Treatment Of Metastatic Colorectal Cancer Research Articles

Carcinoembryonic antigen kinetics predict response to first-line treatment in metastatic colorectal cancer: Analysis from PRODIGE 9 trial.

To examine the relationship between carcinoembryonic antigen (CEA) kinetics and prognosis in metastatic colorectal cancer (mCRC) patients receiving first-line chemotherapy in the PRODIGE9 trial. Associations between monthly CEA measurements within 6 months since baseline and progression-free survival (PFS) were evaluated using a joint-latent class-mixed model. A validation set was used to test our prognosis model. Correlations between CEA trajectories (classes) and baseline characteristics were also investigated. Three classes were identified. Class 1 had low baseline CEA with small variations. Class 2 had high baseline CEA with a rapid decrease reaching the same CEA level at 6 months as in class 1. Class 3 had high baseline CEA with a transient decrease followed by an increase to reach, at 6 months, the same CEA level as at baseline. Six-month PFS was significantly lower in class 3 than in classes 1 and 2 (57% vs. 91% and 93% respectively; p<0.01). Class 3 was significantly associated with ECOG 2 status, a high LDH level and non-resected primary tumor. Variations in CEA kinetics correlate with prognosis in patients receiving first-line chemotherapy for mCRC. We propose here a user-friendly application to classify CEA trajectory.

FOLFOXIRI plus bevacizumab and atezolizumab as upfront treatment of unresectable metastatic colorectal cancer (mCRC): Updated and overall survival results of the phase II randomized AtezoTRIBE study.

3500 Background: AtezoTRIBE (NCT03721653) is a phase II randomized trial in which unresectable mCRC pts were randomized 1:2 to 1st-line FOLFOXIRI/bev [arm A] or FOLFOXIRI/bev/atezo [arm B]. Adding atezo to FOLFOXIRI/bev was safe and improved PFS (primary endpoint), with a modest benefit also among pts with pMMR tumors. Subgroup analyses suggest that TMB and Immunoscore IC (IS IC) -an IHC biomarker measuring CD8 and PD-L1 cell densities and their proximity- may identify pts with pMMR tumors deriving benefit from adding atezo to FOLFOXIRI/bev. Methods: The study had 85% power to detect a HR for PFS (time from randomization to 1st PD or death [PD1]) of .66 in favor of arm B with 1-sided α error of .10. Secondary endpoints included PFS2 (time from randomization to PD on any treatment given after PD1 or death [PD2]), 2nd PFS (time from PD1 to PD2), and OS. MMR, TMB, IS IC were correlated to clinical outcome. Results: 218 pts (arm A/B:73/145) were enrolled. Main pts’ characteristics were right-sided 44%/45%, RAS mut 71%/74%, BRAF mut 14%/8%, dMMR 7%/6%, high TMB 10%/12%, high IS IC 32%/32%. At a median follow-up of 37.0 mos, 175 (80%, arm A/B: 64/111) PD1, 150 (69%, arm A/B: 53/97) PD2, and 118 (54%, arm A/B: 43/75) OS events were collected. Out of 175 pts with a PD1 event, 135 (77%, arm A/B:50/85) received a subsequent treatment; among them, 121 pts (arm A/B: 43/78) had a PD2 event. PFS, PFS2, 2nd PFS and OS results in the intention-to-treat (ITT) population and the pMMR group are listed in the Table. In the ITT population, significant interactions between treatment and MMR status (Pint .011), TMB (Pint .008), and IS IC (Pint .037) were reported in terms of PFS. Only IS IC was associated with a differential OS benefit (Pint .065), with pts bearing IS IC-high tumors deriving benefit from adding atezo (HR 0.43, 95%CI 0.19-1.00), differently than those with IS IC-low tumors (HR 1.09, 95%CI 0.65-1.83). In the pMMR group, significant interactions between treatment and TMB and IS IC were reported in terms of PFS (Pint .016 and .051, respectively) and OS (Pint .043 and .063, respectively). Pts bearing IS IC-high tumors derived higher OS benefit from adding atezo (HR 0.44, 95%CI 0.19-1.03), than those with IS IC-low tumors (HR 1.15, 95% CI 0.67-1.97). Conclusions: Pts with IS IC-high and/or TMB high pMMR mCRC seem to derive a survival benefit from adding atezo to FOLFOXIRI/bev as upfront treatment. These findings deserve confirmation in a properly designed phase III trial. Clinical trial information: NCT03721653 . [Table: see text]

SO-25 Modified (m)-FOLFOXIRI plus cetuximab versus m-FOLFOXIRI plus bevacizumab as initial treatment for RAS and BRAF wild-type metastatic colorectal cancer: Updated survival analysis of the DEEPER trial by JACCRO

SO-25 Modified (m)-FOLFOXIRI plus cetuximab versus m-FOLFOXIRI plus bevacizumab as initial treatment for RAS and BRAF wild-type metastatic colorectal cancer: Updated survival analysis of the DEEPER trial by JACCRO

Metastatic colorectal cancer-Modern treatment strategies and sequences

The treatment of metastatic colorectal cancer (mCRC) has been considerably expanded and relevantly improved in recent years with new strategies, such as resection of liver and/or lung metastases, induction and maintenance treatment, the establishment of targeted therapies and molecularly defined strategies in defined subgroups. This article presents evidence-based treatment options and algorithms, with afocus on systemic treatment.

A Systematic Review and Meta-Analysis of Trifluridine/Tipiracil plus Bevacizumab for the Treatment of Metastatic Colorectal Cancer: Evidence from Real-World Series.

Colorectal cancer is the most prevalent gastrointestinal neoplasm. When metastatic, the disease has limited systemic treatment options. Novel targeted therapies have expanded these options for subsets with specific molecular alterations, such as microsatellite instability (MSI)-high cancers, but additional treatments and combinations are in urgent need to improve outcomes and improve survival of this incurable disease. The fluoropyrimidine-derivative trifluridine, in combination with tipiracil, has been introduced as a third-line treatment, and more recently, it was studied in combination with bevacizumab. This meta-analysis reports on studies with this combination in clinical practice outside clinical trials. A literature search in the Medline/PubMed and Embase databases was executed for finding series of trifluridine/tipiracil with bevacizumab in metastatic colorectal cancer. Criteria for inclusion in the meta-analysis were English or French language of the report, inclusion of twenty or more patients with metastatic colorectal cancer treated with trifluridine/tipiracil in combination with bevacizumab outside of a trial and containing information regarding response rates, progression-free survival (PFS), and overall survival (OS). Information on the demographics of the patients and on adverse effects of treatment was also collected. Eight series with a total of 437 patients were eligible for the meta-analysis. The performed meta-analysis discovered a summary response rate (RR) of 2.71% (95% confidence interval (CI): 1.11-4.32%) and a disease control rate (DCR) of 59.63% (95% CI: 52.06-67.21%). Summary PFS was 4.56 months (95% CI: 3.57-5.55 months), and summary OS was 11.17 months (95% CI: 10.15-12.19 months). Common adverse effects identified mirrored the adverse-effect profile of the two components of the combination. The current systematic review and meta-analysis reports the efficacy of trifluridine/tipiracil with bevacizumab in advanced lines of therapy for metastatic colorectal cancer in the setting of clinical practice outside clinical trials. Discovery of predictive biomarkers of response to trifluridine/tipiracil with bevacizumab will promote the tailoring of this treatment to individual patients to maximize clinical benefit.

P173 THERAPEUTIC MANAGEMENT OF FLUOROPYRIMIDINE CARDIOTOXICITY: AN ANECDOTAL CASE

Abstract Background Fluoropirimidine represents one of the staple treatment of metastatic colorectal cancer; chemoterapy–based cardiotoxicity is unfortunately habitual in clinical practice. Raltitrexed could represent a valid alterantive to 5–FU in patients with cardiovascular comorbidities or in which 5–FU Has not been tolerated. Case Report Our patient is a 73 years–old woman, who underwent left colon surgical resection due to subocclusion; a whola body staging was not performed. After surgery, patient underwent CT scan,i n which multiple liver, lung and peritoneal metastases were identified. Biomolecular profiling assessment was perfomed (RAS, BRAF Wild type, DPYD*6 heterozigosis mutation). On January 2020, patient began FOLFIRI + PANITUMUMAB scheme as first line treatment (total cycles perfomed: 15). On January 2021, PD was detected though restaging imaging, and patient was subsequently treated with FOLFOX + BEvacizumab as second line. After 5 cycles, patient developed dyspnoea and palpitation; EKG was performed depicting Atrial fibrillation with heart rate: 73bpm, preserved biventricular systolic function and increased BNP and NT–pro–BNP serum concentration. According to patient’s high thromboembolic risk, oral anticoagulation (NOAC) was administered and multidisciplinary discussion was scheduled. NAO were preferred to Vitamin K antagonists due to drug–drug interactions; the treatment–of–choice was Apixaban 2.5 mg bis in die. Given the fact that aforementioned condition could have been attributed to 5–FU cardiologic toxicity, Raltitrexed was administered in lieu thereof 5–FU once synusal rythm was restored (TOMOX scheme). Bevacizumab administration was restored after a longer waiting (ca 2 months); the patient uderwent systematic and serial cardiologic assessment through clinical and EKG consults. Conclusion Our case report depicts the undelayable necessity of a Multidisciplinar collaboration in which oncologists and cardiologists could propose personalized treatment strategies which ensure correct antitumoral activities without significant and life–threatening toxicities.

Cost-Effectiveness Analysis of Monoclonal Antibodies Associated With Chemotherapy in First-Line Treatment of Metastatic Colorectal Cancer

ObjectivesThis study aimed to evaluate the cost-effectiveness of anti–epidermal growth factor receptor (cetuximab and panitumumab) or anti–vascular endothelial growth factor (bevacizumab) monoclonal antibodies associated with conventional chemotherapy (CT) (fluorouracil and leucovorin with irinotecan) as a first-line treatment for unresectable metastatic colorectal cancer. MethodsA partitioned survival analysis model was adopted to simulate direct health costs and benefits comparing therapeutic options in a 10 years’ time horizon. Model data were extracted from the literature and costs were obtained from Brazilian official government databases. The analysis considered the perspective of the Brazilian Public Health System; costs were measured in local currency (BRL) and benefits in quality-adjusted life-years (QALY). A 5% discount rate was applied to costs and benefits. Alternative willingness-to-pay scenarios, varying from 3 to 5 times the cost-effectiveness threshold established in Brazil, were estimated. The results were presented incremental cost-effectiveness ratio (ICER), and both deterministic and probabilistic sensitivity analyses were performed. ResultsThe most cost-effective choice would be the association of CT with panitumumab, with an ICER of $58 330.15/QALY compared with isolated CT. The second-best option was CT with bevacizumab and panitumumab, with an ICER of $71 195.40/QALY compared with panitumumab alone. Although having higher costs, the second-best option was the most effective. Both strategies were cost-effective in part of the Monte Carlo iterations, considering the 3× threshold. ConclusionsThe therapeutic option CT + panitumumab + bevacizumab represents the most significant effectiveness gain in our study. It is the second-lowest cost-effectiveness, and this option includes monoclonal antibodies association for patients with and without KRAS mutation.

ADAMDEC1 induces EMT and promotes colorectal cancer cells metastasis by enhancing Wnt/β-catenin signaling via negative modulation of GSK-3β

Colorectal cancer (CRC) is a highly invasive malignant tumor with pronounced proliferation capacity and is prone to epithelial-mesenchymal transition (EMT) and subsequent metastasis. A disintegrin and metalloproteinase domain-like decysin 1 (ADAMDEC1) is a proteolytically active metzincin metalloprotease that is involved in extracellular matrix remodeling, cell adhesion, invasion, and migration. However, the effects of ADAMDEC1 on CRC are unclear. This study was conducted to investigate the expression and biological role of ADAMDEC1 in CRC. We found that ADAMDEC1 was differentially expressed in CRC. Further, ADAMDEC1 was found to enhance CRC proliferation, migration, and invasion while inhibiting apoptosis. Exogenous ADAMDEC1 overexpression elicited EMT in CRC cells, as evidenced by alterations in E-cadherin, N-cadherin, and vimentin expression. In ADAMDEC1 knockdown or ADAMDEC1 overexpressed CRC cells, the western blotting analysis revealed that Wnt/β-catenin signaling pathway-related proteins were down-regulated or up-regulated. Furthermore, an inhibitor of the Wnt/β-catenin pathway (FH535) partially negated the effect of ADAMDEC1 overexpression on EMT and CRC cell proliferation. Further mechanistic research suggested that ADAMDEC1 knockdown may upregulate GSK-3β and inactivate the Wnt/β-catenin pathway, accompanied by suppressing the expression of β-catenin. Additionally, the blocker of GSK-3β (CHIR-99021) markedly abolished the inhibitory effect of ADAMDEC1 knockdown on Wnt/β-catenin signaling. Our results indicate that ADAMDEC1 promotes CRC metastasis by negatively regulating GSK-3β, activating the Wnt/β-catenin signaling pathway, and inducing EMT, presenting its potential as a therapeutic target for the treatment of metastatic CRC.

Suvemcitug as second-line treatment of advanced or metastatic solid tumors and with FOLFIRI for pretreated metastatic colorectal cancer: phase Ia/Ib open label, dose-escalation trials

Suvemcitug (BD0801), a novel humanized rabbit monoclonal antibody against vascular endothelial growth factor, has demonstrated promising antitumor activities in preclinical studies. The phase Ia/b trials investigated the safety and tolerability and antitumor activities of suvemcitug for pretreated advanced solid tumors and in combination with FOLFIRI (leucovorin and fluorouracil plus irinotecan) in second-line treatment of metastatic colorectal cancer using a 3+ 3 dose-escalation design. Patients received escalating doses of suvemcitug (phase Ia: 2, 4, 5, 6, and 7.5 mg/kg; phase Ib: 1, 2, 3, 4, and 5 mg/kg plus FOLFIRI). The primary endpoint was safety and tolerability in both trials. All patients in the phase Ia trial had at least one adverse event (AE). Dose-limiting toxicities included grade 3 hyperbilirubinemia (one patient), hypertension and proteinuria (one patient), and proteinuria (one patient). The maximum tolerated dose was 5 mg/kg. The most common grade 3 and above AEs were proteinuria (9/25, 36%) and hypertension (8/25, 32%). Forty-eight patients (85.7%) in phase Ib had grade 3 and above AEs, including neutropenia (25/56, 44.6%), reduced leucocyte count (12/56, 21.4%), proteinuria (10/56, 17.9%), and elevated blood pressure (9/56, 16.1%). Only 1 patient in the phase Ia trial showed partial response, [objective response rate 4.0%, 95% confidence interval (CI) 0.1% to 20.4%] whereas 18/53 patients in the phase Ib trial exhibited partial response (objective response rate 34.0%, 95% CI 21.5% to 48.3%). The median progression-free survival was 7.2 months (95% CI 5.1-8.7 months). Suvemcitug has an acceptable toxicity profile and exhibits antitumor activities in pretreated patients with advanced solid tumors or metastatic colorectal cancer.

Variability in surgical treatment of metastatic colorectal cancer (literature review)

Background. Colorectal cancer (CRC) is one of the most common cancers and one of the most leading causes of cancer-related deaths worldwide. Approximately 35 % of CRC patients have liver metastases at the time of diagnosis. These patients have a poor prognosis, with the 5-year survival rate of 15 %. Given the poor survival with currently approved methods, the development of the optimal treatment options is needed.The purpose of the study was to search for data on the development of surgical techniques for the treatment of patients with metastatic CRC (mCRC) with isolated liver metastasis.Material and Methods. Literature search was carried out in Medline, Cochrane Library, Elibrary and Pubmed databases, including publications characterizing historical and modern results (from 1976 to 2021).Results. Liver resection in mCRC patients with isolated liver metastasis is the only treatment that offers a chance of increasing the 5-year survival rate up to 45–60 %. Radical surgery should include the removal of the primary tumor and all metastases with negative histological resection margins while preserving sufficient functional liver parenchyma. The paper discusses various approaches to surgical treatment of mCRC patients with liver metastases, with an assessment of their advantages and disadvantages, as well as presents data on perioperative and oncological outcomes.Conclusion. The surgical treatment strategy should be adapted for each mCRC patient with synchronous liver metastases. The core function of a multidisciplinary team is to determine the patient’s treatment plan combining surgery and systemic chemotherapy, which will improve the immediate and long-term treatment outcomes.

SEOM-GEMCAD-TTD clinical guidelines for the systemic treatment of metastatic colorectal cancer (2022)

Colorectal cancer (CRC) is the second leading cause of cancer deaths in Spain. Metastatic disease is present in 15–30% of patients at diagnosis and up to 20–50% of those with initially localized disease eventually develop metastases. Recent scientific knowledge acknowledges that this is a clinically and biologically heterogeneous disease. As treatment options increase, prognosis for individuals with metastatic disease has steadily improved over recent decades. Disease management should be discussed among experienced, multidisciplinary teams to select the most appropriate systemic treatment (chemotherapy and targeted agents) and to integrate surgical or ablative procedures, when indicated. Clinical presentation, tumor sidedness, molecular profile, disease extension, comorbidities, and patient preferences are key factors when designing a customized treatment plan. These guidelines seek to provide succinct recommendations for managing metastatic CRC.

Predictive potential of angiopoietin-2 in a mCRC subpopulation treated with vanucizumab in the McCAVE trial.

Angiopoetin-2 (Ang-2) is a key mediator of tumour angiogenesis. When upregulated it is associated with tumour progression and poor prognosis. Anti-vascular endothelial growth factor (VEGF) therapy has been widely used in the treatment of metastatic colorectal cancer (mCRC). The potential benefit of combined inhibition of Ang-2 and VEGF-A in previously untreated patients with mCRC was evaluated in the phase II McCAVE study (NCT02141295), assessing vanucizumab versus bevacizumab (VEGF-A inhibitor), both in combination with mFOLFOX-6 (modified folinic acid [leucovorin], fluorouracil and oxaliplatin) chemotherapy. To date, there are no known predictors of outcome of anti-angiogenic treatment in patients with mCRC. In this exploratory analysis, we investigate potential predictive biomarkers in baseline samples from McCAVE participants. Tumour tissue samples underwent immunohistochemistry staining for different biomarkers, including Ang-2. Biomarker densities were scored on the tissue images using dedicated machine learning algorithms. Ang-2 levels were additionally assessed in plasma. Patients were stratified by KRAS mutation status determined using next generation sequencing. Median progression-free survival (PFS) for each treatment group by biomarker and KRAS mutation was estimated using Kaplan-Meier plots. PFS hazard ratios (and 95% confidence intervals) were compared using Cox regression. Overall low tissue baseline levels of Ang-2 were associated with longer PFS, especially in patients with wild-type KRAS status. In addition, our analysis identified a new subgroup of patients with KRAS wild-type mCRC and high levels of Ang-2 in whom vanucizumab/mFOLFOX-6 prolonged PFS significantly (log-rank p=0.01) by ~5.5 months versus bevacizumab/mFOLFOX-6. Similar findings were seen in plasma samples. This analysis demonstrates that additional Ang-2 inhibition provided by vanucizumab shows a greater effect than single VEGF-A inhibition in this subpopulation. These data suggest that Ang-2 may be both a prognostic biomarker in mCRC and a predictive biomarker for vanucizumab in KRAS wild-type mCRC. Thus, this evidence can potentially support the establishment of more tailored treatment approaches for patients with mCRC.

Updates in the Treatment of Metastatic Colorectal Cancer

Molecular biomarker testing for all patients with metastatic colorectal cancer (CRC) has become increasingly important because identifying targetable alterations can lead to meaningful clinical benefits. At a minimum, testing should include RAS, BRAF mutational status, microsatellite instability status, HER2 expression, NTRK, and RET mutations. For HER2-amplified cancer, the NCCN Guidelines offer multiple treatment options, including trastuzumab in combination with tucatinib or pertuzumab, and trastuzumab-deruxtecan. Combination trastuzumab + tucatinib has recently received approval by the FDA for refractory RAS wild-type, HER2-amplified CRC. The addition of bevacizumab to trifluridine/tipiracil treatment has significantly prolonged median overall survival compared with trifluridine/tipiracil alone, regardless of molecular subtypes. KRAS G12C–targeted therapies are on the horizon, with several agents in ongoing studies. Furthermore, bilevel blockade is important when addressing MAP kinase pathway alterations.

Exploratory randomized phase II trial for optimizing treatment dosage and duration of adjuvant S-1 plus oxaliplatin in patients with stage III colon cancer: YCOG1402 (SOAP trial).

Conventionally, the recommended duration of adjuvant chemotherapy of colon cancer had been 6 months. The IDEA Collaboration suggested that shortening capecitabin and oxaliplatin (CAPOX) adjuvant chemotherapy may be possible. S-1 and oxaliplatin (SOX) treatment is standard treatment in metastatic colorectal cancer in Japan. The aim of this study was to optimize treatment dosage and duration of adjuvant SOX in stage III colon cancer. This trial was as open-label multi-center randomized phase II study. Patients with stage III colon cancer were randomly assigned to 3 months or 6 months of adjuvant SOX treatment in different doses: 130 mg/m2 (3 months) or 100 mg/m2 (6 months) of oxaliplatin. The primary endpoint was 3-year disease-free survival (DFS) and the null hypothesis for the primary endpoint was that the 3-year DFS was ≤72% in each arm and was tested with a one-sided significance level of 10%. Eighty-two patients were assigned to the 6 months arm and 81 to the 3 months arm. The 3-year DFS was 75.0% (80% CI 67.95-80.72, p = 0.282) in the 6 months arm and 76.9% (80% CI 70.1-82.38, p = 0.171) in the 3 months arm. Treatment completion rate and relative dose intensity (RDI) were higher in 3 months than 6 months arm. The adverse events (AE) were similar in both arms. The 3-year DFS was not significantly superior to null hypothesis in both 3 months and 6 months arms for the stage III colon cancer. Primary endpoint was not achieved. The SOX regimen was not feasible in long-term outcomes.

Elevated Preoperative Serum Vascular Endothelial Growth Factor Does Not Predict Poor Outcomes in Curatively Resected Non-metastatic Colorectal Cancer Treated Without Neoadjuvant Therapy.

Vascular endothelial growth factor (VEGF) influences colorectal cancer (CRC) progression and is a key target in the treatment for metastatic CRC. However, the oncological impact of preoperative circulating VEGF in non-metastatic CRC (non-mCRC) has not been clearly elucidated. Herein, we have investigated the prognostic significance of elevated preoperative serum VEGF concentration in curatively resected non-mCRC without neoadjuvant therapy. A total of 474 patients with pStage I-III CRC who underwent curative resection without neoadjuvant therapy were included. The relationship between preoperative serum VEGF concentration and clinicopathologic characteristics, overall survival (OS), and recurrence-free survival (RFS) were investigated. The median follow-up duration was 47.4 months. No significant relationship between preoperative VEGF and clinicopathologic characteristics including tumor markers, pStage, and lymphovascular invasion was identified; however, VEGF values were wide-ranged in every pStage. Patients were categorized into four groups as follows: VEGF < median, median to 75th percentile, 75th percentile to 90th percentile, and ≥90th percentile. A tendency for a difference in 5-year OS (p=0.064) and RFS (p=0.089) was observed among the groups; however, OS and RFS were not correlated with VEGF elevation. In multivariate analyses, VEGF ≥90th percentile was paradoxically associated with better RFS. Preoperative elevated serum VEGF concentration was associated with neither worse clinicopathological characteristics nor worse long-term outcomes in curatively resected non-mCRC. The prognostic value of preoperative circulating VEGF in initially resectable non-mCRC remains limited.

CEA dynamics for predicting response after anti-EGFR monoclonal antibody treatment in metastatic colorectal cancer

Carcinoembryonic antigen (CEA) is the most widely used tumor marker in metastatic colorectal cancer (mCRC). However, its potential as a predictive marker of progression in mCRC during systemic chemotherapy, particularly in patients receiving monoclonal antibodies as a combination therapy, has remained of interest. Herein, we investigated whether CEA changes could predict disease progression and clinical outcomes in patients with mCRC cotreated with systemic chemotherapy and/or biologic agents. A total of 1261 patients with mCRC undergoing a first-line systemic treatment were included in this retrospective study. We analyzed the optimal cut-off value for CEA changes to predict progression at the first response evaluation by the treatment arm (chemotherapy alone, chemotherapy plus anti-vascular endothelial growth factor (VEGF) monoclonal antibody [mAb], and chemotherapy plus anti-epidermal growth factor receptor [EGFR] mAb). These cut-off values were then used to predict overall survival (OS) and progression-free survival (PFS). When stratified by their treatment arm, 891 (70.6%), 266 (21.0%), and 104 (8.2%) of the study patients were included in the chemotherapy alone-, anti-VEGF mAb, and anti-EGFR mAb groups, respectively. The optimal CEA cut-off values were 16.5% and 38.9% increase in the whole cohort and anti-EGFR mAb group, respectively, and these values showed high sensitivity and specificity for predicting disease progression. The patients in the entire population and anti-EGFR mAb group with CEA changes below these cut-off values showed significantly better OS and PFS outcomes compared those whose changes were above cut-off values. Among the patients with mCRC treated with anti-VEGF mAb, no associations were found between OS or PFS outcomes and CEA changes. CEA is potentially a good surrogate marker for predicting disease progression and survival outcomes in patients with mCRC receiving first-line systemic chemotherapy alone or chemotherapy with anti-EGFR mAb, whereas it is less effective in those treated with anti-VEGF mAb.

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.

Dihydropyrimidone Derivatives as Thymidine Phosphorylase Inhibitors: Inhibition Kinetics, Cytotoxicity, and Molecular Docking.

Overexpression of the thymidine phosphorylase (TP) enzyme induces angiogenesis, which eventually leads to metastasis and tumor growth. The crucial role of TP in cancer development makes it an important target for anticancer drug discovery. Currently, there is only one US-FDA-approved drug, i.e., Lonsurf, a combination of trifluridine and tipiracil, for the treatment of metastatic colorectal cancer. Unfortunately, numerous adverse effects are associated with its use, such as myelosuppression, anemia, and neutropenia. Since the last few decades, the discovery of new, safe, and effective TP inhibitory agents has been rigorously pursued. In the present study, we evaluated a series of previously synthesized dihydropyrimidone derivatives 1-40 for their TP inhibitory potential. Compounds 1, 12, and 33 showed a good activity with IC50 = 314.0 ± 0.90, 303.5 ± 0.40, and 322.6 ± 1.60 µM, respectively. The results of mechanistic studies revealed that compounds 1, 12, and 33 were the non-competitive inhibitors. These compounds were also evaluated for cytotoxicity against 3T3 (mouse fibroblast) cells and were found to be non-cytotoxic. Finally, the molecular docking suggested the plausible mechanism of non-competitive inhibition of TP. The current study thus identifies some dihydropyrimidone derivatives as potential inhibitors of TP, which can be further optimized as leads for cancer treatment.

Brevilin A is a potent anti-metastatic CRC agent that targets the VEGF-IL6-STAT3 axis in the HSCs-CRC interplay

BackgroundMore than half of the colorectal cancer (CRC) patients will develop liver metastasis that underlies the cancer mortality. In the hepatic tumor microenvironment, the interplay between CRC cells and hepatic stellate cells (HSCs), and the activation of HSCs to become carcinoma-associated fibroblasts (CAFs) will further promote the cancer development. Nevertheless, the critical signaling molecule that involved in these processes remains unknown, which hinders the development of effective therapeutic agents for the treatment of metastatic CRC (mCRC).MethodsConditioned medium system and co-cultured system were used to examine the interplay between CRC cells and HSCs. Luminex liquid suspension chip detection and enzyme-linked immunosorbent assay were used to screen for the mediators in the conditioned medium that facilitated the CRC-HSCs interplay and HSCs-to-CAFs differentiation. Cell and animal models were used to examine whether brevilin A inhibited CRC liver metastasis via the VEGF-IL6-STAT3 axis.ResultsIn the CRC-HSCs interplay, CRC promoted HSCs-to-CAFs differentiation by releasing vascular endothelial growth factor (VEGF); and HSCs released interleukin 6 (IL6) that activated signal transducer and activator of transcription 3 (STAT3) in the CRC and hence increased the cancer metastatic potential. The functions of the VEGF-IL6-STAT3 axis in the HSCs-CRC interplay were further validated by VEGF recombinant protein and IL6 neutralizing antibody. More importantly, brevilin A, an active compound isolated from Centipeda minima (L.) A. Br. et Aschers, targeted the VEGF-IL6-STAT3 axis in the CRC-HSCs interplay, hence significantly inhibited colorectal liver metastasis and cancer growth both in vitro and in vivo.ConclusionsWe are the first to demonstrate brevilin A possesses potent anti-mCRC effect by targeting the VEGF-IL6-STAT3 axis in the CRC-HSCs interplay. Our findings not only support the development of brevilin A as a novel therapeutic agent for mCRC treatment, but also pave the path for the development of other VEGF-IL6-STAT3 targeting therapeutic strategies.

Maintenance therapy with Fluoropyrimidine and cetuximab or bevacizumab after first line FOLFOX-chemotherapy in metastatic colorectal cancer according to RAS or BRAFV600E mutation status.

Fluoropyrimidine (FP) with oxaliplatin-based chemotherapy is the standard first-line treatment for metastatic colorectal cancer (mCRC); however, oxaliplatin-induced neuropathy critically affects the quality of life of patients. Maintenance strategies with FP plus bevacizumab have been well-established; nonetheless, the real-world outcomes of maintenance therapy with FP and cetuximab are unclear. We investigated the clinical outcomes of patients who underwent maintenance therapy with cetuximab. We retrospectively identified and analyzed patients with mCRC who were treated between 2012 and 2021 with first-line oxaliplatin-based induction chemotherapy (IC) plus biologic agents (either cetuximab or bevacizumab), and underwent maintenance therapy (IC regimen without oxaliplatin) after IC. In total, 19 patients who were treated with mFOLFOX6 (FP/leucovorin/oxaliplatin) with cetuximab, and 26 patients who were treated with mFOLFOX6 with bevacizumab were included. In the cetuximab group, all patients were KRAS-, NRAS-, and BRAF-wild type, whereas most patients in the bevacizumab group harbored KRAS or BRAFV600E or NRAS mutants. During the maintenance treatment, seven patients (four [21%] in the cetuximab group and three [11%] in the bevacizumab group) achieved partial response after achieving nadir during induction chemotherapy. The disease control rates of maintenance therapy were 79% and 74% in the cetuximab and bevacizumab groups, respectively. The median progression-free survival of maintenance therapy and overall survival was 5.98months and 32.4months in the cetuximab group, and 4.83months and 25.6months in the bevacizumab group, respectively. Maintenance therapy with FP plus biologic agents (either bevacizumab or cetuximab) is a feasible strategy for appropriate mCRC patients according to their RAS/BRAF status. Further large-scale randomized studies are needed to validate the efficacy of anti-epidermal growth factor receptor-based maintenance therapy.