the full analysis set, median PFS was significantly inferior in the experimental arm (6.7 months v 10.7 months; hazard ratio [HR], 1.89; P = .006). Median OS analyzed at an event rate of 64.5% showed a trend toward shorter survival in cetuximab-treated patients (12.9 months v 17.1 months; HR, 1.4; P = .20). To our knowledge, FIRE-4.5 is the first prospective and randomized study investigating first-line treatment of BRAFV600E-mutant mCRC. FOLFOXIRI plus cetuximab does not induce a higher ORR when compared with FOLFOXIRI plus bevacizumab in first-line treatment of BRAFV600E-mutant mCRC. Bevacizumab-based chemotherapy remains the preferable first-line treatment of patients with BRAFV600E-mutant mCRC.

Outcome of Second Line Treatment of Recurrent High- Grade Glioma by re-Irradiation or Bevacizumab-based Chemotherapy: A Cross Sectional Study.

Currently, there is no standard of treatment for the management of the recurrent high-grade glioma. Re-resection, re-irradiation, and chemotherapy are among main treatment options without any proven efficacy. To compare the outcome of second line treatment of recurrent high-grade glioma by re-irradiation or bevacizumab-based chemotherapy. Retrospectively, patients with the recurrent high-grade glioma treated by re-irradiation (ReRT group) (34 patients) or bevacizumab-based chemotherapy (Bev group) (40 patients) as the first-file after the first recurrence were compared in term of first-line progression free survival (PFS), second-line PFS, and overall survival (OS). Both groups were similar in term of gender (p=0.859), age (=0.071), type of first-line treatment (p=0.227), and performance status (p=0.150). With a median follow-up of 31 months (m), mortality rate was 41.2% and 70% in the ReRT and Bev groups, respectively. In the Bev and ReRT groups, median OS was 27 m (95% confidence interval (CI) 20-33.9 m) vs. 132 m (95% CI 52.9-211 m) (p<0.0001), median first-line PFS was 11 m (95% CI 7.14-28.7 m) vs. 37 m (95% CI 8.42-65.75 m) (p<0.0001), and median second-line PFS was 7 m (95% CI 3.9-10 m) vs. 9 m (95% CI 5.5-12.4 m) (p=0.564), respectively. The PFS is similar after the second line treatment of recurrent primary central nervous system malignancies either by re-irradiation or bevacizumab-based chemotherapy.

Relationship Between Safety and Cumulative Bevacizumab Dose in Patients With Metastatic Colorectal Cancer Who Received Long-term Bevacizumab Treatment.

Bevacizumab-based chemotherapy is the standard treatment for metastatic colorectal cancer (mCRC) but has several specific adverse events. The cumulative bevacizumab dose (CBD) increases with long-term treatment as it is often used beyond the first disease progression, based on existing evidence. However, the association between CBD and the frequency and severity of adverse events in mCRC patients who received bevacizumab for long-term treatment remains unclear. Among the mCRC patients who received bevacizumab-based chemotherapy between March 2007 and December 2017 at the University of Tsukuba Hospital, those who continued treatment for more than 2 years were eligible for the study. The onset and worsening of proteinuria, hypertension, bleeding, and thromboembolic events were assessed to determine their relationship with CBD. Of the 109 patients who received bevacizumab-based chemotherapy, 24 were included in the study. Grade 3 proteinuria was observed in 21 (88%) and 9 (38%) patients. The severity of proteinuria markedly increased after administering >100 mg/kg of CBD and progressed to grade 3 at concentrations exceeding 200 mg/kg. Thromboembolic events were observed in three (13%) patients, and two of them developed acute myocardial infarction after receiving a CBD of >300 mg/kg. Grade 2 or higher hypertension and grade 1 bleeding were observed in 9 (38%) patients and in 6 (25%) patients, respectively, regardless of the CBD. Proteinuria and thromboembolic events occurred and worsened in mCRC patients when the bevacizumab dose exceeded the threshold dose.

Drug-eluting beads loaded with irinotecan to treat synchronous liver-only metastases of colorectal cancer non-responsive to bevacizumab-based chemotherapy.

To evaluate the efficacy of drug-eluting beads loaded with irinotecan (DEBIRI) in colorectal cancer (CRC) patients with synchronous liver-only metastases non-responsive to bevacizumab-based chemotherapy (BBC). Fifty-eight patients were enrolled in this study. Treatment response to BBC and DEBIRI were determined by the morphological criteria and Choi's criteria, respectively. Progression-free survival (PFS) and overall survival (OS) were recorded. The correlation between pre-DEBIRI CT parameters and treatment response to DEBIRI was analyzed. CRC patients were divided into the BBC responsive group (R group) (n = 16) and the non-responsive group (n = 42), which was further divided into the NR group (23 patients who did not receive DEBIRI) and the NR+DEBIRI group (19 patients who received DEBIRI after failing BBC). Among the R, NR and NR+DEBIRI groups, the median PFS were 11, 12, and 4 months, respectively (p < 0.01); median OS were 36, 23, and 12 months, respectively (p = 0.01). In the NR+DEBIRI group, 33 metastatic lesions were treated with DEBIRI, of which 18 (54.5%) reached objective response. The receiver operating characteristic curve showed that the contrast enhancement ratio (CER) before DEBIRI could predict objective response (AUC = 0.737, p < 0.01). In CRC patients, DEBIRI can achieve acceptable objective response for liver metastases non-responsive to BBC. However, this locoregional control does not prolong survival. The pre-DEBIRI CER can predict OR in these patients. DEBIRI can act as an acceptable locoregional management in CRC patients with liver metastases non-responsive to BBC, and the pre-DEBIRI CER is a potential indicator of locoregional control.

Impact of genetic variants involved in the lipid metabolism pathway on progression free survival in patients receiving bevacizumab-based chemotherapy in metastatic colorectal cancer: a retrospective analysis of FIRE-3 and MAVERICC trials.

Antiangiogenic drug (AAD)-triggered oxygen and nutrient depletion through suppression of angiogenesis switches glucose-dependent to lipid-dependent metabolism. Blocking fatty acid oxidation can enhance AAD-mediated anti-tumor effects in colorectal cancer (CRC). Therefore, we hypothesised that genetic variants in the lipid metabolism pathway may predict clinical outcomes [overall response rate (ORR), overall survival (OS) and progression-free survival (PFS)] in metastatic CRC (mCRC) patients receiving bevacizumab-based first-line treatment. Genomic DNA from blood samples of patients enrolled in FIRE-3 (a global, randomised, open-label, phase 3 trial, between 2007-6-23 and 2012-9-19, discovery cohort: FOLFIRI/bevacizumab arm, n=107; control cohort: FOLFIRI/cetuximab arm, n=129) and MAVERICC (a global, randomised, open-label, phase II study, between 2011-8 and 2015-7, in United States, Canada, Estonia, Ireland, Switzerland, Norway, and Portugal. Validation cohort: FOLFIRI/bevacizumab arm, n=163) trials, was genotyped using the OncoArray-500K beadchip panel. The impact on OS and PFS of 17 selected SNPs in 7 genes involved in the lipid metabolism pathway (CD36, FABP4, LPCAT1/2, CPT1A, FASN, ACACA) was analysed using Kaplan-Meier curves, the log-rank test for univariate analyses and likelihood ratio tests of Cox proportional hazards regression parameters for multivariable analyses. ORR and SNP associations were evaluated using Chi-square or Fisher's exact tests. In the discovery cohort, patients with FASN rs4485435 any C allele (n=21) showed significantly shorter PFS (median PFS: 8.69 vs 13.48 months) compared to carriers of G/G (n=62) in multivariable (HR=2.87; 95%CI 1.4-5.9; p=0.00675) analysis. These data were confirmed in the validation cohort in multivariable analysis (HR=2.07, 95%CI: 1.15-3.74; p=0.02), but no association was observed in the cetuximab cohort of FIRE-3. In the comparison of bevacizumab vs cetuximab arm in FIRE-3, a significant interaction was shown with FASN rs4485435 (p=0.017) on PFS. Our study demonstrates for the first time, to our knowledge, that FASN polymorphisms may predict outcome of bevacizumab-based treatment in patients with mCRC. These findings support a possible role of the lipid metabolism pathway in contributing to resistance to anti-VEGF treatment. This work was supported by the National Cancer Institute [P30CA 014089 to H.-J.L.], Gloria Borges WunderGlo Foundation, Dhont Family Foundation, Victoria and Philip Wilson Research Fund, San Pedro Peninsula Cancer Guild, Ming Hsieh Research Fund, Eddie Mahoney Memorial Research Fund, Shanghai Sailing Program (22YF1407000), China National Postdoctoral Program for Innovative Talents (BX20220084), China Postdoctoral Science Foundation (2022M710768), National Natural Science Foundation of China (82202892).

Real-world utilization and acceptance of biosimilar bevacizumab in metastatic colorectal cancer in India

Background: To describe the patient characteristics and usage pattern of biosimilar bevacizumab for the treatment of metastatic colorectal cancer (mCRC) in India.Methods: This real-world, retrospective analysis included adult patients receiving biosimilar bevacizumab between April 2021 and March 2022.Results: A total of 1125 patients with mCRC who received biosimilar bevacizumab-based chemotherapy were included. The mean age at diagnosis was 57.8 years. Majority of the patients were males (71%) and belonged to the age groups of 41-76 years. The primary tumor site was right colon (52.6%) followed by left colon (29.2%) and rectum (17.3%), and tumor grade was reported as high in most (88.7%) of the patients. Majority of the patients received biosimilar bevacizumab-based chemotherapy as first-line therapy (61.3%), followed by second-line (31.9%) and third-line therapy (6.8%). In combination with biosimilar bevacizumab, FOLFOX (folinic acid, 5-fluorouracil, and oxaliplatin) was the most commonly administered chemotherapy regimen (42.9%), followed by CAPOX (capecitabine and oxaliplatin, 26.5%) and FOLFIRI (folinic acid, 5-fluorouracil, and irinotecan, 22.8%).Conclusions: Biosimilar bevacizumab-based chemotherapy is being widely used in real‑world clinical setting in India for the management of patients with mCRC.

Safety Assessment on Serious Adverse Events of Targeted Therapeutic Agents Prescribed for RAS Wild-Type Metastatic Colorectal Cancer: Systematic Review and Network Meta-Analysis.

Despite substantially elevated risk of serious adverse events (SAEs) from targeted therapy in combination with chemotherapy, comprehensive pharmacovigilance research is limited. This study aims to systematically assess SAE risks of commonly prescribed targeted agents (bevacizumab, cetuximab, and panitumumab) in patients with rat sarcoma viral oncogene homolog (RAS) wild-type metastatic colon cancer. Keyword searches of Cochrane Library, Clinical Key and MEDLINE were conducted per PRISMA-NMA guidelines. Frequentist network meta-analysis was performed with eight randomized controlled trials to compare relative risk (RR) of 21 SAE profiles. The risks of hematological, gastrointestinal, neurological SAE were insignificant among targeted agents (p > 0.05). The risk of serious hypertension was substantially elevated in bevacizumab-based chemotherapy (p < 0.05), whereas panitumumab-based chemotherapy had markedly elevated risk of serious thromboembolism (RR 3.65; 95% CI 1.30–10.26). Although both cetuximab and panitumumab demonstrated increased risk of serious dermatological and renal toxicities, panitumumab-based chemotherapy has relatively higher risk of skin toxicity (RR 15.22; 95% CI 7.17–32.35), mucositis (RR 3.18; 95% CI 1.52–6.65), hypomagnesemia (RR 20.10; 95% CI 5.92–68.21), and dehydration (RR 2.81; 95% CI 1.03–7.67) than cetuximab-based chemotherapy. Thus, further studies on risk stratification and SAE management are warranted for safe administration of targeted agents.

A Genetic Variant in CD274 Is Associated With Prognosis in Metastatic Colorectal Cancer Patients Treated With Bevacizumab-Based Chemotherapy.

Bevacizumab plus chemotherapy is a well-established first-line treatment for metastatic colorectal cancer (mCRC). We investigated whether polymorphisms of genes involved in immune regulation signaling are related to the clinical outcome of mCRC patients treated with bevacizumab-based chemotherapy. In this study, we genotyped 14 single-nucleotide polymorphisms (SNP) in IFN-γ/IFNGRs/JAKs/STATs/PD-L1 pathway by using DNA from blood samples of 141 mCRC patients treated with first-line bevacizumab-based chemotherapy. In the univariate and multivariate analysis, patients with AA genotype of CD274:rs2297136 had a significantly better PFS and OS than patients with AG or GG genotype (10.8 versus 9.8, log-rank P=0.0031; 31.4 versus 20.9, log-rank P=0.0233). Patients with AG/GG genotype of IFNGR1:rs2234711, CT/TT genotype of IFNGR1:rs9376267 also showed longer OS than patients with AA or CC genotype, however, the statistic did not reach significant after adjusted by clinical factors in the multivariate analysis. A nomogram based on the genetic variants and clinic characteristics was developed with a good accuracy to predict patients’ survival. Our result indicates that CD274:rs2297136 is one of the most important predictors for the prognosis of mCRC patients treated with bevacizumab-based chemotherapy, if further validated in larger population.

Tolerability on Serious Adverse Events of First-Line Bevacizumab and Cetuximab for RAS Wild-Type Metastatic Colorectal Cancer: A Systematic Review and Meta-Analysis.

Proper medication management is crucial in metastatic colorectal cancer because of its substantially low survival rate. There has been advancing evidence on the efficacy of the two most prescribed targeted agents (bevacizumab and cetuximab); however, comprehensive analyses on their safety are limited. This study aims to comprehensively assess the clinical safety of first-line bevacizumab and cetuximab-based chemotherapy in unresectable RAS wild-type metastatic colorectal cancer patients and to provide guidance on the selection of appropriate targeted therapeutic agents. Keyword searches of MEDLINE, Cochrane Library, and ClinicalKey were conducted per PRISMA guidelines. We performed pooled analysis on safety outcomes from six studies which administered FOLFOX (5-fluorouracil, leucovorin, and oxaliplatin) or FOLFIRI (5-fluorouracil, leucovorin, irinotecan) as backbone chemotherapy. Thirty different adverse events from six categories were compared. First-line bevacizumab-based chemotherapy substantially lowered the risks of adverse events related to the dermatological (RR 0.24, 95% CI: 0.11–0.53, p < 0.00001) and renal systems (RR 0.57, 95% CI: 0.37–0.86, p = 0.007), while significantly increasing the incidence of cardiovascular adverse events (RR 4.65, 95% CI: 1.83–11.78, p = 0.001). Thus, first-line cetuximab-based chemotherapy increases patient susceptibility to dermatological and renal adverse events, especially with rash and electrolyte disorders, whereas bevacizumab-based chemotherapy increases cardiovascular risks such as hypertension and arrhythmia.

481P Evaluation of serum mid-infrared spectroscopy as new prognostic marker for bevacizumab-based chemotherapy in first-line treatment of metastatic colorectal cancer

Bevacizumab-based chemotherapy is the recommended first-line therapeutic strategy for metastatic colorectal cancer (mCRC). Yet, some patients do not benefit from this association and until now robust predictive or prognostic biomarker with clinical practice applicability have not been identified. Serum analysis by mid-infrared spectroscopy (SMIRS) allows a rapid and non-invasive metabolomic profiling of an individual. Its prognostic value has never been assessed in mCRC. The aim of this study was to evaluate the prognostic yield of SMIRS in patients receiving first-line bevacizumab-based treatment for mCRC.

A Case of Granulocyte Colony-stimulating Factor-producing Pulmonary Pleomorphic Carcinoma with Metastasis to the Small Intestine in Which Surgery and Bevacizumab-based Chemotherapy Were Effective

A Case of Granulocyte Colony-stimulating Factor-producing Pulmonary Pleomorphic Carcinoma with Metastasis to the Small Intestine in Which Surgery and Bevacizumab-based Chemotherapy Were Effective

Occurence of RAS reversion in metastatic colorectal cancer patients treated with bevacizumab.

Background: A disappearance of RAS mutations in the plasma of about 50% of mCRCs (metastatic colorectal cancers) treated with bevacizumab-based chemotherapy has been reported. Our aim was to evaluate the same issue at tissue level.Materials and Methods: Using next-generation sequencing and real-time PCR approaches, we characterized the primary tumor (PT) and paired liver metastases in 28 RAS mutant mCRCs. Patients were subdivided into 3 treatment groups: 1) bevacizumab plus chemotherapy; 2) chemotherapy alone; 3) any systemic therapy (control group). In groups 1 and 2, liver metastases were resected after removal of PT and subsequent neoadjuvant systemic therapy.Results: RAS mutant alleles are at the same percentage in PT and liver metastases in the control group, while a significant reduction of the level of RAS mutations was detected in 57.1% of cases in group 1 and in 8.3% of cases in group 2. Differences among groups are statistically significant (p = 0.038).Conclusions: Most of mCRC patients treated with bevacizumab-containing regimens experience a strong reduction of RAS mutant cells, suggesting bevacizumab as particularly active against RAS mutant cells. This finding might have potential therapeutic implications, as anti-EGFR could be reconsidered in primarily RAS mutant patients reverted to a wild-type status after bevacizumab exposure.

Treatment responses and disease dynamics in patients with untreated metastatic colorectal cancer receiving bevacizumab-based sequential versus combination chemotherapy: Analysis of a phase 3 trial (AIO KRK0110, XELAVIRI study).

3571 Background: Early response parameters such as early tumor shrinkage (ETS), depth of response (DpR), and time to DpR represent exploratory endpoints that may serve as early efficacy endpoints and potential predictors of long-term outcome. We analyzed the association of these endpoints with bevacizumab-based sequential (initial fluoropyrimidines) versus combination (initial fluoropyrimidines plus irinotecan) chemotherapy within a randomized phase III trial. Methods: DpR (change from baseline to smallest tumor diameter), ETS (≥20% reduction in tumor diameter at first reassessment), and time to DpR (study randomization to DpR-image) were analyzed in the XELAVIRI-trial. Moreover, progression-free survival (PFS) and overall survival (OS) were evaluated with ETS as stratification parameter (ETS vs. no ETS) according to treatment arm, molecular subgroup, and sex. Results: 370 patients were available for analysis of early treatment response parameters. A higher rate of ETS (60.9% vs. 43.5%; p = 0.001) and significantly greater DpR (-40.0% vs. -24.7%; p &lt; 0.001) were observed in the initial combination compared to the sequential therapy arm, respectively. The improvement of ETS and DpR was pronounced in the subpopulation of RAS/ BRAF wildtype patients. Male in contrast to female patients significantly benefitted from initial combination treatment in terms of median DpR (male: -40.0% vs. -22.2%; p &lt; 0.001; female: -34.0% vs. -24.4%; p = 0.13) and rate of ETS (male: 64.8% vs. 40.2%; p &lt; 0.001; female: 52.5% vs. 49.3%; p = 0.73). Achievement of ETS correlated with improved survival irrespective of treatment arm (PFS: p &lt; 0.001; OS: p = 0.012) and molecular subgroup (PFS: p &lt; 0.001; OS: p &lt; 0.001). Whereas the survival benefit in male patients achieving ETS was statistically significant (PFS: p &lt; 0.001, HR 0.532 (0.409-0.692); OS: p &lt; 0.001, HR 0.574 (0.437-0.756)), there were no significant differences in PFS (p = 0.107) and OS (p = 0.965) of female patients depending on ETS. Conclusions: In the XELAVIRI trial, initial irinotecan-based combination therapy with bevacizumab improves ETS and DpR in mCRC patients. Improvement in early response parameters appears pronounced in patients with RAS/ BRAF wildtype tumors suggesting a high sensitivity to irinotecan-based treatment. ETS was predictive of PFS and OS regardless of treatment arm. This finding was rather driven by male than female patients, potentially indicating that ETS might be less predictive of long-term outcome in an elderly, female population.

First-line therapy of bevacizumab plus chemotherapy versus cetuximab plus chemotherapy for metastatic colorectal cancer patients with mucinous adenocarcinoma or mucinous component.

BackgroundTo compare the efficacy of first‐line bevacizumab plus chemotherapy with cetuximab plus chemotherapy based on the stratification of metastatic colorectal cancer (mCRC) patients with mucinous adenocarcinoma (MA) or mucinous component (MC).MethodsA retrospective study involving all mCRC patients receiving first‐line bevacizumab‐based or cetuximab‐based chemotherapy at our hospital from September 2013 to January 2020 was conducted. Overall survival (OS), progression‐free survival (PFS), and objective response rate (ORR) were compared between the cetuximab‐chemotherapy group and the bevacizumab‐chemotherapy group on the basis of the conventional pathological classification of MA or MC.ResultsA total of 620 patients with mCRC were included in our study, consisting of 141 (22.7%) patients with MA/MC and 479 (77.3%) patients with non‐mucinous adenocarcinoma (NMA). In the MA/MC cohort, patients who were treated with bevacizumab‐based chemotherapy were associated with significantly better OS than those treated with cetuximab‐base chemotherapy (30.0 vs. 26.3 months, p = 0.002), irrespective of tumor sites. The efficacy of bevacizumab‐based chemotherapy was higher in nearly all subgroups as shown in the subgroup analysis. In the NMA cohort, median OS was better in the cetuximab plus chemotherapy group than that in the bevacizumab plus chemotherapy group (32.2 vs. 27.0 months, p = 0.005) for left‐side mCRC patients, whereas OS was significantly longer in the bevacizumab plus chemotherapy group for right‐side mCRC patients (26.0 vs. 20.9 months, p = 0.013).ConclusionConventional pathological classification (e.g. MA/MC) should be considered when tailoring the individualized optimal treatment for mCRC. Bevacizumab plus chemotherapy as first‐line therapy may be the optimal option for patients with MA/MC.

Enhanced Rim on MDCT of Colorectal Liver Metastases: Assessment of Ability to Predict Progression-Free Survival and Response to Bevacizumab-Based Chemotherapy.

OBJECTIVE. The purpose of this article is to evaluate the enhanced rim on the portal venous phase (PVP) on MDCT as a predictor of 1-year progression-free survival (PFS) and response to bevacizumab-based chemotherapy in patients with colorectal liver metastases (CRLM). MATERIALS AND METHODS. We retrospectively identified 111 patients with primary unresectable CRLM treated with bevacizumab-based chemotherapy at two institutions between 2012 and 2018. Pretreatment contrast-enhanced MDCT images were reviewed and data on clinical characteristics were collected from the electronic medical records. Univariable and multivariable analyses were conducted to assess several imaging features and clinical characteristics as potential predictors of 1-year PFS and objective response rate (ORR). RESULTS. After 1 year of follow-up, liver metastatic tumor progression was detected in 52 patients (46.8%) after bevacizumab-based chemotherapy. A log-rank test showed that enhanced rim on PVP (chi-square test, 5.862; p = 0.015) and the occurrence of liver resection surgery (chi-square test, 7.836; p = 0.005) were significant predictors of 1-year PFS. Multivariable analysis showed that enhanced rim on PVP images was an independent predictor of 1-year PFS (hazard ratio, 0.510; 95% CI, 0.282-0.926; p = 0.027) and ORR (odds ratio, 4.694; p < 0.001). CONCLUSION. The presence of an enhanced rim on PVP MDCT is an independent predictor of survival and response to bevacizumab-based chemotherapy among patients with CRLM.

P-225 KRAS codon 12 and 13 mutations in metastatic colorectal cancer: Predictive marker in first-line bevacizumab-based chemotherapy

The three human RAS genes (KRAS, NRAS, and HRAS) are the most frequently mutated oncogenes and present in 45% of patients with colorectal cancer, being known as an early event in tumorigenesis. Most KRAS mutations (90%) occur in codons 12 and 13 of exon 2. However, the role of different KRAS mutations and its prognostic value remains controversial, with few studies showing a worse progression-free survival and overall survival with codon 12 KRAS mutation. The aim of our study was to evaluate KRAS codon mutation (codon 12 and 13) as a predictive marker of first-line bevacizumab-based chemotherapy response.