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Colorectal adenocarcinoma is the most prevalent form of colorectal cancer, representing the majority of cases in the United States. The disease is driven by a series of genetic mutations, including alterations in the adenomatous polyposis coli (APC), Kirsten rat sarcoma viral oncogene homolog G12D (KRAS), human epidermal growth factor receptor 2 immunohistochemistry 3+ (HER-2 IHC3+), checkpoint kinase 2 (CHEK-2) and tumor protein P53 (TP53) genes, which lead to malignant transformation. While the standard treatment for metastatic colorectal cancer (mCRC) typically involves chemotherapy and targeted therapies, many patients experience disease progression, necessitating the exploration of novel treatments. Fruquintinib, a highly selective vascular endothelial growth factor (VEGFR) inhibitor, has emerged as a promising option for mCRC patients who have exhausted conventional therapies. However, its use is associated with significant bleeding risks, including rare but severe complications such as cerebellar hemorrhage. This case report presents a patient with mCRC who developed a cerebellar hemorrhage shortly after initiating fruquintinib therapy, highlighting the need for careful patient monitoring and individualized risk assessment to mitigate such serious adverse events.

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OBJECTIVES: Clinical studies have shown that bevacizumab plus chemotherapy significantly improves efficacy in metastatic colorectal cancer (mCRC). This prospective study aims to investigate the efficacy and safety of changing second-line treatment to raltitrexed-based chemotherapy regimens plus bevacizumab in mCRC patients who have failed the first-line fluorouracil-based chemotherapy regimen with or without bevacizumab/cetuximab. METHODS: This is a prospective, open-label, multicenter, phase II clinical study. A total of 100 patients with mCRC after failure of the first-line fluorouracil-based chemotherapy regimen with or without bevacizumab/cetuximab were enrolled from November 2016 to October 2021, and received second-line raltitrexed-based chemotherapy regimen plus bevacizumab. Patients were treated for 6 cycles, and efficacy evaluation over stable disease were followed by maintenance treatment of bevacizumab and raltitrexed until disease progression or intolerable toxicity. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR), safety, and toxicity. RESULTS: Ninety-four patients were treated with SALIRI (raltitrexed + irinotecan) plus bevacizumab, and six patients with SALOX (raltitrexed + oxaliplatin) plus bevacizumab. Median PFS was 8.4 (95% CI: 6.2-11.0) months, including 8.2 (95% CI 6.2, 11.0) months in the SALIRI group and 11.6 (95% CI 3.1, NA) months in the SALOX group. Median OS was 17.6 (95% CI 15.2, 22.0) months in the SALIRI group and 17.1 (95% CI 4.1, NA) months in the SALOX group. ORR and DCR were 25.5% and 87.2% in the SALIRI group, and 33.3% and 83.3% in the SALOX group, respectively. A low incidence of grade 3-4 adverse events was observed. CONCLUSIONS: Raltitrexed-based chemotherapy regimens plus bevacizumab improved survival duration in mCRC patients with failed first-line therapy. Therefore, treatment with raltitrexed-based chemotherapy regimens plus bevacizumab could be a superior therapeutic option for second-line chemotherapy in mCRC (ClinicalTrials.gov registration number: NCT03126071).

Asunto(s)

Protocolos de Quimioterapia Combinada Antineoplásica , Bevacizumab , Neoplasias Colorrectales , Quinazolinas , Tiofenos , Humanos , Bevacizumab/administración & dosificación , Bevacizumab/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Masculino , Femenino , Quinazolinas/administración & dosificación , Quinazolinas/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Persona de Mediana Edad , Estudios Prospectivos , Anciano , Adulto , Tiofenos/administración & dosificación , Tiofenos/uso terapéutico

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PURPOSE: To evaluate the safety, efficacy and oncological outcomes of irreversible electroporation (IRE) of unresectable colorectal liver metastases (CRLM) close to critical structures. MATERIALS AND METHODS: This is a single center, IRB approved, retrospective analysis of patients who underwent percutaneous, CT-guided IRE of CRLM. Between August 2018 and October 2023, 26 patients had 46 tumors treated with percutaneous IRE in 30 ablation sessions. Primary endpoints were tumor response and local progression-free survival (LPFS) analyzed using Kaplan-Meier survival curves. Secondary endpoints were overall survival (OS), and distant progression-free survival (DPFS) using Kaplan-Meier survival curves, adverse events rated according to Common Terminology Criteria for Adverse Events, and length of hospital stay. RESULTS: All tumors were close to critical structures, including portal and hepatic veins, inferior vena cava, bile ducts and the gallbladder. All patients received preprocedural systemic therapy (median ten cycles). Median length of hospital stay was one night. Adverse events occurred in seven out of 30 (23%) procedures, with four grade 1 and two grade 2 adverse events, including pleural effusions (n=2), ileus (n=1), small hematoma (n=1) and pneumothorax (n=2) requiring chest tube placements. Following IRE, 1- and 2-year LTPFS was 55.0% and 51.3%. Median DPFS was 3.5 months, with 1- and 2-year DPFS of 23.3% and 9.7%. Six patients died during follow-up (23.1%), with a median OS of 40.4 months. The 1- and 2-year OS were 90.9% and 83.9%. CONCLUSION: IRE is a safe and viable option in the treatment of unresectable CRLM in locations close to critical structures.

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We report the case of a patient with a BRAFV600E mutant mCRC, with evidence of acquired 'NeoBRAF wild-type' (wt) state. The patient, longitudinally assessed by liquid biopsy, obtained a remarkable clinical outcome with a multimodal approach including surgery, systemic treatment and targeted therapy. In patients with newly diagnosed RAS and BRAFV600E mutant mCRC, longitudinal assessment with liquid biopsy is not routinely used in clinical practice. We report the case of a patient with a BRAFV600E mutant mCRC, with evidence of acquired 'neoBRAF wild-type' (wt) state. The patient obtained a remarkable clinical outcome and has been longitudinally assessed by liquid biopsy.

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PURPOSE: This phase I trial is to determine the recommended dose of the TAS-102, irinotecan plus bevacizumab regimen and assess its safety and efficacy in patients with metastatic colorectal cancer refractory to fluoropyrimidine and oxaliplatin treatment. METHODS: A 3 + 3 designed dose escalation was performed. Patients were administered TAS-102 (30-35 mg/m2 twice daily on days 1-5) and irinotecan (150-165 mg/m2 on day 1) combined with a fixed dose of bevacizumab (5 mg/kg on day 1) every two weeks. The primary endpoint was the determination of the recommended phase II dose. RESULTS: Eighteen patients were enrolled: 6 at the Level 1 (TAS-102 30 mg/m2 twice daily, irinotecan 150 mg/m2 plus bevacizumab 5 mg/kg), six at the Level 2 (TAS-102 35 mg/m2 twice daily, irinotecan 150 mg/m2 plus bevacizumab 5 mg/kg), and six at the Level 3 (TAS-102 30 mg/m2 twice daily, irinotecan 165 mg/m2 plus bevacizumab 5 mg/kg). Five dose-limiting toxicities occurred: one observed at Level 1 (thrombocytopenia), two at Level 2 (neutropenia and diarrhea), and two at Level 3 (fatigue and neutropenia). The RP2D was established as TAS-102 30 mg/m2 twice daily and irinotecan 150 mg/m2 plus bevacizumab 5 mg/kg. The most frequent grade 3/4 treatment-related adverse events were neutropenia (33.3%), diarrhea (16.7%), and thrombocytopenia (11.1%). No treatment-related death occurred. Two patients (11.1%) experienced partial responses and 14 (77.8%) had stable disease. CONCLUSION: The regimen of TAS-102, irinotecan, and bevacizumab is tolerable with antitumor activity for metastatic colorectal cancer patients refractory to first-line fluoropyrimidines and oxaliplatin treatment.

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Protocolos de Quimioterapia Combinada Antineoplásica , Bevacizumab , Neoplasias Colorrectales , Combinación de Medicamentos , Irinotecán , Pirrolidinas , Timina , Trifluridina , Uracilo , Humanos , Timina/administración & dosificación , Trifluridina/administración & dosificación , Trifluridina/uso terapéutico , Trifluridina/efectos adversos , Bevacizumab/administración & dosificación , Bevacizumab/efectos adversos , Bevacizumab/uso terapéutico , Masculino , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Femenino , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Persona de Mediana Edad , Pirrolidinas/administración & dosificación , Pirrolidinas/efectos adversos , Pirrolidinas/uso terapéutico , Anciano , Irinotecán/administración & dosificación , Irinotecán/efectos adversos , Irinotecán/uso terapéutico , Uracilo/análogos & derivados , Uracilo/administración & dosificación , Uracilo/uso terapéutico , Uracilo/efectos adversos , Adulto , Metástasis de la Neoplasia

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BACKGROUND: Recent studies have linked alterations in the gut microbiome and metabolic disruptions to the invasive behavior and metastasis of colorectal cancer (CRC), thus affecting patient prognosis. However, the specific relationship among gut microbiome, metabolite profiles, and mutated-RAS/BRAF metastatic colorectal cancer (M-mCRC) remains unclear. Furthermore, the potential mechanisms and prognostic implications of metabolic changes induced by gut microbiome alterations in patients with M-mCRC still need to be better understood. METHODS: We conducted Mendelian randomization (MR) to evaluate the causal relationship of genetically predicted 196 gut microbiome features and 1400 plasma metabolites/metabolite ratios on M-mCRC-specific survival. Additionally, we identified significant gut microbiome-metabolites/metabolite ratio associations based on M-mCRC. Metabolite information was annotated, and functional annotation and pathway enrichment analyses were performed on shared proteins corresponding to significant metabolite ratios, aiming to reveal potential mechanisms by which gut microbiome influences M-mCRC prognosis via modulation of human metabolism. RESULTS: We identified 11 gut microbiome features and 49 known metabolites/metabolite ratios correlated with M-mCRC-specific survival. Furthermore, we identified 17 gut microbiome-metabolite/metabolite ratio associations specific to M-mCRC, involving eight lipid metabolites and three bilirubin degradation products. The shared proteins corresponding to significant metabolite ratios were predominantly localized within the integral component of the membrane and exhibited enzymatic activities such as glucuronosyltransferase and UDP-glucuronosyltransferase, crucial in processes such as glucuronidation, bile secretion, and lipid metabolism. Moreover, these proteins were significantly enriched in pathways related to ascorbate and aldarate metabolism, pentose and glucuronate interconversions, steroid hormone biosynthesis, and bile secretion. CONCLUSION: Our study offers novel insights into the potential mechanisms underlying the impact of the gut microbiome on the prognosis of M-mCRC. These findings serve as a meaningful reference for exploring potential therapeutic targets and strategies in the future.

Asunto(s)

Neoplasias Colorrectales , Microbioma Gastrointestinal , Mutación , Metástasis de la Neoplasia , Proteínas Proto-Oncogénicas B-raf , Humanos , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/microbiología , Neoplasias Colorrectales/sangre , Neoplasias Colorrectales/genética , Microbioma Gastrointestinal/genética , Proteínas Proto-Oncogénicas B-raf/genética , Pronóstico , Análisis de la Aleatorización Mendeliana , Análisis de Supervivencia , Proteínas ras/metabolismo , Proteínas ras/genética , Metaboloma

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BACKGROUND: Evaluating transarterial radioembolization (TARE) in patients with metastatic colorectal carcinoma of the liver who have progressed on first-line chemotherapy (EPOCH) demonstrated superior outcomes using yttrium-90 glass microspheres plus chemotherapy (TARE/Chemo) vs chemotherapy (Chemo) to treat colorectal liver metastases. Additional exploratory analyses were undertaken to assess the impact of TARE/Chemo on efficacy, safety, time to subsequent therapy, time to deterioration in quality of life (QoL), and identify criteria for improved patient selection. METHODS: Time to deterioration in QoL was analyzed for the primary study population. Subsequently, a post hoc analysis was undertaken to identify subgroups for which time to deterioration in QoL was improved with TARE/Chemo vs Chemo. Progression-free survival (PFS), hepatic (h)PFS, time to subsequent therapy, and safety outcomes were compared between treatments. RESULTS: The primary population showed no significant difference in time to deterioration in QoL between treatment arms; however, significance was seen in 2 identified subgroups, namely: Subgroup A (N = 303) which excluded patients with both Eastern Cooperative Oncology Group (ECOG) 1 and baseline CEA ≥ 35 ng/mL from both treatment arms; subgroup B (N = 168) additionally excluded patients with KRAS (Kirsten rat sarcoma) mutation. In subgroup A, TARE/Chemo patients (N = 143) demonstrated superior outcomes vs Chemo (N = 160): PFS (9.4 vs. 7.6 months, hazard ratio (HR): 0.64; 1-sided P = .0020), hPFS (10.8 vs. 7.6 months, HR: 0.53; 1-sided P < .0001), time to deterioration in QoL (5.7 vs. 3.9 months, HR: 0.65; 1-sided P = .0063), and time to subsequent therapy (21.2 vs. 10.5 months, HR: 0.52; 1-sided P < .0001). Subgroup B patients showed similar but larger significant differences between treatment arms. Median PFS, hPFS, and time to deterioration in QoL were numerically greater for TARE/Chemo in both subgroups vs the primary population, with the greatest magnitude of difference in subgroup B. Both subgroups exhibited higher percentage of CEA responders and improved ORR with TARE/Chemo vs chemo alone. Safety (reported as event rate/100 patient-years) was higher with Chemo in all populations. Additional efficacy analyses in the primary population are also reported. CONCLUSIONS: Careful patient selection, including consideration of the prognostic factors ECOG, baseline CEA, and KRAS status, sets outcome expectations in patients with colorectal liver metastases suitable for TARE/Chemo as second-line treatment (Trial Registry Number: NCT01483027).

Asunto(s)

Neoplasias Colorrectales , Neoplasias Hepáticas , Calidad de Vida , Radioisótopos de Itrio , Humanos , Neoplasias Hepáticas/secundario , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/terapia , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/terapia , Radioisótopos de Itrio/uso terapéutico , Masculino , Femenino , Persona de Mediana Edad , Anciano , Selección de Paciente , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Vidrio

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Predictive biomarkers of response to chemotherapy in patients with metastatic colorectal cancer (mCRC) are needed to better characterize tumors and enable more tailored therapies. Here we used serum proteomics to screen for chemotherapy predictive markers. We found that higher baseline serum inter-α-trypsin inhibitor Heavy Chain 4 (ITIH4) expression in newly diagnosed mCRC patients was associated with poorer response to standard first-line chemotherapy. In addition, the higher expression of ITIH4 in CRC tissue also suggested poorer prognosis mCRC patients. Moreover, the overexpression of ITIH4 could promote the proliferation of CRC cells and reduce the sensitivity of CRC cells to 5-fluorouracil (5-FU) by inhibiting apoptosis in vivo and vitro. Through RNA-seq combined with bioinformatics analysis, we speculated that ITIH4 may activate phosphatidyl 3-kinase-protein kinase B (PI3K-AKT) pathway to inhibit apoptosis, thereby reducing the sensitivity of CRC cells to 5-FU. In conclusion, our findings unveil that ITIH4 is associated with CRC resistance to 5-FU, and may serve as a potential predictive biomarker for the sensitivity of advanced CRC patients to standard first-line chemotherapy regimens, and also provide a potential therapeutic target to render 5-FU resistance in CRC patients.

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Over the course of nearly six decades since the inception of initial trials involving 5-FU in the treatment of mCRC (metastatic colorectal cancer), our progressive comprehension of the pathophysiology, genetics, and surgical techniques related to mCRC has paved the way for the introduction of novel therapeutic modalities. These advancements not only have augmented the overall survival but have also positively impacted the quality of life (QoL) for affected individuals. Despite the remarkable progress made in the last two decades in the development of chemotherapy, immunotherapy, and target therapies, mCRC remains an incurable disease, with a 5-year survival rate of 14%. In this comprehensive review, our primary goal is to present an overview of mCRC treatment methods following the latest guidelines provided by the National Comprehensive Cancer Network (NCCN), the American Society of Clinical Oncology (ASCO), and the American Society of Colon and Rectal Surgeons (ASCRS). Emphasis has been placed on outlining treatment approaches encompassing chemotherapy, immunotherapy, targeted therapy, and surgery's role in managing mCRC. Furthermore, our review delves into prospective avenues for developing new therapies, offering a glimpse into the future of alternative pathways that hold potential for advancing the field.

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Background: The majority of studies of regorafenib now were small-sample and single-arm, which potentially limits the strength of evidence. We conduct the study to identify the efficacy and safety of regorafenib for patients with metastatic colorectal cancer (mCRC) in real-world applications. Methods: mCRC patients who underwent regorafenib second line or post-second line treatment with at least one assessable lesion were analyzed. Patients received different doses of regorafenib and different combination regimens. The patients were followed up with laboratory tests and imaging examinations every 3 months to evaluate the efficacy and adverse events (AEs). The primary endpoint of this study was median overall survival (mOS), and the secondary endpoints were median progression-free survival (mPFS), the objective response rate (ORR), the disease control rate (DCR), and AEs. Results: A total of 77 patients (45 males and 32 females, aged 58.80±11.65 years) were enrolled in the study. Most primary tumors were located in the rectum (59.74%), and the vast majority of tumors (89.62%) had an adenocarcinoma histological type. The 77 patients had an mOS of 17.8 months, a progression-free survival (PFS) of 4.63 months, an ORR of 6.76%, and a DCR of 55.41%. Patients underwent regorafenib third-line therapy had significantly higher overall survival (OS) than those underwent regorafenib post- third-line treatment (P=0.03). The neutrophil to lymphocyte ratio (NLR) was an independent factor affecting the OS of the mCRC patients [hazard ratio (HR) =1.12, P=0.03]. In both univariate and multivariate analyses, discontinued use of regorafenib after progression reduced patients' PFS (HR =3.07, P<0.001; HR =2.78, P=0.007). In terms of the tolerated dose, patients receiving 120 mg regorafenib had the longest OS numbers, but there was no statistical difference. We analyzed the effect of the baseline NLR on the OS of patients receiving regorafenib combined with immunotherapy, and found that the NLR ratio cut-off value was 4.4, and patients with a NLR ratio ≤4.4 benefited significantly in terms of OS (P=0.03). The AEs included 21 (27.27%) cases of hand and foot skin reaction, 15 (19.48%) cases of fatigue, 9 (11.69%) cases of pain, 9 (11.69%) cases of nausea, 9 (11.69%) cases of fever, 9 (11.69%) cases of cough, and so on. Conclusions: Regorafenib is relatively effective and safe as a third-line and posterior treatment of mCRC. Patients underwent regorafenib third-line therapy had longer OS than those underwent regorafenib post- third-line treatment. Moreover, PFS benefits can still be obtained by continuing regorafenib treatment after progression. Grade 1-2 AEs were common, but these were usually tolerated by most patients.

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Background: Treatment of advanced liver tumors remains challenging. Although immune checkpoint inhibition has revolutionized treatment for many cancers, responses in colorectal liver metastases and biliary tract cancers remain suboptimal. Investigation into additional immunomodulatory therapies for these cancers is needed. Interleukin-12 (IL-12) is a pro-inflammatory cytokine with robust anti-tumor activity, but systemic adverse effects largely terminated therapeutic development of recombinant human IL-12 (rhIL-12). PDS01ADC is a novel human monoclonal antibody (NHS76) conjugated to two IL-12 heterodimers with established safety in phase I trials. The NHS76 antibody specifically targets histone/DNA complexes which are accessible only in regions of cell death and this antibody has been shown to accumulate locally in tumors. Methods: Patients with unresectable metastatic colorectal cancer (mCRC) or unresectable intrahepatic cholangiocarcinoma (ICC) will receive synchronization of subcutaneous PDS01ADC with floxuridine delivered via a hepatic artery infusion pump (HAIP). The primary outcome measured in this study will be overall response rate as measured by Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Secondary outcomes measured in this study will include hepatic and non-hepatic progression-free survival (PFS), overall survival, and safety of PDS01ADC combination therapy with HAIP. Discussion: Poor clinical response of these liver tumors to immunotherapy is likely due to various factors, including poor immune infiltrate into the tumor and immunosuppression by the tumor microenvironment. By exploiting the tumor cell death induced by HAIP locoregional therapy in combination with systemic chemotherapy, PDS01ADC is poised to modulate the tumor immune microenvironment to improve outcomes for patients undergoing HAIP therapy. Trial Registration: ClinicalTrials.gov (ID NCT05286814 version 2023-10-18); https://clinicaltrials.gov/study/NCT05286814?term=NCT05286814&rank=1.

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BACKGROUND: This was an observational study prospectively evaluating the effectiveness and safety of aflibercept/FOLFIRI administered in second-line mCRC per the reimbursement criteria in Poland. METHODS: Consecutive mCRC patients who progressed with first-line oxaliplatin-based chemotherapy received aflibercept (4 mg/kg IV) followed by FOLFIRI every 2 weeks until progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS); overall survival (OS) and safety were the secondary endpoints. RESULTS: A total of 93 patients were treated at 17 Polish sites. A median of 10 cycles was administered. Over a median treatment duration of 5.3 months, median PFS and median OS were 8.4 months [95% CI, 6.9-9.9] and 27.0 months [95% CI, 23.9-30.1], respectively. There was no significant impact of primary tumor location, metastatic site, or KRAS status on PFS and OS. Main grade ≥ 3 adverse events were neutropenia (16%), hypertension (8%), diarrhea (4%), and stomatitis (4%). CONCLUSIONS: The benefits/risks of Aflibercept plus FOLFIRI administered per the Polish reimbursement criteria in second-line treatment of mCRC after failure of a prior oxaliplatin-based regimen is confirmed.

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Background: After the failure of standard first- and second-line treatments, including oxaliplatin, irinotecan, and 5-fluorouracil (5-FU) combined with targeted drugs, the currently recommended third-line regimens for metastatic colorectal cancer (mCRC) include TAS-102, regorafenib, and fruquintinib. However, these regimens have the drawbacks of mediocre efficacy, substantive side effects, and high cost. Therefore, more effective, economical regimens with fewer side effects are needed in clinical practice. In this study, we assessed the efficacy and safety of gemcitabine plus raltitrexed or S-1 as a third- or later-line treatment in comparison to those of standard third-line therapies for patients with mCRC. Methods: Patients with previous failures of at least two lines of standard therapy with oxaliplatin, 5-FU, irinotecan, or capecitabine combined with targeted drugs were included. The participants received standard third-line therapies (including TAS-102, regorafenib, and fruquintinib) or gemcitabine plus raltitrexed or S-1 until disease progression, death, or intolerable toxicity arose. Imaging follow-up was performed every 3 months during their treatment. Progression-free survival (PFS) and overall survival (OS) were recorded. Cox regression analysis was used to investigate the potential predictors of survival. Results: From April 2018 to October 2022, 60 patients with mCRC were enrolled in our study. The numbers of patients in the chemotherapy, fruquintinib, regorafenib, and TAS-102 groups were 13, 15, 17, and 15, respectively; the median OS of the four groups was 7.4, 6.1, 8.3, and 6.7 months (P=0.384), respectively; the median PFS was 4.1, 3.4, 4.4, and 2.3 months (P=0.656), respectively; the overall response rate was 7.69%, 6.67%, 0.00%, and 13.33%, respectively; and the disease control rate was 61.54%, 60.00%, 70.59%, and 60.00%, respectively. Additionally, multivariate analysis revealed that primary lesion located in the rectum was adverse independent prognostic factors for OS. A typical case is presented in this article. Conclusions: The gemcitabine plus raltitrexed or S-1 regimen is a potential regimen with tolerable adverse reactions and low cost for patients with mCRC.

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BACKGROUND: Colorectal cancer is a significant health concern worldwide, with metastatic CRC (mCRC) presenting a particularly challenging prognosis. The FRESCO-2 trial highlighted the potential of fruquintinib in heavily pretreated mCRC patients. AIM: Given the recent changes in drug pricing in China and the evolving mCRC treatments, this study aimed to evaluate the cost-effectiveness of fruquintinib in the context of current Chinese healthcare standards. METHOD: This study utilized data from the FRESCO-2 trial, incorporating a partitioned-survival model to simulate three health states: Progression-Free Survival, Progressive Disease, and death. Costs and utility values were derived from published literature and the FRESCO-2 trial. Sensitivity analyses were conducted to assess the robustness of the base-case result and to understand the impact of various parameters on the ICER. RESULTS: The base-case analysis revealed a total cost of $11,089.05 for the fruquintinib group and $5,374.48 for the placebo group. The overall QALYs were higher in the fruquintinib group (0.61 QALYs) compared to the placebo group (0.43 QALYs). The ICER was calculated to be $31,747.67 per QALY. Sensitivity analyses identified the utility of progression-free survival, the cost of fruquintinib, and the costs of best supportive care as significant determinants of ICER. CONCLUSION: Fruquintinib emerges as a promising therapeutic option for refractory mCRC. However, its cost-effectiveness depends on selected willingness-to-pay (WTP) threshold. While the drug's ICER surpasses the WTP based on China's 2022 GDP per capita, it remains below the threshold set at three times the national GDP.

Asunto(s)

Benzofuranos , Neoplasias Colorrectales , Análisis Costo-Beneficio , Quinazolinas , Humanos , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/economía , Benzofuranos/economía , Benzofuranos/uso terapéutico , Quinazolinas/uso terapéutico , Quinazolinas/economía , China , Años de Vida Ajustados por Calidad de Vida , Metástasis de la Neoplasia , Antineoplásicos/economía , Antineoplásicos/uso terapéutico , Supervivencia sin Progresión , Costos de los Medicamentos , Masculino , Femenino , Persona de Mediana Edad , Análisis de Costo-Efectividad

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PURPOSE: RAS (KRAS/NRAS) mutational status on a tumor biopsy is mandatory to guide the best treatment in metastatic colorectal cancer (mCRC). Determining the RAS mutational status by tumor-tissue biopsy is essential in guiding the optimal treatment decision for mCRC. RAS mutations are negative predictive factors for the use of EGFR monoclonal antibodies. Cell-free DNA (cfDNA) analysis enables minimally invasive monitoring of tumor evolution. METHODS/PATIENTS: PERSEIDA was an observational, prospective study assessing cfDNA RAS, BRAF and EGFR mutations (using Idylla™) in first-line mCRC, RAS wild-type (baseline tumor-tissue biopsy) patients (cohort 2). Plasma samples were collected before first-line treatment, after 20 ± 2 weeks, and at disease progression. RESULTS: 117 patients were included (103 received panitumumab + chemotherapy as first-line treatment). At baseline, 7 (6.8%) patients had RAS mutations, 4 (3.9%) BRAF mutations and no EGFR mutations were detected (cfDNA, panitumumab + chemotherapy subpopulation [panitumumab + Ch]). The baseline RAS mutational status concordance between tissue and liquid biopsies was 94.0% (93.2%, panitumumab + Ch). At 20 weeks, only one patient in the study (included in the panitumumab + Ch) had an emerging cfDNA RAS mutation. No emerging BRAF or EGFR mutations were reported. At disease progression, 6 patients had emergent mutations not present at baseline (RAS conversion rate: 13.3% [6/45]; 15.0% [6/40], panitumumab + Ch). CONCLUSIONS: The concordance rate between liquid and solid biopsies at baseline was very high, as previously reported, while our results suggest a considerable emergence of RAS mutations during disease progression. Thus, the dynamics of the genomic landscape in ctDNA may provide relevant information for the management of mCRC patients.

Asunto(s)

Ácidos Nucleicos Libres de Células , Neoplasias Colorrectales , Mutación , Panitumumab , Proteínas Proto-Oncogénicas B-raf , Humanos , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/sangre , Femenino , Masculino , Estudios Prospectivos , Anciano , Persona de Mediana Edad , Ácidos Nucleicos Libres de Células/genética , Ácidos Nucleicos Libres de Células/sangre , Proteínas Proto-Oncogénicas B-raf/genética , Panitumumab/uso terapéutico , Proteínas Proto-Oncogénicas p21(ras)/genética , Receptores ErbB/genética , Adulto , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , GTP Fosfohidrolasas/genética , Progresión de la Enfermedad , Proteínas de la Membrana/genética

RESUMEN

BACKGROUND: The purpose of this study was to explore the dynamic changes of genomic mutations and their correlations with the efficacy in metastatic colorectal cancer (mCRC) patients treated with cetuximab plus mFOLFOX as the first-line treatment. METHODS: We included mCRC patients from January 2018 to October 2020 as a studied cohort which were treated with cetuximab plus mFOLFOX as first line therapy. Blood samples were collected for circulating tumor DNA (ctDNA) test at three timepoints: before the first-line therapy(baseline), at the time of first-line progression and at the time of second-line progression. Progression-free survival was considered as the primary endpoint while objective response rate and overall survival were determined as the secondary endpoints. RESULTS: Totally 39 patients received first-line treatment, of which 25 patients entered the second-line treatment, while 10 patients entered the third-line treatment. The median follow-up time was 16.4 months (95 %CI, 14.8-19.3). Along the treatment from first-line progress disease (PD) to second-line PD, proportions of TP53 (12/18, 67 %), APC (10/18, 56 %), FBXW7 (3/18, 17 %), and AMER1 (2/18, 11 %) were gradually increased according to results of single nucleotide variation (SNV). CONCLUSIONS: Resistant gene mutations caused by anti-EGFR drugs in RAS/BRAF wild-type mCRC patients can be observed by dynamic ctDNA analysis. TP53 and AMER1 mutations, tumor mutational burden (TMB) levels, and TP53/AMER1 co-mutation may predict the efficacy of the first-line cetuximab-contained treatment. Situations of genetic mutations were differentiated from first-line PD to second-line PD, which indicated that mutation detection may contribute to predict prognosis of mCRC patients.

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Neoplasias del Colon , Neoplasias Colorrectales , Neoplasias del Recto , Humanos , Cetuximab/uso terapéutico , Proteínas Proto-Oncogénicas B-raf/genética , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Recto/tratamiento farmacológico , Mutación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos

RESUMEN

BACKGROUND: The phase 3 BEACON CRC study demonstrated the survival benefits of encorafenib and cetuximab, with or without binimetinib (the BEACON triplet or doublet regimen), for BRAFV600E-mutant metastatic colorectal cancer (mCRC). This expanded access program (EAP) and subsequent follow-up study assessed the efficacy and safety of the BEACON triplet regimen in Japanese patients with BRAFV600E-mutant mCRC. MATERIALS AND METHODS: The EAP was an open-label, single-arm study including Japanese patients with BRAFV600E-mutant mCRC whose disease progressed after 1 to 2 prior regimens. The patients received the BEACON triplet regimen with 28-day cycles. The subsequent follow-up study assessed the survival outcomes following EAP completion. Safety was assessed only during the EAP. RESULTS: Among the 86 enrolled patients, 81 received the BEACON triplet regimen. The objective response rate and median progression-free survival were 27.6% (95% confidence interval [CI], 18.0%-39.1%) and 5.26 (95% CI, 4.14-5.52) months, respectively. Grade 3 to 4 adverse events and treatment-related adverse events occurred in 43.2% and 28.4% of patients, respectively. No new safety signals were observed during the EAP. Among 58 patients with confirmed survival at EAP completion, 57 were included in the follow-up study. With a median observation period of 9.17 months through the EAP and follow-up study, the median overall survival was 10.38 (95% CI, 9.00-16.16) months. CONCLUSION: The efficacy and safety of the BEACON triplet regimen in Japanese patients with BRAFV600E-mutant mCRC were consistent with those reported in the BEACON CRC trial, supporting its use as a standard treatment for pretreated patients with BRAFV600E-mutant mCRC.

Asunto(s)

Protocolos de Quimioterapia Combinada Antineoplásica , Bencimidazoles , Carbamatos , Cetuximab , Neoplasias Colorrectales , Sulfonamidas , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Bencimidazoles/efectos adversos , Bencimidazoles/uso terapéutico , Carbamatos/efectos adversos , Carbamatos/uso terapéutico , Cetuximab/efectos adversos , Cetuximab/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/mortalidad , Pueblos del Este de Asia , Estudios de Seguimiento , Japón , Mutación , Supervivencia sin Progresión , Proteínas Proto-Oncogénicas B-raf/genética , Sulfonamidas/efectos adversos , Sulfonamidas/uso terapéutico

RESUMEN

Patients with metastatic colorectal cancer often have poor outcomes, primarily due to hepatic metastasis. Colorectal cancer (CRC) cells have the ability to secrete cytokines and other molecules that can remodel the tumor microenvironment, facilitating the spread of cancer to the liver. Kupffer cells (KCs), which are macrophages in the liver, can be polarized to M2 type, thereby promoting the expression of adhesion molecules that aid in tumor metastasis. Our research has shown that huachanshu (with bufalin as the main active monomer) can effectively inhibit CRC metastasis. However, the underlying mechanism still needs to be thoroughly investigated. We have observed that highly metastatic CRC cells have a greater ability to induce M2-type polarization of Kupffer cells, leading to enhanced metastasis. Interestingly, we have found that inhibiting the expression of IL-6, which is highly expressed in the serum, can reverse this phenomenon. Notably, bufalin has been shown to attenuate the M2-type polarization of Kupffer cells induced by highly metastatic Colorectal cancer (mCRC) cells and down-regulate IL-6 expression, ultimately inhibiting tumor metastasis. In this project, our aim is to study how high mCRC cells induce M2-type polarization and how bufalin, via the SRC-3/IL-6 pathway, can inhibit CRC metastasis. This research will provide a theoretical foundation for understanding the anti-CRC effect of bufalin.

Asunto(s)

Bufanólidos , Neoplasias del Colon , Interleucina-6 , Macrófagos del Hígado , Neoplasias Hepáticas , Macrófagos del Hígado/efectos de los fármacos , Macrófagos del Hígado/metabolismo , Bufanólidos/farmacología , Bufanólidos/uso terapéutico , Neoplasias Hepáticas/secundario , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Humanos , Animales , Interleucina-6/metabolismo , Interleucina-6/genética , Neoplasias del Colon/patología , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/metabolismo , Neoplasias del Colon/genética , Línea Celular Tumoral , Ratones , Antineoplásicos/farmacología , Microambiente Tumoral/efectos de los fármacos , Polaridad Celular/efectos de los fármacos , Metástasis de la Neoplasia

RESUMEN

【Objective】 To compare the diagnostic performance of gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB) enhanced magnetic resonance imaging (MRI) and multi-detector computed tomography (MDCT) in detecting liver metastases from metastatic colorectal cancer (mCRC). 【Methods】 We made a retrospective collection of 128 patients diagnosed with mCRC from May 2019 to June 2022 at Haikou Hospital, Xiangya School of Medicine, Central South University and Xijing Hospital, Air Force Military Medical University. All patients underwent Gd-EOB MRI and MDCT imaging. Three radiologists judged the accuracy, sensitivity, specificity, positive predictive value and negative predictive value of the two modalities for colorectal liver metastases, respectively. 【Results】 Of the 128 patients diagnosed with mCRC, a total of 462 lesions were obtained, with 424 positive and 38 negative metastases confirmed by pathology. In the interpretation of physician A, Gd-EOB MRI judged 404 positive and 38 negative liver metastases, with accuracy of 95.67%, sensitivity of 95.28%, specificity of 100.00%, a positive predictive value of 100%, and a negative predictive value of 65.52%. MDCT judged 337 positive and 37 negative liver metastases, with accuracy of 80.95%, sensitivity of 79.48% and specificity of 97.37%, a positive predictive value of 99.70%, and a negative predictive value of 29.84%. In the interpretation of physician B, Gd-EOB MRI judged 403 positive and 36 negative liver metastases, with accuracy of 95.02%, sensitivity of 95.05%, specificity of 94.74%, a positive predictive value of 99.51%, and a negative predictive value of 64.91%. MDCT judged 335 positive and 35 negative liver metastases, with accuracy of 80.09%, sensitivity of 79.01%, specificity of 92.11%, a positive predictive value of 99.11%, and a negative predictive value of 28.23%. In the interpretation of physician C, Gd-EOB MRI judged 406 positive and 38 negative liver metastases, with accuracy of 96.10%, sensitivity of 95.75%, specificity of 100.00%, a positive predictive value of 100.00%, and a negative predictive value of 67.86%. MDCT judged 352 positive and 34 negative liver metastases, with accuracy of 83.55%, sensitivity of 83.02%, specificity of 89.47%, a positive predictive value of 98.88%, and a negative predictive value of 32.08%. Gd-EOB MRI judged the nature of liver metastases with higher accuracy, sensitivity and negative predictive value than MDCT, and had better agreement with pathological examination results in the judgment of physician A and physician C (Kappa=0.770, 0.788). In physician B’s judgment, the agreement with pathological findings was fair (Kappa=0.731), while the agreement between the results of MDCT examination and pathological findings was poor (Kappa=0.379, 0.378 and 0.400). 【Conclusion】 Gd-EOB MRI has higher accuracy, sensitivity and positive predictive rate than MDCT in diagnosing colorectal liver metastasis, and has higher diagnostic performance. Therefore, it can provide more valuable reference information for clinical differential diagnosis. Subcapsular lesions, peribiliary metastases and hepatic steatosis can reduce the diagnostic performance of MDCT, while Gd-EOB MRI detection can provide more accurate results than MDCT.

RESUMEN

BACKGROUND: This study aims to assess predictive markers for response to immunotherapy in dMMR/MSI-H metastatic colorectal cancer (mCRC) patients. MATERIALS AND METHODS: A study using two prospective cohorts from MD Anderson Cancer Center and Sheba Medical Center of consecutive patients with dMMR/MSI-H mCRC that were treated with immunotherapy between 2014-2022. Primary outcome was progression-free survival (PFS) and secondary outcome was overall response rate (ORR). Evaluated predictors included ECOG-PS score, RAS/BRAF status, single-agent versus doublet immunotherapy, metastatic sites, disease burden, and CEA levels prior to treatment initiation. Kaplan-Meier analysis and Cox proportional hazard regression model were used to analyze the effect of exposure variables on PFS. RESULTS: The study included 153 patients. Median follow-up time was 26 months (IQR 11-48). Median PFS was 51.6 months (95%CI 38.1-NR) and ORR was 58.1%. In a univariate analysis, male sex was associated with worse PFS with a HR of 1.67 (95% CI 1.00-2.79); Right-sided tumors were associated with improved PFS with a HR of 0.56 (95% CI 0.32-0.97); Liver or lung metastasis were associated with worse PFS with HRs of 2.35 (95%CI 1.43-3.88) and 2.30 (95%CI 1.31-4.04), respectively; ECOG-PS score ≥ 2, CEA levels ˃5 µg/L prior to treatment initiation and ≥ 3 metastatic sites were associated with worse PFS with HRs of 2.09 (95%CI 0.98-4.47), 2.23 (95%CI 1.30-3.81) and 3.11 (95%CI 1.61-6.03), respectively. Liver or lung metastasis remained significant in a multivariable model. CONCLUSIONS: Extent of disease (worse PFS with high CEA, poor ECOG-PS and ≥3 metastatic sites) and disease location (worse PFS with liver or lung metastasis and left sided tumor) were associated with immunotherapy outcome in dMMR/MSI-H mCRC.

Asunto(s)

Neoplasias Encefálicas , Neoplasias del Colon , Neoplasias Colorrectales , Neoplasias Pulmonares , Síndromes Neoplásicos Hereditarios , Humanos , Masculino , Reparación de la Incompatibilidad de ADN , Estudios Prospectivos , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/terapia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/terapia , Inmunoterapia , Inestabilidad de Microsatélites