Treatment Of Colorectal Cancer Research Articles

Prevalent Types of Peristomal Skin Damage During Chemoradiotherapy and Their Risk Factors.

Significance: Colorectal cancer is currently ranked third in terms of the global cancer incidence. Enterostomy, a common surgical procedure for colorectal cancer treatment, creates a temporary or permanent stoma in the abdominal wall for waste excretion. Cancer itself and the associated treatments, such as chemotherapy and radiation therapy, increase the likelihood of various types of peristomal skin damage. Recent Advances: Recent research has focused on developing more targeted treatment approaches for peristomal moisture-associated skin damage (P-MASD). In addition, studies are investigating the potential of novel wound care products and therapies to enhance healing and reduce the risk of complications. There is also growing interest in understanding the different types except P-MASD during chemoradiotherapy. Different types match the varied treatments. Thus, we aimed to comprehensively review the most prevalent types of peristomal skin damage during chemoradiotherapy and their associated risk factors. Critical Issues: The five prevalent types of peristomal skin damage that occur during chemoradiotherapy are peristomal radiodermatitis, P-MASD, peristomal acneiform rash, peristomal pyoderma gangrenosum, and peristomal abscess/infection/fistula. The risk factors vary depending on the type; however, they include the radiation dose, ileostomy surgery, chemoradiotherapy-associated diarrhea, use of epidermal growth factor receptor inhibitors, inflammatory bowel disease, and unclear factors. Future Directions: This review guides the clinical identification of peristomal skin damage during chemoradiotherapy, laying a solid foundation for developing effective strategies to prevent this condition.

Advancements in cellular immunotherapy: overcoming resistance in lung and colorectal cancer

Immunotherapy has revolutionized cancer treatment, offering hope for patients with otherwise treatment-resistant tumors. Among the most promising approaches are cellular therapies, particularly chimeric antigen receptor T-cell (CAR-T) therapy, which has shown remarkable success in hematologic malignancies. However, the application of these therapies to solid tumors, such as lung and colorectal cancers, has faced significant challenges. Tumor resistance mechanisms—ranging from immune evasion, antigen loss, and immune checkpoint upregulation, to tumor microenvironment immunosuppression—remain major obstacles. This mini-review highlights the latest advancements in tumor immunotherapy, with a focus on cellular therapies, and addresses the resistance mechanisms that hinder their effectiveness in lung and colorectal cancers. We examine the evolution of CAR-T cell therapy, as well as the potential of engineered natural killer (NK) cells and macrophages in solid tumor treatment. The review also explores cutting-edge strategies aimed at overcoming resistance, including combination therapies, gene editing technologies, and nanotechnology for targeted drug delivery. By discussing the molecular, cellular, and microenvironmental factors contributing to resistance, we aim to provide a comprehensive overview of how these challenges can be overcome, paving the way for more effective, personalized immunotherapies in lung and colorectal cancer treatment.

ALDOB suppresses the activity of CD8+ Tcells in colorectal cancer via the WNT signaling pathway.

The glycolytic enzyme, fructose-1,6-bisphosphate aldolase B (ALDOB), is recognized for its key role in shaping tthe umor immune microenvironment. However, the precise ways in which it influences the CD8+ Tcell immune response in colorectal cancer (CRC) are still largely unknown. This study is designed to elucidate the interplay between ALDOB and the immune system in CRC. We analyzed the high expression of ALDOB in CRC tissues and cells through bioinformatics, clinical samples and in vitro experiments, finding that it promoted tumor progression. Its high expression was negatively correlated with CD8 expression and positively correlated with PDL1 expression. Further cell experiments revealed that ALDOB overexpression enhanced the expression of WNT signaling pathway-related proteins (β-catenin and c-myc), which in turn promoted PDL1 expression in CRC cells, inhibiting the proliferation and killing effect of CD8+ Tcells in co-culture systems. Our findings disclose how ALDOB influences CD8+ Tcell recruitment and antitumor immune function, proposing it as a potential target for the treatment of CRC.

Apatinib Degrades PD-L1 and Reconstitutes Colon Cancer Microenvironment via the Regulation of Myoferlin

Background: For most colorectal cancer (CRC) patients, expanding the benefits of immunotherapy, particularly through blocking programmed cell death-1 (PD-1) and its ligand (PD-L1), is crucial, especially in cases with limited response to neoadjuvant therapy. This study investigates the role of Myoferlin (MYOF) as a novel target in CRC immunotherapy. Methods: Human CRC cell lines (RKO, HCT116), normal intestinal epithelial cells (HIEC-6), and the murine CRC cell line MC38 were used to study the effects of apatinib and MYOF in CRC cells. RNA sequencing, the CPTAC and TCGA databases, and other molecular and cellular methods were applied to disclose the mechanisms involved. A series of mouse models were established to assess the effects of apatinib and MYOF knockdown on tumor progression, immune cell infiltration, and immune checkpoint protein response. Results: We found that MYOF is overexpressed in CRC and linked to immune cell infiltration and checkpoint expression. Suppression of MYOF expression significantly inhibited CRC cell proliferation and migration, as well as reduced PD-L1 protein levels. Integrative analysis showed that apatinib modulates MYOF expression via VEGFR2, resulting in decreased PD-L1 expression, increased CD8+ T cell infiltration, and reduced pro-tumor M2 macrophages. Animal experiments further revealed that apatinib treatment or MYOF knockdown enhanced the efficacy of immune checkpoint blockade (ICB) in CRC. Conclusions: These findings highlight novel antitumor mechanisms of MYOF and suggest that combining apatinib with ICB therapy may improve CRC treatment outcomes, offering a promising strategy to enhance immune responses.

Development and prospects of natural orifice specimen extraction surgery for colorectal cancer: a review article.

The natural orifice specimen extraction surgery (NOSES) procedure is an innovative approach to treating colorectal cancer that offers several advantages. First, the NOSES technique is minimally invasive, reducing the incidence of postoperative complications such as wound infection and fat liquefaction. Second, it provides excellent pain relief and improves cosmetic outcomes by requiring fewer abdominal incisions, thereby increasing patient satisfaction. Additionally, NOSES provides all of the advantages of minimally invasive surgery and enables patients to recover quickly, helping patients return to their normal lives faster. This approach aligns with the concept of patient-centered care and significantly improves patient quality of life. The positive results noted at both short- and long-term postoperative follow-up indicate that NOSES is a valuable option in cancer care. Despite its many benefits, NOSES has also been challenged by bacteriology, oncology, and ethics. This paper presents a review of recent research progress regarding NOSES in the treatment of colorectal cancer. In this article, we examined the advantages and disadvantages of NOSES in clinical practice and discussed potential issues and solutions.

The Current Status of Adjuvant Chemotherapy for Colorectal Cancer in Japan: A Paradigm Shift from Oral Fluoropyridine Single Therapy to the Oxaliplatin Regimen

The effectiveness of oxaliplatin (L-OHP) has been reported overseas; however, in Japan, the prognosis of colorectal cancer (CRC) patients is reported to be good, and there has been a long debate about the applicability of L-OHP combination therapy in Japan. In recent years, the results of the ACHIEVE trial have become clear, and the standard consensus in Japan establishes L-OHP combination therapy for a duration of 3 months as the adjuvant treatment for CRC.

The Endocannabinoid System: Implications in Gastrointestinal Physiology and Pathology

The endocannabinoid system (ECS), composed of receptors, endocannabinoids, and enzymes that regulate biosynthesis and degradation, plays a fundamental role in the physiology and pathology of the gastrointestinal tract, particularly in the small and large intestine and liver. Specifically, cannabinoid receptor type 1 (CB1R) and cannabinoid receptor type 2 (CB2R), located principally in the nervous system and immune cells, orchestrate processes such as intestinal motility, intestinal and hepatic inflammation, and energy metabolism, respectively. The main endocannabinoids, anandamide (AEA) and 2-arachidonoylglycerol (2-AG), influence appetite, body weight regulation, and inflammatory states and thus have implications in obesity, non-alcoholic fatty liver disease (NAFLD) and irritable bowel syndrome (IBS). Recent studies have highlighted the therapeutic potential of targeting the ECS to modulate gastrointestinal and metabolic diseases. In particular, peripheral CB1R antagonists and CB2R agonists have shown efficacy in treating intestinal inflammation, reducing hepatic steatosis, and controlling IBS symptoms. Moreover, the ECS is emerging as a potential target for the treatment of colorectal cancer, acting on cell proliferation and apoptosis. This review highlights the opportunity to exploit the endocannabinoid system in the search for innovative therapeutic strategies, emphasizing the importance of a targeted approach to optimize treatment efficacy and minimize side effects.

Efficacy and safety of anlotinib as a later-line treatment for advanced colorectal cancer.

194 Background: Colorectal cancer (CRC) is increasingly prevalent in China, with rising incidence and mortality rates. Often, early-stage CRC presents with no symptoms, leading to most patients being diagnosed at an advanced stage, where prognosis is poor. First- and second-line treatments for advanced CRC typically include chemotherapy combined with cetuximab or bevacizumab. However, third-line therapies such as regorafenib, furosemide, and TAS102 have shown limited efficacy. Anlotinib, a multi-targeted tyrosine kinase inhibitor (TKI), has demonstrated improved progression-free survival (PFS) in refractory metastatic CRC (mCRC) in a phase III trial (NCT02332499), showing both efficacy and manageable toxicity. This report provides updated results from extended follow-up. Methods: This study enrolled 73 patients with advanced colorectal cancer who had undergone at least two prior standard treatments and were treated with oral anlotinib hydrochloride (8-12 mg daily, days 1-14 of a 21-day cycle) between November 2021 and March 2024 at Tangdu Hospital. Patients were treated until disease progression or intolerable adverse events. Efficacy was assessed using RECIST version 1.1, and adverse reactions were evaluated using CTCAE version 5.0. The primary endpoints were PFS, disease control rate (DCR), and adverse events (AEs), while secondary endpoints included overall survival (OS). Results: Of the 73 patients included, 38 had an ECOG performance status (PS) of 0-1, and 35 had a PS of 2. Clinical staging identified 18 patients with stage IIIB/IIIC and 55 with stage IV disease. Patients received anlotinib doses of 8 mg (n=11), 10 mg (n=44), or 12 mg (n=18), with 48 patients also receiving chemotherapy and 25 receiving anlotinib alone. The median PFS was 4.0 months (95% CI: 3.4-4.6), and the median OS was 7.0 months (95% CI: 5.7-8.3). Subgroup analysis indicated that patients under 60 years of age, those without liver metastases, and those with ECOG PS 0-1 derived greater benefit from anlotinib. The most common treatment-related adverse event was hypertension (19.2%). Other notable adverse events included elevated AST (11.0%), proteinuria (6.8%), and jaundice (6.8%). Most adverse reactions were grade 1-2, although 1 patient experienced grade ≥3 gastrointestinal bleeding. Conclusions: Anlotinib showed promising efficacy and a favorable safety profile as a later-line treatment for advanced colorectal cancer. These findings suggest that anlotinib may be a viable clinical option for advanced CRC, though larger-scale clinical trials are necessary to confirm these results and further define its role in treatment.

Illness behavior and its predictors in young and middle-aged colorectal cancer patients: A latent profile analysis.

To describe the characteristics of sick role adaptation and understand the differences in young and middle-aged colorectal cancer (CRC) patients. 225 colorectal cancer patients aged 18-59 admitting to a specialized oncology hospital in Guangzhou, China were involved from January to April 2022. Socio-demographic characteristics, disease-related characteristics, scores of Illness Behavior Questionnaire, Hospital Anxiety and Depression Scale, the Brief Illness Perception Questionnaire, Mishel Uncertainty in Illness Scale and Medical Coping Modes Questionnaire were applied to collect quantitative data. Latent profile analysis (LPA) of illness behavior, analysis of variance (ANOVA) and multiple logistic regression were performed. Three latent classes of illness behavior were identified: low maladaptive illness behavior group, moderate maladaptive illness behavior group, and high maladaptive illness behavior group. Univariate analysis revealed statistically significant differences among the three latent classes with respect to education level, anxiety and depression, illness perception, uncertainty in illness and coping modes. Multiple logistic regression analysis revealed that marital status, family history of cancer, education level, family monthly income, anxiety and depression, illness perception, uncertainty in illness and coping modes were predictors of maladaptive illness behaviors among young and middle-aged CRC patients. The results of the study raise a concern of maladaptive illness behaviors in young and middle-aged colorectal cancer patients, highlighting the need for age-appropriate psychosocial care approaches to promote adjustment of the illness behaviors followed by the diagnosis and treatment of CRC.

Leveraging large-scale PDO-based assays to optimize antibody-drug conjugate efficacy in CRC.

261 Background: Clinical trials are one of the major barriers in contemporary drug development. Functional assays based on patient-derived organoids (PDO) are a promising new tool for derisking clinical development of new therapies, but their use has been limited due to small cohort sizes and the absence of systematic validation studies. Using the largest cohort of matched PDOs, longitudinal clinical data, transcriptomic and WES data in CRC, we explore the use of large PDOs collections to characterize ADC efficacy and affinity through systematic mapping of the relationship between target antigen affinity and payload efficacy. Methods: We have assembled a collection of 85 PDOs from colorectal cancer (CRC), generated from primary tumour samples and metastatic biopsies. Patients ranged from 32 to 89 years old and had experienced an average of 1.54 lines of treatment prior to the PDO-generating tissue sampling. Using gene expression levels of well known target antigens such as CEACAM5, ERBB2, MSLN and TROP2 as a proxy for protein concentration, we explore the relationship between the target antigen affinity and the efficacy of a subset of common payloads including topoisomerase and microtubule inhibitors. This allows us to identify the relationship between two of the three main vectors of ADC efficacy in CRC. Results: We show that topoismerase inhibitor and microtubule inhibitor efficacy relates to the RNA expression level of multiple target antigens commonly used in active clinical trials in CRC. These data match the target antigen and payload couples currently under development or approved in the clinic. We are developing a tool to optimize clinical trial design. This approach will allow us to match patients more accurately with the appropriate payload, ensuring a higher likelihood of response. Conclusions: We report that large-scale PDO-based assays can be a useful tool to anticipate clinical readouts. This work suggests that well-characterized PDO collections could also help redefine patient populations, increasing the likelihood of identifying those more likely to respond to a given ADC, and thus improving the success rates of clinical studies for new treatments in CRC.

Real-world genomic testing performance in colorectal cancer (CRC): The MultiTEAM Systems Framework Precision Oncology Reflex Testing (TEAMSPORT).

108 Background: Genomic testing plays a pivotal role in personalizing treatment for CRC patients. Despite recommendations from NCCN, adoption remains uneven. Research indicates that only 64.7% of patients with metastatic CRC (mCRC) underwent molecular testing nationwide. TEAMSPORT seeks to address this gap by evaluating the feasibility of reflex testing and examining how pathology and oncology teams integrate genomic testing into routine practice. Methods: This quasi-experimental study tracks testing over time. Eligible patients were 18 years or older, with a histological diagnosis of adenocarcinoma, who received treatment at the University of Kansas Health System (TUKHS). Exclusion criteria included patients discharged to hospice after diagnosis, those whose last contact with TUKHS occurred within 30 days of diagnosis, and patients who passed away within 30 days of diagnosis. Testing rates were calculated as the number of tests performed divided by the number of testing opportunities, where "testing opportunities" refer to NCCN-recommended tests based on cancer stage. An intervention to increase adherence to NCCN-recommended testing began in December 2022. Results: From January 2022 to December 2023, 564 colorectal cancer (CRC) cases were eligible for genomic testing, resulting in 1,525 testing opportunities. In localized CRC, testing rates steadily improved, from 92% in January-June 2022 to 98% by July-December 2023 for patients diagnosed outside of TUKHS. At TUKHS, the rates remained high, reaching 100% in the first two periods and staying over 90% in subsequent periods. Patients with mCRC saw similar trends, particularly in the control arm where rates went from 61% to 71%. Specific molecular NCCN-recommended tests were assessed. At TUKHS, testing rates were high for microsatellite instability (MSI - 98%) which is caused by deficiency of the DNA mismatch repair (dMMR) system. Lower testing rates were observed for other markers like KRAS (70%), BRAF (67%) and HER2 (48%). Testing rates were assessed based on primary insurance. At TUKHS, the testing rates for Medicaid patients reached 94%, private insurance patients at 78%, and Tricare/VA at 100%. Outside of TUKHS, Medicaid patients had lower testing rates at 21%, private insurance patients at 74%, and CMS patients at 66%. Time to test by processing lab will be presented at the meeting. Conclusions: Despite the high testing rates for MSI/dMMR, the overall genomic testing in CRC remains imperfect, with lower rates for BRAF and HER2 . This discrepancy may be related to the fact that targeted therapies for BRAF and HER2 are not yet part of first-line treatment for CRC. Causes for the discrepancy in testing rates by primary insurance have yet to be determined. Future research should address these gaps to enhance precision oncology in CRC management.

Development of new therapeutic strategies to enhance the effectiveness of irinotecan in colorectal cancer treatment.

217 Background: Chemotherapy plays an important role in the treatment of colorectal cancer. Irinotecan, a topoisomerase I inhibitor, is used in therapies such as FOLFIRI and FOLFOXIRI. However, many patients become resistant to irinotecan, and the detailed mechanisms of resistance are not fully understood. The aim is to develop new therapeutic strategies by elucidating the mechanisms of irinotecan resistance. Methods: We used in vitro approach to demonstrate the mechanism of topoI degradation. Immunohistochemistry staining was used to explore the biomarker for irinotecan, Finally, in vivo approach was used to develop a new strategy for irinotecan treatment. Results: Mechanism of topoisomerase I (topoI) degradation: We investigated the molecular mechanism of topoI degradation in detail. After irinotecan administration, double-strand breaks occur in the DNA, activating DNA-PK. This activated DNA-PK phosphorylates the S10 residue of topoI, and BRCA1-BARD1 ubiquitinates the phosphorylated topoI. Eventually, topoI is degraded by the proteasome. Colorectal cancer cell lines where topoI degradation occurred after irinotecan administration showed irinotecan resistance. Development of a biomarker for irinotecan sensitivity: We created a monoclonal antibody that labels the phosphorylated S10 residue of topoI (topoI-pS10). We examined topoI-pS10 expression in colorectal cancer cases with a history of irinotecan treatment. The results showed a sensitivity of 87.5%, accuracy of 70%, positive predictive value of 70.7%, and negative predictive value of 87%, indicating that topoI-pS10 expression could serve as a biomarker for irinotecan sensitivity.Development of new therapeutic strategies: The degradation of topoI, which causes irinotecan resistance, is carried out via the ubiquitin-proteasome pathway. It is expected that combining irinotecan with a proteasome inhibitor, which blocks this pathway, will enhance irinotecan’s effectiveness. When irinotecan was combined with a proteasome inhibitor in irinotecan-resistant colorectal cancer cell lines, cell death occurred at a higher rate compared to when they were not combined. Similar results were observed in experiments using mice. Conclusions: Based on the mechanism of topoI degradation, we developed a biomarker for irinotecan sensitivity and a new therapeutic strategy. This study suggests the potential for further improvements in irinotecan therapy.

Efficacy of plogosertib (CYC149462), a novel orally bioavailable PLK1 inhibitor, on patient-derived models of colorectal cancer.

209 Background: Colorectal cancer (CRC) is the third most common cancer in adults in the United States. Given the relative rapid cell division in cancer cells compared to most normal cells, drugs targeting mitosis and other cell cycle checkpoints are of interest in CRC treatment. One multi-tasking protein in cell division is polo-like kinase 1 (plk1). Plk1 is a serine threonine kinase that is highly expressed during mitosis and involved in a variety of functions, including spindle assembly, chromosome segregation, G2/M transition, and cytokinesis. Encouragingly, its expression is also significantly higher in CRC compared to normal mucosa, which makes it an attractive cancer-specific target in CRC. In this study, we sought to evaluate the efficacy of plogosertib (CYC149462), a novel plk1 inhibitor, in a series of preclinical models of advanced CRC. Methods: Fourteen CRC patient-derived organoids (PDOs) were generated from patients who underwent biopsy or resection for their primary or metastatic CRC under an IRB approved protocol at Duke University. Diagnosis of CRC is confirmed in PDOs using H&E and IHC. Subsequently, PDOs were treated with plogosertib in a range of concentrations from 256pM to 100µM. Drug screens were performed for standard of care agents 5FU, oxaliplatin, and SN38. Viability was assessed with Cell-Titer Glo (CTG) 72 hours after treatment. Using a matched PDX, mice were treated with vehicle or 40 mg/kg daily of plogosertib via oral gavage for 2 weeks, 5 days per week. Cell cycle analysis was performed by flow cytometry, and localization of DNA during mitosis was done by fluorescence staining. Results: CRC PDOs were more sensitive to plogosertib (CYC149462) than 5FU, and oxaliplatin, with significantly lower IC 50 values (518.86±377.47nM for plogosertib vs. 38.87±45.63µM for 5FU, and 37.78±39.61µM for oxaliplatin respectively (ANOVA, P < 0.05). Subsequently, we validated our findings in vivo using a matched PDX in which plogosertib treatment led to significant tumor growth inhibition compared to vehicle (t-test, p < 0.05) without serious adverse effects. Furthermore, we showed that plogosertib induces dysfunction in alignment of chromosomes and subsequent G2/M cell cycle arrest (p < 0.05). Conclusions: Together, our study shows that pharmacological inhibition of Plk1 using plogosertib represents a promising therapeutic approach for advanced CRC.

A comprehensive update on the potential of curcumin to enhance chemosensitivity in colorectal cancer.

Colorectal cancer (CRC) is one of the most common cancers and a major cause of cancer-related mortality worldwide. The efficacy of chemotherapy agents in CRC treatment is often limited due to toxic side effects, heterogeneity of cancer cells, and the possibility of chemoresistance which promotes cancer cell survival through several mechanisms. Combining chemotherapy agents with natural compounds like curcumin, a polyphenol compound from the Curcuma longa plant, has been reported to overcome chemoresistance and increase the sensitivity of cancer cells to chemotherapeutics. Curcumin, alone or in combination with chemotherapy agents, has been demonstrated to prevent chemoresistance by modulating various signaling pathways, reducing the expression of drug resistance-related genes. The purpose of this article is to provide a comprehensive update on studies that have investigated the ability of curcumin to enhance the efficacy of chemotherapy agents used in CRC. It is hoped that it can serve as a template for future research on the efficacy of curcumin, or other natural compounds, combined with chemotherapy agents to maximize the effectiveness of therapy and reduce the side effects that occur in CRC or other cancers.

Liposomal irinotecan + 5-fluorouracil + leucovorin + bevacizumab as second-line therapy in metastatic colorectal cancer (IRIS): A multi-center, single-arm, prospective, phase II study.

195 Background: In patients with advanced colorectal cancer (CRC), the recommended second-line treatment following first-line therapy with oxaliplatin-based regimens is irinotecan-based therapy. Liposomal irinotecan, a novel formulation of traditional irinotecan, has demonstrated potential to enhance efficacy while minimizing toxicity. This study aims to investigate the efficacy and safety of liposomal irinotecan in combination with 5-FU/LV and bevacizumab as a second-line treatment option for metastatic CRC. Methods: This is a multi-center, single-arm, prospective, phase II study. Patients with metastatic CRC who received oxaliplatin-based chemotherapy as first-line treatment were enrolled to receive liposomal irinotecan + 5-fluorouracil + leucovorin + bevacizumab regimen until disease progression and/or unacceptable toxicity. The primary endpoint is objective response rate (ORR), secondary endpoints include disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. Results: A total of 50 patients were enrolled from Jan 2024 to Jul 2024 across 6 sites in China. The median age was 56.5 years (range: 30.0-76.0), with 58.0% male and 36.0% ECOG 0. Among the patients, 38.0% had left-sided colon cancer, 24.0% had right-sided colon cancer, and 38.0% had rectal cancer. As of Sept 14, 2024, 39 patients had at least one tumor assessment and 19 patients were still on treatment. ORR and DCR were 20.5% (8/39, 95% CI: 9.3%-36.5%) and 84.6% (33/39, 95% CI: 69.5%-94.1%), respectively. Eleven patients had disease progression and 5 patients died, and the median PFS and OS were not reached. The relative dose intensity of liposomal irinotecan and 5-fluorouracil were 92.8% (range: 23.6%-109.6%) and 89.5% (range: 13.3%-116.8%), respectively. During treatment, 43 (86.0%) patients had at least one adverse event (AE) and 24 (48.0%) had grade 3-4 AE. Most common (≥ 10%) grade 3-4 AEs were neutropenia (20.0%), leukocytopenia (16.0%) and diarrhea (10.0%). No unexpected toxicities observed in this study. Conclusions: These preliminary results reveled that liposomal irinotecan + 5-fluorouracil + leucovorin + bevacizumab after oxaliplatin-based treatment for metastatic CRC was well tolerated with encouraging clinical activity, which warrants further follow up. Clinical trial information: NCT06184698 .

Meta-analysis of randomized controlled trials (RCTs) to evaluate the incidence of hemorrhage and venous thromboembolism (VTE) events in patients with gastrointestinal (GI) cancers treated with fruquintinib.

118 Background: Fruquintinib is a novel cancer therapy that was recently approved by the US FDA as a third-line treatment for metastatic colorectal cancer (mCRC). It works by inhibiting the vascular endothelial growth factor receptors, that leads to blocking of angiogenesis which is essential for the tumor proliferation. Close monitoring is always crucial in order to promptly detect and manage any adverse events. This study aims to assess the risk of hemorrhagic and VTE events in patients with GI cancers treated with fruquintinib. Methods: A comprehensive literature search was conducted using MEDLINE, EMBASE, and COCHRANE databases from inception through August 12th, 2024. Phase II/III RCTs utilizing fruquintinib in GI cancers reporting hemorrhage or VTE events as an adverse event were included. Mantel-Haenszel method was used to calculate the estimated pooled risk ratio (RR) with 95% confidence interval (CI). Heterogeneity was assessed with Cochran’s Q-statistic. Random effects model was applied. Results: A total of 1872 patients were included. Data were pooled from three phase III RCTs (FRESCO, FRESCO-2, FRUTIGA) and one phase II RCT, all reporting VTE events including deep vein thrombosis and pulmonary embolism and hemorrhage. FRESCO, FRESCO-2, and the phase II trials involved patients with mCRC, comparing fruquintinib to placebo. FRUTIGA trial incorporated patients with gastric or gastroesophageal junction adenocarcinoma, comparing fruquintinib + paclitaxel to placebo + paclitaxel. High-grade hemorrhage incidence was higher in the fruquintinib arm compared to the control arm (29.00% vs 21.18%, RR 1.62; 95% CI: 1.26-2.08, P=0.0001). In the mCRC subgroup, high-grade hemorrhage rate was also higher and statistically significant in the fruquintinib arm 20.87% vs 11.22% (RR 1.84; 95% CI: 1.25-2.70; P=0.002). Incidence of any grade or high grade VTE events was neither statistically significant in GI cancer population or mCRC subgroup. Incidence of any grade VTE events in GI cancer group and mCRC subgroup was 2.74% vs 2.15% (RR, 1.23; 95% CI: 0.53-2.88; P=0.63) and 2.68% vs 1.53% (RR, 0.95; 95% CI: 0.09-9.67; P=0.97), respectively. Rate of high grade VTE events in GI cancer cohort was 1.67% vs 0.67% (RR, 1.96; 95% CI: 0.52-7.36; P=0.32), while in mCRC subgroup was 1.79% vs 0.76% (RR, 1.08; 95% CI: 0.06-19.98; P=0.96). Conclusions: This meta-analysis demonstrates that patients with GI cancers, including mCRC, treated with fruquintinib have higher incidence of high-grade hemorrhage. These findings underscore the importance of individualized risk assessment, especially for patients predisposed to hemorrhagic complications. No increased risk of VTE events was noted in patients treated with fruquintinib compared to placebo.

Meta-analysis of phase II/III randomized controlled trials (RCTs) to determine the incidence of hypertension and proteinuria in patients with gastrointestinal (GI) cancers treated with fruquintinib.

119 Background: Fruquintinib is a selective inhibitor of vascular endothelial growth factor receptors which impedes angiogenesis associated with tumor growth. On November 8th, 2023, the US FDA approved fruquintinib for use as a third-line treatment for metastatic colorectal cancer (mCRC). With the introduction of novel cancer therapies, monitoring for adverse events is critical. This meta-analysis aims to assess the risk of hypertension (HTN) and proteinuria in patients with GI cancers treated with fruquintinib. Methods: We conducted a comprehensive search of MEDLINE, EMBASE, and COCHRANE databases from inception through August 12th, 2024, identifying Phase II/III RCTs that employed fruquintinib in GI cancers and reported HTN and proteinuria as adverse effects. The Mantel-Haenszel method was used to calculate pooled risk ratios (RR) with 95% confidence intervals (CI). Heterogeneity was assessed using Cochran’s Q-statistic, and a random effects model was applied. Results: Our analysis included 1872 patients, 1131 (60%) of whom received fruquintinib, from three Phase III RCTs (FRESCO, FRESCO-2, FRUTIGA) and one Phase II RCT. FRESCO, FRESCO-2, and the phase II trials compared fruquintinib to placebo in patients with mCRC. FRUTIGA trial involved patients with gastric or gastroesophageal junction adenocarcinoma, comparing fruquintinib + paclitaxel to placebo + paclitaxel. The incidence of any-grade HTN was higher in the fruquintinib group, 34.92% vs 7.55% (RR 3.96; 95% CI: 3.05-5.13; P<0.00001); the rate of high-grade HTN was 13.96% vs 1.21% (RR 9.01; 95% CI: 4.67-17.40; P<0.00001). In the mCRC subgroup, incidence of any-grade and high-grade HTN was 43.02% vs 10.45% (RR 3.97; 95% CI: 2.95-5.33; P<0.00001), and 17.28% vs. 1.27% (RR 12.06; 95% CI: 5.19-28.01; P<0.00001), respectively. Incidence of any-grade proteinuria was also found to be statistically significant and higher in the fruquintinib arm in both GI cancer cohort and mCRC subgroup: 27.3% vs 16.19% (RR 1.89; 95% CI: 1.30-2.74; P=0.0008), and 25.22% vs 11.73% (RR 2.29; 95% CI: 1.17-4.51; P=0.02). The rate of high-grade proteinuria was not statistically significant in both cohorts. In GI cancer group, 1.85% vs 0.53% (RR, 2.49; 95% CI: 0.86-7.16; P=0.09), and mCRC subgroup 2.17% vs 0.51% (RR, 2.87; 95% CI: 0.74-11.12; P=0.13). Conclusions: This meta-analysis revealed a higher incidence of any-grade and high-grade HTN with fruquintinib in GI cancer patients, with significant association in the mCRC subgroup. Fruquintinib was also noted to be associated with increased risk of any-grade proteinuria, however, incidence of high-grade proteinuria was not different in patients treated with fruquintinib compared to placebo. Prompt identification and early management of these adverse events are crucial.

A phase two trial evaluating FOLFIRI plus aflibercept after failure of FOLFOXIRI plus bevacizumab in patients with unresectable metastatic colorectal cancer.

FOLFOXIRI plus bevacizumab (BEV) is an option for first-line treatment of metastatic colorectal cancer (mCRC). However, there is no consensus on the optimal treatment strategy when disease progresses. The EFFORT open-label, multicenter, single-arm phase II study investigated whether FOLFIRI plus aflibercept retains activity after progression of FOLFOXIRI plus BEV treatment. The patients with unresectable mCRC who failed first-line FOLFOXIRI plus BEV received FOLFIRI plus aflibercept. The primary endpoint was progression-free survival (PFS) in the full analysis set (FAS). Angiogenic biomarkers were measured before treatment initiation. From April 2019 to May 2021, 35 patients were enrolled and 34 were analysed in the FAS population (men, 18; median age, 63years [range: 32-78]). The primary tumor was left-sided in most cases (23/34), 23 patients were RAS mutant, 3 patients had BRAF V600E mutation and 27 patients had liver metastases. The primary end-point was met with a median PFS of 4.3months [80% confidence interval [CI] 3.7-5.1]. Median overall survival was 15.2months [95% CI 8.9-22.7]. Per RECIST, there were 1 complete response, 4 partial responses, 21 stable diseases and 8 disease progressions. Overall response rate was 14.7% [95% CI 5.0-31.1], and disease control rate was 76.5% [95% CI 58.8-89.3]. Responses were more common in patients with high VEGF-C, low VEGF-D and low PlGF levels before treatment. FOLFIRI plus aflibercept, administered after failure of FOLFOXIRI plus BEV, is effective and has a manageable safety profile. This regimen may be a useful second-line treatment option for these patients.

Comparison of risk factors, treatment strategy, and outcomes of early- vs. older-onset colorectal cancer within the prospective ColoCare study.

95 Background: The incidence of colorectal cancer among young adults aged 20-49 has continually increased in recent decades. Early-onset colorectal cancer (EOCRC) patients are more likely to be diagnosed at a more advanced stage of disease, have hereditary cancer syndromes, and have different molecular pathological features of disease than later-onset patients. Herein we compare the risk factors, treatment approaches, and responses to treatment of early-onset versus later-onset colorectal cancer within. Methods: The ColoCare Study is a prospective cohort enrolling individuals diagnosed with primary colorectal cancer at six different cancer centers in the United States and one in Germany. Serial questionnaires assess demographic characteristics and symptoms experienced prior to diagnosis, while clinical characteristics (including staging, pathology, treatments given) are abstracted from medical records. Restricting to patients with available age and stage, patients diagnosed <50 years old were labeled as “early-onset” and ≥50yo as “later-onset.” Associations between patient age and characteristics of interest were tested using Fisher’s Exact Test for count data. Results: Of the3,173 patients included in this analysis, 78% were later-onset (mean: 65 years) and 22% were early-onset (mean: 42 years). Demographic data was comparable between the two groups, with 43% being female. Though similar rates of ever alcohol use were seen between the two groups, early-onset patients reported consuming fewer weekly alcoholic beverages than later-onset patients (mean (standard deviation) of 5.5 (6.6) vs. 8.4 (9.3)). Early-onset patients were less likely to have ever smoked tobacco (38% vs 51%, p<0.001) and had lower rates of obesity (27% vs 31%) or overweight (34% vs 40%) than later-onset patients (p<0.001). For stage II/III disease, early-onset patients were more likely to have received chemotherapy and/or radiation treatment compared to later-onset patients (87% vs 70%, p<0.001), though both groups had similar rates of surgery. Despite this, younger patients did not appear to experience better outcomes, with 21% of younger patients experiencing a recurrence or new metastasis during follow-up versus 20% of later-onset patients. Conclusions: The risingincidence of colorectal cancer in early-onset patients does not appear to be explained by traditional risk factors such as alcohol use, tobacco use, or high BMI. Early-onset patients are more likely to receive chemotherapy or radiation, but observed outcomes are notably poorer compared to later-onset patients. Further statistical analysis on specifics of treatments by stage is ongoing.

Efficacy and safety of reduced-port laparoscopic surgery versus conventional laparoscopic surgery for colorectal cancer

BackgroundLaparoscopic radical resection has become the most important treatment for resectable colorectal cancer (CRC). However, there is still a lack of researches on the efficacy and safety of reduced-port laparoscopic surgery (RPLS) versus conventional laparoscopic surgery (CLS) in the treatment of CRC.Patients and methodsFrom January 2019 to July 2022, 698 patients with CRC received surgical treatment in the Sixth Affiliated Hospital of Sun Yat-sen University were enrolled in this retrospective cohort study. Patients were divided into RPLS group (n = 220) and CLS group (n = 478) according to their surgical procedures. Propensity score matching (PSM) was used to adjust the differences in baseline characteristics. The incidence of perioperative outcomes and survival rates related results were analyzed after PSM.ResultsFour hundred twenty-two patients were equally divided into RPLS group (n = 211) and CLS group (n = 211) after PSM. There were no statistically significant differences in overall survival (OS) and progression-free survival (PFS) between the two groups (P value was 0.773 and 0.579 respectively). The perioperative outcomes of patients between the two groups were comparable, except that patients in the RPLS group had a shorter postoperative hospital stay (P value < 0.001).ConclusionFor patients with CRC, both RPLS and CLS might be acceptable surgical options. No significant differences in perioperative outcomes, PFS rates and OS rates were observed between the two groups. For certain cases, RPLS was superior to CLS in terms of postoperative recovery.