Biosimilars to originator bevacizumab (Avastin), such as bevacizumab-bvzr (Zirabev), can deliver substantial savings and/or expanded access to biologic therapy for patients with metastatic colorectal (mCRC) and non-squamous non-small cell lung cancer (mNSCLC). The objective of this study is to explore the cost-efficiency and budget-neutral expanded access of bevacizumab-bvzr in mCRC and mNSCLC in Medicare.

We developed a Medicare payer perspective simulation model of patients treated for mCRC and mNSCLC to estimate cost-savings from converting bevacizumab (originator) to bevacizumab-bvzr or alternative biosimilars such as bevacizumab-awwb, -maly, and -abcd. The target patient population receiving annual first-line systemic therapy was calculated using Medicare enrollment data, SEER cancer incidence rates in patients age ≥65, and an assumption that 39.3% and 77.2% of new diagnoses receive systemic therapy for mCRC and mNSCLC respectively based on recent evidence. 76.0% of systemically treated mCRC patients and 11.4% of incident mNSCLC patients were expected to be treated with bevacizumab-based regimens based on recent evidence. Costs were derived from the 2024 Average Sales Price (ASP). Results include per-patient per-month (PPPM) cost savings (vs. originator), total monthly savings in the cohort, and number needed to convert (NNC) to biosimilar to fund the treatment of an additional 100 patients.

PPPM savings from conversion to bevacizumab-bvzr were $4,205 in mCRC and $8,410 in mNSCLC. In 100% conversion scenarios, full cohort monthly savings were $27,664,432 in mCRC (n = 6,579) and $32,319,323 in mNSCLC (n = 3,843), respectively. At 100% conversion, monthly savings from biosimilar conversion could fund up to 13,887 additional mCRC patient-months of treatment with bevacizumab-bvzr + FOLFOX, and up to 8,959 additional mNSCLC patient-months of treatment with bevacizumab-bvzr + paclitaxel + carboplatin. In mCRC and mNSCLC the biosimilar NNC from the originator was 47 and 43, respectively. The biosimilar NNC from other biosimilars ranged from 60-4,564 and 55-4,422 for mCRC and NSCLC, respectively.

In the first cost-efficiency and expanded access study of biosimilar bevacizumab in mCRC and mNSCLC, we find that bevacizumab-bvzr-based regimens can result in substantial cost savings relative to originator-based first line treatment in Medicare. These cost savings could be reinvested to treat a substantial number of additional patients with mCRC or mNSCLC, or fund other costs of care in Medicare, on a budget-neutral basis.

To investigate whether the administration of bevacizumab in combination with cytostatics could cause an oxidative response in the submandibular gland of an animal model.

48 Male Wistar rats (350-400 g) were used. Group 1: Control; Group 2: 5-Flourouracil + Leucovorin calcium (Intraperitoneal injection for five consecutive days with 20 mg/kg+10 mg/kg); Group 3: Bevacizumab, two intraperitoneal doses of 0.2 mg/kg on days 1 and 15; Group 4: Oxaliplatin, one intraperitoneal dose of 25 mg/kg on days 1 and 15; Group 5: Bevacizumab+Oxaliplatin+ 5-Fluorouracil+Leucovorin calcium, single intraperitoneal dose of 20 mg/kg, 10 mg/kg, 0.2 mg/kg, and 25 mg/kg on days 1 and 15; Group 6: pair-fed group without drugs. In submandibular gland homogenates, Uric Acid, Lipid Peroxides, Aqueous Peroxides, and Superoxide Dismutase activity were measured.

Uric Acid in Groups 1, 3, and 6 were higher than in cytostatic groups (p < 0.02, 0.02, and 0.001). Lipid Peroxides and Aqueus Peroxides were similar. Superoxide Dismutase Activity was higher in Groups 2, 3, 4, 5, and 6 compared to Group 1 (p < 0.0001). In Group 3, Superoxide Dismutase Activity was lower than in cytostatic-treated groups but higher than Group 6 (p < 0.001). Group 2 showed higher activity compared to Groups 3 and 6 (p < 0.0001).

Cytostatic treatment exerted a pro-oxidant effect at the acinar level. Conversely, bevacizumab may promote an antioxidant glandular response. Further research into these treatments' effects on the stomatognathic system is crucial for improving quality of life in patients undergoing anti-tumour therapy.

The addition of bevacizumab to trifluridine-tipiracil (FTD/TPI) therapy improves outcomes in patients with refractory metastatic colorectal cancer (CRC). However, predictive factors of efficacy for FTD/TPI when used in combination with bevacizumab are not yet fully recognized.

Patients included in the Spanish cohort of the SUNLIGHT trial were evaluated. The primary endpoint of this post-hoc exploratory subanalysis was overall survival (OS). Secondary endpoints included progression-free survival (PFS), disease control rate (DCR), safety and the assessment of potential predictive factors of efficacy for FTD/TPI plus bevacizumab, such as age, KRAS mutational status, the incidence of neutropenia, patient prognosis, and prior administration of bevacizumab.

A total of 115 patients were analysed, 58 receiving FTD/TPI and 57 FTD/TPI plus bevacizumab. The median OS was 8.5 vs. 10.6 months (p = 0.254), respectively, and the median PFS was 2.4 vs. 4.7 months (p < 0.0001), respectively. Severe neutropenia affected 20% more patients in the experimental arm than in the control arm (51% vs. 31%, respectively). The univariate analysis showed that a benefit of adding bevacizumab to FTD/TPI in terms of PFS was observed in all previously defined patient subgroups and was accompanied by DCR of 69% for FTD/TPI plus bevacizumab vs. 45% in arm of FTD/TPI alone.

The addition of bevacizumab to FTD/TPI tends to improve OS probably due to the reduced number of patients included in this cohort and significantly improved PFS in all patient subgroups with metastatic CRC. Prospective studies are needed to confirm these results and to find out additional predictive factors that help us to discriminate which patients would benefit most from FTD/TPI plus bevacizumab.

Bevacizumab shows inter-individual pharmacokinetic variability, with an exposure-response relationship in metastatic colorectal cancer (mCRC) patients. This study explores whether a double dose of bevacizumab, compared to a standard dose, increases efficacy in mCRC patients treated with bevacizumab-based chemotherapy as first-line therapy and who have a low initial trough concentration of bevacizumab. PHARBEVACOL is a multicenter, randomized, double-blind, two-parallel group trial. All patients will receive first-line bi-weekly 5 mg/kg bevacizumab-based chemotherapy and those with low initial bevacizumab concentrations (≤15.5 mg/L) will be randomized to either continue the standard dose (5 mg/kg every 14 days) or receive a double dose (10 mg/kg every 14 days). The primary objective is to evaluate the effect of doubling dose on progression-free survival (PFS). During a screening phase, the first serum trough concentration will be measured on day 14, before the second infusion of bevacizumab. We hypothesize a 40 % PFS in the control group at 9 months versus 60 % in the study group, corresponding to a hazard ratio of 0.56. With 80 % power, a 5 % two-sided type I error, and a minimum 12-month follow-up, 116 patients need to be included. Since only 50 % of screened patients will be eligible for randomization, approximately 244 patients will be screened. Recruitment is scheduled to begin in February 2025.

We have made steady gains in improving overall survival in patients with metastatic, unresectable, colon cancer in the last 5 to 10 years. The backbone of systemic treatment for most patients remains combination chemotherapy, but the field is becoming increasingly biomarker driven, with exciting new targeted therapies on the horizon. This review is organized in sections corresponding to currently relevant biomarkers in colon cancer and will summarize first-, second-, and third-line standard of care for metastatic, unresectable, colon cancer. The last section is intended to introduce the reader to promising agents and novel therapeutic strategies currently under investigation.

PurposeThis study aimed to investigate the effects of preparation conditions and external factors, particularly ultraviolet (UV) exposure, on inline-filter clogging in liquid monoclonal antibody (l-mAb) formulations. Bevacizumab (BmAb) was used as a model drug to address the critical question of how UV exposure impacts protein stability and filter performance during clinical administration.MethodsBevacizumab solutions were exposed to UV-C (254 nm) light to evaluate its effects on protein stability and filter clogging. Scanning electron microscopy (SEM) was used to visualize protein aggregates on the filter surface. Dynamic light scattering (DLS) analysis measured particle size distribution and average particle size. To assess the effectiveness of light shielding, additional samples were prepared under conditions that minimized UV exposure.ResultsUV-C exposure induced significant precipitate formation, with SEM images revealing protein aggregates on the filter surface. DLS analysis showed a broader particle size distribution and an increase in average particle size (18.1 nm) in UV-exposed solutions compared to non-exposed controls. Light shielding effectively suppresses precipitate formation, maintaining the stability of BmAb solutions and preventing inline-filter clogging.ConclusionUV-C destabilizes BmAb solutions, leading to protein aggregation and inline-filter clogging. Light shielding was identified as an effective strategy to maintain the stability and safety of l-mAb formulations, particularly in settings where prolonged exposure to environmental light is possible. These findings emphasize the importance of implementing protective measures against UV exposure and call for further research on additional environmental factors and optimized protocols to enhance l-mAb formulation reliability.

Although cancer chemopreventive agents have been confirmed to effectively protect high-risk populations from cancer invasion or recurrence, only over ten drugs have been approved by the U.S. Food and Drug Administration. Therefore, screening potent cancer chemopreventive agents is crucial to reduce the constantly increasing incidence and mortality rate of cancer. Considering the lengthy prevention process, an ideal chemopreventive agent should be nontoxic, inexpensive, and oral. Natural compounds have become a natural treasure reservoir for cancer chemoprevention because of their superior ease of availability, cost-effectiveness, and safety. The benefits of natural compounds as chemopreventive agents in cancer prevention have been confirmed in various studies. In light of this, the present review is intended to fully delineate the entire scope of cancer chemoprevention, and primarily focuses on various aspects of cancer chemoprevention based on natural compounds, specifically focusing on the mechanism of action of natural compounds in cancer prevention, and discussing in detail how they exert cancer prevention effects by affecting classical signaling pathways, immune checkpoints, and gut microbiome. We also introduce novel cancer chemoprevention strategies and summarize the role of natural compounds in improving chemotherapy regimens. Furthermore, we describe strategies for discovering anticancer compounds with low abundance and high activity, revealing the broad prospects of natural compounds in drug discovery for cancer chemoprevention. Moreover, we associate cancer chemoprevention with precision medicine, and discuss the challenges encountered in cancer chemoprevention. Finally, we emphasize the transformative potential of natural compounds in advancing the field of cancer chemoprevention and their ability to introduce more effective and less toxic preventive options for oncology.

Children's risk of developing colorectal cancer (CRC) is relatively low. In this report, we present our experience with CRC in the pediatric age group, together with an extensive review of the literature.

Between the years 2013 and 2024, a total of five patients diagnosed with CRC underwent treatment at the Department of Pediatric Surgery in our tertiary hospital. A retrospective evaluation was conducted on patients' charts, encompassing demographics, admission symptoms, patient and family histories, laboratory and radiologic findings, operative and pathology reports, genetic and molecular study results, treatment protocols, and follow-up data.

There were three males and two females, with a mean age of 13.5 ± 2.5 years. The primary sites were the sigmoid and rectosigmoid. Two patients were diagnosed with mucinous adenocarcinoma based on histopathological examination. Among the three remaining patients, one presented with signet ring cells, one displayed moderately differentiated adenocarcinoma characteristics, and one exhibited well-differentiated adenocarcinoma characteristics. At the time of the most recent follow-up, two patients have demonstrated survival.

The two main factors contributing to poor survival in pediatric CRC were concluded to be at an advanced stage during diagnosis and having an aggressive histologic subtype. Including CRC in the preliminary diagnosis list is essential for an early diagnosis in the pediatric age group.

Backgrounds and ObjectivesColorectal cancer is one of the leading causes of mortality both globally and in our country. In Turkey, we conducted a multicenter investigation into the effectiveness of second-line treatments and real-life data for patients with RAS wild-type metastatic colorectal cancer (NCT04757311).Materials and MethodsIn this retrospective analysis, records from 28 centers were collected, and histopathological, molecular, and clinical characteristics were documented. Patients were categorized into groups based on their second-line biological treatments: anti-EGFR (Group A and Group B, panitumumab and cetuximab) and anti-VEGF (Group C, bevacizumab and aflibercept). They were then compared within these groups.ResultsA total of 588 patients with documented RAS wild-type status were evaluated. The median OS was 15.7, 14.3 and 14.7 months in Group A, Group B and Group C, respectively (p  =  0.764). The median PFS of the patients in second-line setting that received panitumumab, cetuximab and bevacizumab/aflibercept were 7.8, 6.6 and 7.4 months, respectively (p  =  0.848).ConclusionAccording to the results of our real-life data study, there is no significant difference in efficiency between the combination of biological agent and chemotherapy used in the second-line treatments.

Background/Objectives: Worldwide, colon cancer is a major cause of cancer-related mortality, with an increasing incidence influenced by genetic, environmental, and lifestyle factors. Despite advances in diagnosis and personalized treatments, challenges remain in improving patient prognosis, particularly in metastatic colorectal cancer (mCRC). Bevacizumab (BEV), a monoclonal antibody, is widely used in colorectal cancer treatment. This study aimed to analyze adverse events associated with BEV compared with other therapies based on data from the EudraVigilance (EV) database. Methods: A descriptive and disproportionality analysis was conducted on signals reported in the EV database related to BEV. The study included comparisons with other antineoplastic treatments, such as chemotherapy, targeted therapy, and immunotherapy. Patient demographics, severity of adverse drug reactions (ADRs), and distribution patterns were analyzed to assess the safety profile of BEV in colorectal cancer treatment. Results: The majority of the signals for BEV were from patients aged 18-64 years (39.42%) and 65-85 years (34.08%). Hypertension, thromboembolism, proteinuria, and gastrointestinal disorders have been the most frequently reported. Serious ADRs, including gastrointestinal perforations, hemorrhage, and arterial thromboembolism, were observed in 93.74% of Individual Case Safety Reports. BEV was associated with a higher likelihood of vascular and endocrine disorders compared with chemotherapy and other targeted therapies. Immunotherapy was linked to increased immunological ADRs, while BEV demonstrated fewer immune-related toxicities. Conclusions: Continuous monitoring is necessary to optimize patient management, particularly in elderly patients or those with cardiovascular comorbidities. Understanding BEV's safety profile allows for better personalization of treatment strategies, minimizing risks while enhancing therapeutic outcomes.

The "angiogenesis switch"-defined as the active process by which solid tumors develop their own circulation-plays an important role in both tumoral growth and propagation. As the malignant tumor grows and reaches a critical size, the metabolic needs as a function of an ever-increasing distance to the nearest emergent blood vessel, can no longer be covered by the microenvironment of the peritumoral tissue. Although a relatively discrete process, the "angiogenic switch" acts as a limiting stage of tumoral development present from the avascular hyperplasia phase to the vascularized neoplastic phase, providing support for tumor expansion and metastasis. Over time, research has focused on blocking the angiogenetic pathways (such as VEGF/VEGFR signaling axis) leading to the development of targeted therapeutic agents such as Bevacizumab. Objectives: We conducted a review of the molecular principles of tumoral angiogenesis and we tried to follow the history of Bevacizumab from its first approval for human usage 20 years ago to current days, focusing on the impact this agent had in solid tumor therapy. A comprehensive review of clinical trials pertaining to Bevacizumab (from the era of the preclinic trials leading to approval for human usage, to the more recent randomized trial focusing on combination targeted therapy) further details the role of this drug. We aimed to establish if this ancient drug continues to have a place in modern oncology. Conclusions: Bevacizumab, one of the first drugs targeting tumoral microenvironment, remains one of the most important oncologic agents blocking the VEGF/VEGFR angiogenic pathway. otherwise, history of 20 years marked by numerous controversies (ranging from methodological errors of clinical trials to withdrawal of approval for human usage in breast cancer patients, from discussions about severe side effects to resistance to therapy and limited efficacity), Bevacizumab continues to provide an optimal therapeutic option for many solid tumors that previously had little to no means of treatment, improving otherwise bleak outcomes. Even in the era of personalized precision oncology, Bevacizumab continues to be a key element in many therapeutic regimens both as monotherapy and in combination with newer targeted agents.

Currently, guidelines prohibit the addition of targeted drugs in neoadjuvant chemotherapy (NAC) for initially resectable colorectal liver metastasis (CRLM).

Nevertheless, efficacy data of NAC combined with bevacizumab (Bev) for initially resectable CRLM with risk factors for recurrence (RFR) are lacking.

We conducted a multicenter real-world cohort study to retrospectively analyze the efficacy and feasibility of NAC combined with Bev for CRLM with RFR.

The patients were divided into the NAC alone group and NAC combined with the Bev group. We designated progression-free survival (PFS), objective response rate (ORR), and overall survival (OS) as the outcomes. Kaplan-Meier, Cox proportional hazards regression models, and subgroup analysis were utilized. RFR was a clinical risk score of 3-5. Subgroup analysis was applied to explore which subgroup was more suitable for NAC combined with Bev.

Between 2015 and 2020, this multicenter real-world study encompassed 335 CRLM patients from six medical centers who underwent curative hepatectomy following NAC. Two hundred seventeen patients were in the NAC alone group, and 118 received NAC combined with Bev. The NAC alone group exhibited an ORR of 51.15%, compared to 66.95% in the NAC combined with Bev (p = 0.005). The R0 resection rates achieved 91.71% for the NAC alone group and 94.92% for the NAC combined with Bev (p = 0.276). Three-year PFS rate was 27.6% for NAC alone and 41.5% for the NAC combined with the Bev group (p = 0.006). Furthermore, the 3-year OS was calculated to be 57.0% for the NAC alone and 66.7% for the NAC combined with Bev patients (p = 0.079).

For initially resectable CRLM patients with RFR, NAC combined with Bev exhibited a higher ORR and longer PFS.

ChiCTR2400082966.

Nanotechnology has revolutionized cancer diagnostics and therapy, offering unprecedented possibilities to overcome the constraints of conventional treatments. This study provides a detailed overview of the current progress and difficulties in the creation of nanostructured materials, with a specific emphasis on their use in drug and gene delivery systems. The study examines tactics that attempt to improve the effectiveness and safety of chemotherapeutic drugs such as doxorubicin (Dox) by focusing on the potential of antibody-drug conjugates and functionalized nanoparticles. Moreover, it clarifies the challenges encountered in administering nanoparticles orally for gastrointestinal treatments, emphasizing the crucial physicochemical properties that affect their behavior in the gastrointestinal system. This study highlights the transformational potential of nanostructured materials in precision oncology by examining advanced breakthroughs such cell membrane-camouflaged nanoparticles and inorganic nanoparticles designed for gastrointestinal disorders. The text investigates the processes involved in the absorption of nanoparticles and their destruction in lysosomes, revealing the many methods in which enterocytes take up these particles. This study strongly supports the use of advanced nanoparticle-based methods to reduce the harmful effects on the whole body and improve the effectiveness of therapy, based on a thorough examination of current experiments on animals and humans. The main objective of this paper is to provide a fundamental comprehension that will stimulate more investigation and practical use in the field of cancer nanomedicine, advancing its boundaries.

Self-supervised learning (SSL) automates the extraction and interpretation of histopathology features on unannotated hematoxylin-eosin-stained whole slide images (WSIs). We train an SSL Barlow Twins encoder on 435 colon adenocarcinoma WSIs from The Cancer Genome Atlas to extract features from small image patches (tiles). Leiden community detection groups tiles into histomorphological phenotype clusters (HPCs). HPC reproducibility and predictive ability for overall survival are confirmed in an independent clinical trial (N = 1213 WSIs). This unbiased atlas results in 47 HPCs displaying unique and shared clinically significant histomorphological traits, highlighting tissue type, quantity, and architecture, especially in the context of tumor stroma. Through in-depth analyses of these HPCs, including immune landscape and gene set enrichment analyses, and associations to clinical outcomes, we shine light on the factors influencing survival and responses to treatments of standard adjuvant chemotherapy and experimental therapies. Further exploration of HPCs may unveil additional insights and aid decision-making and personalized treatments for colon cancer patients.

The 2024 updates of the Chinese Society of Clinical Oncology (CSCO) Clinical Guidelines for the diagnosis and treatment of colorectal cancer emphasize standardizing cancer treatment in China, highlighting the latest advancements in evidence-based medicine, healthcare resource access, and precision medicine in oncology. These updates address disparities in epidemiological trends, clinicopathological characteristics, tumor biology, treatment approaches, and drug selection for colorectal cancer patients across diverse regions and backgrounds. Key revisions include adjustments to evidence levels for intensive treatment strategies, updates to regimens for deficient mismatch repair (dMMR)/ microsatellite instability-high (MSI-H) patients, proficient mismatch repair (pMMR)/ microsatellite stability (MSS) patients who have failed standard therapies, and rectal cancer patients with low recurrence risk. Additionally, recommendations for digital rectal examination and DNA polymerase epsilon (POLE)/ DNA polymerase delta 1 (POLD1) gene mutation testing have been strengthened. The 2024 CSCO Guidelines are based on both Chinese and international clinical research, as well as expert consensus, ensuring their relevance and applicability in clinical practice, while maintaining a commitment to scientific rigor, impartiality, and timely updates.

Subsequent lines of therapy for chemotherapy-resistant metastatic colorectal cancer (CRC) have shown limited efficacy. Herein, we retrospectively investigated the efficacy and safety of hepatic artery infusion chemotherapy (HAIC) using oxaliplatin plus 5-FU/FUDR in patients with unresectable colorectal liver metastases (CRLM) who progressed following standard chemotherapy regimens.

From March 2017 to April 2023, CRC patients with unresectable CRLM who progressed following standard chemotherapy and subsequently received HAIC oxaliplatin plus 5-FU/FUDR were evaluated. Objective response rate (ORR), disease control rate (DCR), median depth of tumor response (DpR), no evidence of disease (NED) rate, progression-free survival (PFS), overall survival (OS), and safety were assessed.

A total of 21 patients who progressed after a median of two (range: 1-4) lines of standard systemic chemotherapy were included. The ORR and DCR were 28.6 % and 95.2 %, respectively, with six patients reaching partial response. Additionally, the median DpR was 10.6 %, and seven patients underwent successful conversion surgery. Stratification revealed significantly better PFS in patients with liver-limited metastases compared to those with concurrent hepatic and extrahepatic metastases (P = 0.0003).

HAIC oxaliplatin plus 5-FU/FUDR is a robust regimen for treatment-resistant CRC patients with unresectable CRLM, particularly those with liver-limited disease.

The progression of malignant tumors leads to the development of secondary tumors in various organs, including bones, the brain, liver, and lungs. This metastatic process severely impacts the prognosis of patients, significantly affecting their quality of life and survival rates. Research efforts have consistently focused on the intricate mechanisms underlying this process and the corresponding clinical management strategies. Consequently, a comprehensive understanding of the biological foundations of tumor metastasis, identification of pivotal signaling pathways, and systematic evaluation of existing and emerging therapeutic strategies are paramount to enhancing the overall diagnostic and treatment capabilities for metastatic tumors. However, current research is primarily focused on metastasis within specific cancer types, leaving significant gaps in our understanding of the complex metastatic cascade, organ-specific tropism mechanisms, and the development of targeted treatments. In this study, we examine the sequential processes of tumor metastasis, elucidate the underlying mechanisms driving organ-tropic metastasis, and systematically analyze therapeutic strategies for metastatic tumors, including those tailored to specific organ involvement. Subsequently, we synthesize the most recent advances in emerging therapeutic technologies for tumor metastasis and analyze the challenges and opportunities encountered in clinical research pertaining to bone metastasis. Our objective is to offer insights that can inform future research and clinical practice in this crucial field.

Approximately 50% of colorectal cancer patients develop liver metastases. Hepatic metastases represent the most common cause of colorectal cancer-related mortality. Metastasectomy, if possible, represents the most effective treatment strategy; 20% of patients will be cured and more than 50% survive at least 5 years. Nuances to treatment planning hinge on whether patients present with resectable disease upfront, whether the future liver remnant is adequate, and whether the primary tumor, if present, is colon versus rectal in origin. This article discusses considerations impacting our approach to patients with colorectal liver metastases and the role for various multimodal treatment options.

The management of patients with diffuse liver metastases remains a significant clinical challenge. In many cancer patients, metastatic disease may be isolated to the liver or the liver may be the dominant site of progressive metastatic cancer. In this setting, progression of disease in the liver generally is the most significant cause of morbidity and mortality.

Targeted therapy, the milestone in the development of human medicine, originated in 2004 when the FDA approved the first targeted agent bevacizumab for colorectal cancer treatment. This new development has resulted from drug developers moving beyond traditional chemotherapy, and several trials have popped up in the last two decades with an unprecedented speed. Specifically, EGF/EGFR, VEGF/VEGFR, HGF/c-MET, and Claudin 18.2 therapeutic targets have been developed in recent years. Some targets previously thought to be undruggable are now being newly explored, such as the RAS site. However, the efficacy of targeted therapy is extremely variable, especially with the emergence of new drugs and the innovative use of traditional targets for other tumors in recent years. Accordingly, this review provides an overview of the major signaling pathway mechanisms and recent advances in targeted therapy for gastrointestinal cancers, as well as future perspectives.

The prolongation of survival along with the preservation of quality of life, possibly avoiding harmful cumulative toxicities, is the primary therapeutic aim for patients with metastatic colorectal cancer (mCRC) in the third-line setting. Several therapeutic options are now available, although some differences across countries in drug approval and the optimal therapeutic sequencing associated with each peculiar patient subgroup represent a clinical challenge for oncologists. Among various options, the SUNLIGHT trial showed how the combination of trifluridine/tipiracil (FTD/TPI) with bevacizumab is effective with an easily manageable toxicity profile compared to FTD/TPI alone. Of note, the efficacy is confirmed independently from KRAS mutational status and also for patients who had breaks in anti-vascular endothelial growth factor (anti-VEGF) therapy. Herein, we describe the current state of the art in the landscape of treatments after the second progression in mCRC. Based on a critical review of the literature aimed to guide clinicians in their daily decision-making, we point out that the combination of FTD/TPI with bevacizumab produces a clinical benefit in unselected mCRC patients. Therefore, the FTD/TPI plus bevacizumab regimen can represent a new standard of care for the treatment of patients with refractory mCRC who have progressed after two lines of therapy.

Cancers of the digestive system are major contributors to global cancer-associated morbidity and mortality, accounting for 35% of annual cases of cancer deaths. The etiologies, molecular features, and therapeutic management of these cancer entities are highly heterogeneous and complex. Over the last decade, genomic and functional studies have provided unprecedented insights into the biology of digestive cancers, identifying genetic drivers of tumor progression and key interaction points of tumor cells with the immune system. This knowledge is continuously translated into novel treatment concepts and targets, which are dynamically reshaping the therapeutic landscape of these tumors. In this review, we provide a concise overview of the etiology and molecular pathology of the six most common cancers of the digestive system, including esophageal, gastric, biliary tract, pancreatic, hepatocellular, and colorectal cancers. We comprehensively describe the current stage-dependent pharmacological management of these malignancies, including chemo-, targeted, and immunotherapy. For each cancer entity, we provide an overview of recent therapeutic advancements and research progress. Finally, we describe how novel insights into tumor heterogeneity and immune evasion deepen our understanding of therapy resistance and provide an outlook on innovative therapeutic strategies that will shape the future management of digestive cancers, including CAR-T cell therapy, novel antibody-drug conjugates and targeted therapies.

Concurrent inhibition of angiogenesis and immune checkpoints represents a potent therapeutic approach. We conducted a phase 2, multicenter, basket study to assess the efficacy and safety of combination therapy of famitinib (anti-angiogenic agent) plus camrelizumab (PD-1 antagonist) in patients with metastatic solid tumors across 11 cohorts (this study was registered at Clinicaltrials.gov [NCT04346381]). This report focuses on the cohort of patients with metastatic or advanced colorectal cancer. Eligible patients, who had previously received ≥2 lines of systemic treatments for their metastatic disease, were treated with famitinib (20 mg once daily) in combination with camrelizumab (200 mg intravenously every 3 weeks). The primary endpoint was the objective response rate, with secondary endpoints encompassing progression-free survival, overall survival, duration of response, safety and exploratory biomarkers. A total of 44 patients were enrolled and treated. With a median follow-up time of 9.46 months (range 2.0-22.5 months), objective responses were observed in 6 patients (13.6%; 95% confidence interval [CI], 5.2%-27.4%), all of whom had rectal cancer. The median duration of response is 6.2 months (95% CI, 2.3-10.6 months). Median progression-free survival was 3.3 months (95% CI, 2.1-4.1 months), and median overall survival was 10.9 months (95% CI, 7.6-15.2 months). Among the 44 patients, 29 (65.9%) experienced grade 3 or 4 treatment-related adverse events, predominantly hypertension and proteinuria. In conclusion, the combination of famitinib and camrelizumab demonstrates promising antitumor activity with a manageable safety profile in metastatic colorectal cancer patients. Further research is warranted to confirm and extend these findings.

The FRESCO-2 trial established the efficacy and safety of fruquintinib in patients with refractory metastatic colorectal cancer. However, its cost-effectiveness in the US context is not well documented.

This study evaluates the cost-effectiveness of fruquintinib versus placebo for this patient population from the perspective of US payers.

We developed a partitioned survival model on the basis of patient-level data reconstructed from the survival curves of the FRESCO-2 trial. Parametric estimation was conducted to estimate long-term clinical outcomes and medical costs over a lifetime horizon. Cost inputs and utilities were sourced from public data and previous literature. We used a discount rate of 3.0% per year for both clinical outcomes and costs. We adopted an incremental cost-effectiveness ratio (ICER) threshold of US$100,000 per quality-adjusted life-year (QALY) gained. We performed sensitivity and scenario analyses to examine the robustness of cost-effectiveness results.

Fruquintinib treatment resulted in incremental gains of 0.108 life years (LYs) and 0.073 QALYs compared with the placebo, at an additional cost of US$112,294, primarily driven by medication expenses. The ICER for fruquintinib versus placebo was calculated at US$1,037,855 per LY and US$1,546,619 per QALY gained, exceeding the predefined cost-effectiveness threshold. The cost-effectiveness results were robust across all sensitivity and scenario analyses.

Despite the survival benefit, fruquintinib was not cost-effective compared with the placebo in patients with refractory metastatic colorectal cancer in the US setting, on the basis of the conventional willingness-to-pay threshold. Our findings may provide a basis for informing the pricing and reimbursement decisions regarding fruquintinib.

Metastatic colorectal cancer (mCRC) is mainly treated with 5-Fluoro-Uracil (5-FU), Oxaliplatin and Irinotecan chemotherapies and anti-Epidermal Growth Factor Receptor (EGFR) or anti-Vascular Endothelial Growth Factor (VEGF) targeted therapies. Due to chemotherapy-related toxicity, patients receive induction treatment to achieve tumour response followed by maintenance therapy with less cytotoxic molecules or a chemotherapy-free interval to reduce chemotherapy-related toxicity. In this study, the aim was to determine the patient, cancer and treatment factors that influence the duration of maintenance therapy (DMT).

We collected retrospective data on a cohort of 133 patients treated at the Centre Georges François Leclerc (CGFL) cancer centre in Dijon between March 2014 and June 2022. Patients had unresectable or potentially resectable diseases. They received first-line induction treatment with chemotherapy and/or targeted therapy and maintenance treatment, defined as the interruption of at least one chemotherapy agent.

In the multivariate analysis, age (HR: 1.02, 95% CI 1.00-1.04, p = 0.031), N2 nodal status (HR: 1.78, 95% CI 1.09-2.89, p = 0.021) and the presence of peritoneal metastases (HR: 2.05, 95% CI 1.25-3.36, p = 0.004), as well as baseline carcino-embryonic antigen (CEA) level (HR: 1.10, 95% CI 1.00-1.20, p = 0.052), were significantly associated to poor DMT. Local treatment of liver metastases also significantly reduced the DMT (HR: 0.49, 95% CI 0.28-0.86, p = 0.013). In our cohort, induction triplet chemotherapy significantly increased the CEA delta (70% vs. 44%, p = 0.047) compared to doublet chemotherapy and led to a higher rate of liver surgery (40% vs. 21%, p = 0.014) and a trend for a higher rate of local treatment of metastases (62% vs. 45%, p = 0.059).

Duration of maintenance therapy is determined by the initial patient and colorectal cancer characteristics. However, it is significantly increased by local treatment of liver metastases. By reducing the tumour burden, a triplet induction chemotherapy regimen increases the rate of liver metastase resection.

This phase 2/3 trial (NCT04856787) assessed the efficacy and safety of SHR-1701, a bifunctional protein targeting PD-L1 and TGF-β, in combination with BP102 (a bevacizumab biosimilar) and XELOX (capecitabine plus oxaliplatin) as a first-line treatment for unresectable metastatic colorectal cancer (mCRC). In this phase 2 study, a total of 62 patients with untreated, histologically confirmed colorectal adenocarcinoma and no prior systemic therapy for metastatic disease were enrolled. Patients received SHR-1701 (30 mg/kg), bevacizumab (7.5 mg/kg), and oxaliplatin (130 mg/m2) intravenously on day 1, along with oral capecitabine (1 g/m2 twice daily) on days 1-14 of 21-day cycles. Up to eight induction cycles were administered, followed by maintenance therapy for responders or those with stable disease. The primary endpoints were safety and objective response rate (ORR) per RECIST v1.1. The combination achieved an ORR of 59.7% and a disease control rate (DCR) of 83.9%. Median progression-free survival (PFS) was 10.3 months (95% CI: 8.3-13.7), with 6- and 12-month PFS rates of 77.2% and 41.3%, respectively. The estimated 12-month overall survival (OS) rate was 67.7%. Grade ≥3 treatment-related adverse events (TRAEs) were reported in 59.7% of patients, with anemia and neutropenia (8.1% each) being the most common. Retrospective DNA sequencing revealed that high tumor mutational burden, neo-antigens, and SBS15 enrichment correlated with better responses. Elevated baseline lactate dehydrogenase was linked to shorter PFS. SHR-1701 combined with XELOX and bevacizumab demonstrated a manageable safety profile and potent antitumor activity in unresectable mCRC.

The impact of sidedness on survival of later-line treatment in patients with metastatic colorectal cancer (mCRC) is undetermined. This study aimed to investigate the association between sidedness and survival among chemotherapy refractory patients with mCRC treated with trifluridine/tipiracil (TAS-102) or regorafenib or both.

Patients with mCRC treated with TAS-102 or regorafenib between 2015 and 2020 was retrospectively collected. Patients were stratified into TAS-102 first and regorafenib first, then subdivided into TAS-102 followed by regorafenib (T-R) and regorafenib followed by TAS-102 (R-T) groups. The oncologic outcomes were presented with time-to-treatment failure (TTF) and overall survival (OS).

After matching, 376 TAS-102 patients and 376 regorafenib patients were included for outcomes comparison. TTF had insignificant differences while OS was significantly different between TAS-102 and regorafenib groups. Median TTF and OS were 1.9 months versus 2.0 months (P = .701) and 9.1 months versus 7.0 months (P = .008) in TAS-102 and regorafenib, respectively. The OS benefits were consistent regardless primary tumor location. Subgroup analysis with 174 T-R patients and 174 R-T patients was investigated for treatment sequences. TTF and OS had significant differences in both groups. Median TTF and OS were 8.5 months versus 6.3 months (P = .001) and 14.4 months versus 12.6 months (P = .035) in T-R and R-T groups, respectively. The TTF and OS benefits were persisted regardless primary tumor location.

TAS-102 first provided a better survival benefit in chemotherapy refractory patients with mCRC across all sidedness. Further prospective studies are warranted to validate our conclusions.

Liquid biopsy using circulating tumor DNA (ctDNA) has emerged as a minimally invasive, timely approach to provide molecular diagnosis and monitor tumor evolution in patients with cancer. Since the molecular landscape of metastatic colorectal cancer (mCRC) is substantially heterogeneous and dynamic over space and time, ctDNA holds significant advantages as a biomarker for this disease. Numerous studies have demonstrated that ctDNA broadly recapitulates the molecular profile of the primary tumor and metastases, and have mainly focused on the genotyping of RAS and BRAF, that is propaedeutic for anti-EGFR treatment selection. However, ctDNA soon broadened its scope towards the assessment of early tumor response, as well as the identification of drug resistance biomarkers to drive potential molecular actionability. In this review article, we provide an overview of the current state-of-the-art of this methodology and its applications, focusing on ongoing clinical trials that employ ctDNA to prospectively guide treatment in patients with mCRC.

Single-nucleotide polymorphisms (SNPs) in enzyme-coding genes play a role in susceptibility to anti-cancer therapy.

A prospective study was performed of the relationship between enzyme activity and treatment response, drug toxicity and hypersensitivity reactions in 51 patients with colorectal cancer treated with fluoropyrimidine-based chemotherapy. SNP analysis was performed in 22 enzyme-coding genes with a previously described role in treatment efficacy.

SLC6 and MTHR enzyme activity was related with rates of progressive disease, GSTP1 activity with anti-EGFR antibodies-related skin toxicity, CYP3A5 and MTHR with chemotherapy dose reduction, CYP2B6, IL10, MTHR and TYMS activity with the risk of drug hypersensitivity reactions.

Pharmacogenetics is a valuable predictive marker in oncology, related to chemotherapy treatment response, toxicity and hypersensitivity.

Metastatic colorectal cancer is a leading cause of cancer-related death across the world. The treatment paradigm has shifted away from systemic chemotherapy alone to include targeted therapy and immunotherapy. The past two decades have been characterized by increased investigation into molecular profiling of colorectal cancer. These molecular profiles help physicians to better understand colorectal cancer biology among patients with metastatic disease. Additionally, improved data on genetic pathways allow for specific therapies to be targeted at the underlying molecular profile. Investigation of the EGFR, VEGF, HER2, and other pathways, as well as deficient mismatch repair, has led to the development of multiple targeted therapies that are now utilized in the National Comprehensive Cancer Network guidelines for colon and rectal cancer. While these new therapies have contributed to improved survival for metastatic colorectal cancer, long-term survival remains poor. Additional investigation to understand resistance to targeted therapy and development of new targeted therapy is necessary. New therapies are under development and are being tested in the preclinical and clinical settings. The aim of this review is to provide a comprehensive evaluation of molecular profiling, currently available therapies, and ongoing obstacles in the field of colorectal cancer.

Microsatellite instability (MSI) is now widely used as an indispensable biomarker. However, the relationship between MSI-H (high) and defective DNA mismatch repair (MMR) is not as straightforward as has been expected. Genome-edited cells carrying Lynch syndrome mutations do not exhibit drastic MSI typical in MSI-H (i.e. Type B) but more subtle MSI (i.e. Type A). In this study, we explored a connection between Type A MSI and 5-fluorouracil (5-FU) resistance in colorectal cancer patients. Using our precision and high-resolution MSI assay technique, tumour microsatellites were analysed in 30 colorectal cancer patients treated with FOLFOX or CAPOX. Among 30 tumours, eleven (37%) were judged as Type A MSI-positive. In Type A MSI+ tumours, the patient response to fluoropyrimidine and oxaliplatin was significantly poor (Fisher's exact test, p = 0.021). Accordingly, median PFS and OS were significantly poor in Type A+ patients (log-rank test, p < 0.001/p = 0.009). Type A MSI was an independent predictor of patient prognosis in this pilot cohort (Cox regression analysis, p = 0.003). Thus, more subtle Type A MSI better predicts fluoropyrimidine insensitivity in colorectal cancer patients, which may shed light on a hitherto overlooked connection between the MSI phenotypes and drug resistance in human cancer.

Colorectal cancer patients with ≤10 unresectable metastases were treated with single-fraction sub-ablative radiotherapy in addition to standard of care systemic therapy in a single-arm, open-label, multicenter, pilot study (SIRIUS) to assess feasibility and safety. Results indicate that radiotherapy combined with systemic therapy is feasible and safe in this population.

The gut microbiome has emerged as a crucial player in modulating cancer therapies, including radiotherapy. In the case of breast cancer, the interplay between the microbiome and radiotherapy-derived metabolites may enhance therapeutic outcomes and minimize adverse effects. In this review, we explore the bidirectional relationship between the gut microbiome and breast cancer. We explain how gut microbiome composition influences cancer progression and treatment response, and how breast cancer and its treatments influence microbiome composition. A dual role for radiotherapy-derived metabolites is explored in this article, highlighting both their therapeutic benefits and potential hazards. By integrating genomics, metabolomics, and bioinformatics tools, we present a comprehensive overview of these interactions. The study provides real-world insight through case studies and clinical trials, while therapeutic innovations such as probiotics, and dietary interventions are examined for their potential to modulate the microbiome and enhance treatment effectiveness. Moreover, ethical considerations and patient perspectives are discussed, ensuring a comprehensive understanding of the subject. Towards revolutionizing treatment strategies and improving patient outcomes, the review concludes with future research directions. It also envisions integrating microbiome and metabolite research into personalized breast cancer therapy.