Background: Evidence comparing the efficacy of different treatments for patients with unresectable colorectal liver metastases (CRLM) receiving first-line or maintenance therapy is sparse. We aimed to assess the efficacy and safety of these treatments, with a distinct focus on evaluating first-line and maintenance treatments separately. Methods: We conducted Bayesian network meta-analyses, sourcing English-language randomized controlled trials (RCTs) published through July 2023 from databases including PubMed, Embase, the Cochrane Library, ClinicalTrials.gov, and key conference proceedings. Phase Ⅱ or Ⅲ trials that assessed two or more therapeutic regimens were included. Primary outcome was overall survival (OS). Secondary outcomes included progression-free survival (PFS), objective response rate (ORR), adverse events graded as 3 or above (SAE), and R0 liver resection rate. Hazards Ratios (HRs) and 95% confidence intervals (CI) were used as effect size for OS and PFS, Odds Ratios (ORs) and 95% CI were used for ORR, SAEs and R0 resection rate. Subgroup and sensitive analyses were conducted to analysis the model uncertainty (PROSPERO: CRD42023420498). Results: 56 RCTs were included (50 for first-line treatment, six for maintenance therapies), with a total of 21,323 patients. Regarding first-line, for OS, the top three mechanisms were: local treatment + single-drug chemotherapy (SingleCT), Targeted therapy (TAR)+SingleCT, and TAR + multi-drug chemotherapy (MultiCT). Resection or ablation (R/A)+SingleCT, S1, and Cetuximab + intensified fluorouracil-based combination chemotherapy (ICTFU) were identified as the best treatments. For PFS, the top three mechanisms were: Immune therapy + TAR + MultiCT, multi-targeted therapy (MultiTAR), TAR + SingleCT. The top three treatments were: Atezolizumab + Bevacizumab + fluorouracil-based combination chemotherapy (CTFU), TAS-102+bevacizumab, Bevacizumab + ICTFU. Cetuximab + CTFU was the best choice for RAS/RAF wild-type patients. Regarding maintenance treatment, Bevacizumab + SingleCT and Adavosertib were the best options for OS and PFS, respectively. For safety, MultiCT was the safest, followed by local treatment + MultiCT, TAR + MultiCT caused the most SAEs. Bevacizumab plus chemotherapy was found to be the safest among all targeted combination therapies. Conclusion: In first-line, local treatment or targeted therapsy plus chemotherapy are the best mechanisms. R/A + SingleCT or CTFU performed the best for OS, Atezolizumab + Bevacizumab + ICTFU was the best option regarding PFS. For RAS/RAF wild-type patients, Cetuximab + CTFU was the optimal option. Monotherapy may be preferred choice for maintenance treatment. Combination therapy resulted in more SAEs when compared to standard chemotherapy.

OBJECTIVE: To describe the dosing patterns of regorafenib in a real-world population of patients with metastatic colorectal cancer (mCRC) in a routine clinical practice setting in Spain, focusing on the starting dose of regorafenib.
METHODS: An observational, retrospective, multicenter study that included patients ≥ 18 years old who had histologically documented mCRC and who had initiated treatment with regorafenib since January 2017. Post hoc categorization of dosing patterns revealed the following: initial dose < 160 mg and dose escalation, initial dose < 160 mg and maintenance, initial dose equal to 160 mg and maintenance, and initial dose equal to 160 mg and dose reduction.
RESULTS: Most patients (152/241, 63.8%) initiated treatment with regorafenib at doses < 160 mg. There was large variation in the starting dose of regorafenib over time: in 2017, most patients (59%) initiated regorafenib at a dose of 160 mg, this proportion decreased to 6% in 2021. There were no significant differences in the median progression-free survival according to the regorafenib dose patterns during the first two cycles. The proportion of patients who reported at least one adverse event (AE), had a grade 3-4 AE or had an AE leading to dose reduction was greater in the group of patients who received an initial dose equal to 160 and reduction.
CONCLUSIONS: Our results indicate that physicians in Spain have gradually adopted a dose-escalation approach during cycle 1, which is a common practice for starting treatment with a reduced dose (< 160 mg/day), a strategy that seems to improve tolerability while maintaining efficacy.
BACKGROUND: Not applicable.

OBJECTIVE: MVASI (Amgen) and Zirabev (Pfizer) are two of the earliest bevacizumab biosimilars approved for the first-line treatment of metastatic colorectal cancer (mCRC). We aimed to confirm and quantify the real-world cost-savings and cost-effectiveness of MVASI and Zirabev relative to originator bevacizumab for patients with mCRC.
METHODS: We conducted a population-based, retrospective cohort study in Ontario, Canada, where originator and biosimilar bevacizumab are universally publicly funded. All mCRC patients who received originator bevacizumab between January 2008 and August 2019 or biosimilar bevacizumab between August 2019 and March 2021 were propensity score-matched (1:4) to adjust for baseline differences. Total 1-year patient-level costs (CAD) and effects (life years (LY) and quality-adjusted life years (QALY)) were calculated from the public health payer\'s perspective. Primary outcomes included incremental net monetary benefit (INMB) and incremental net health benefit (INHB). Sensitivity analyses included a subgroup analysis by biosimilar type (MVASI/Zirabev) and a 2-year analysis.
RESULTS: The matched cohort included 747 biosimilar cases and 2,945 comparators. Bevacizumab biosimilars were associated with an incremental cost of -$6,379 (95%CI: -9,417, -3,537) (i.e., cost-saving) and incremental effect of 0.0 (95% CI: -0.02, 0.02) LY and -0.01 (95%CI: -0.03, 0) QALY gained. INMB and INHB estimates were $6,331 (95% CI: 6,245, 6,417) and 0.127 LY (95% CI: 0.125, 0.128), respectively, at a willingness-to-pay threshold of $50,000/LYG, with all estimates indicating the cost-effectiveness of biosimilar bevacizumab. Cost-effectiveness remained consistent across biosimilar brand subgroups and 2-year sensitivity analyses.
CONCLUSIONS: Bevacizumab biosimilars demonstrated real-world cost-savings while providing similar survival benefit as originator bevacizumab, confirming the initial expectations of their implementation and supporting health system sustainability.

OBJECTIVE: The value of upfront primary tumor resection (PTR) for asymptomatic unresectable metastatic colorectal cancer (mCRC) patients remains contentious. This meta-analysis aimed to assess the prognostic significance of upfront PTR for asymptomatic unresectable mCRC.
METHODS: A systematic literature search was performed on June 21st, 2024. To minimize the bias and ensure robust evidence, only randomized controlled trials (RCTs) and case-matched studies (CMS) that compared PTR followed by chemotherapy to chemotherapy alone were included. The primary outcome was overall survival (OS), while cancer-specific survival (CSS) served as the secondary outcome.
RESULTS: Eight studies (three RCTs and five CMS) involving 1221 patients were included. Compared to chemotherapy alone, upfront PTR followed by chemotherapy did not improve OS (hazard ratios [HR] 0.91, 95% confidence interval [CI] 0.79-1.04, P = 0.17), but was associated with slightly better CSS (HR 0.59, 95% CI 0.40-0.88, P = 0.009).
CONCLUSIONS: The current limited evidence indicates that upfront PTR does not improve OS but may enhance CSS in asymptomatic unresectable mCRC patients. Ongoing trials are expected to provide more reliable evidence on this issue.

BACKGROUND: The randomized, dose-optimization, open-label ReDOS study in US patients with metastatic colorectal cancer (CRC) showed that, compared with a standard dosing approach, initiating regorafenib at 80 mg/day and escalating to 160 mg/day depending on tolerability increased the proportion of patients reaching their third treatment cycle and reduced the incidence of adverse events without compromising efficacy. Subsequently, the ReDOS dose-escalation strategy was included as an alternative regorafenib dosing option in the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines. A retrospective analysis was conducted using a US claims database to assess whether inclusion of this dose-escalation strategy in NCCN Guidelines has influenced the use of flexible dosing in routine US clinical practice, and to describe clinical outcomes pre- and post-inclusion in NCCN Guidelines.
METHODS: Patients with CRC in the Optum\'s de-identified Clinformatics® Data Mart database initiating regorafenib for the first time between January 2016 and June 2020 were stratified based on whether they initiated regorafenib pre- or post-inclusion of ReDOS in NCCN Guidelines, and in two groups: flexible dosing (< 160 mg/day; < 84 tablets in the first treatment cycle) and standard dosing (160 mg/day; ≥ 84 tablets in the first treatment cycle). The primary endpoints were the proportion of patients who initiated their third treatment cycle and the mean number of treatment cycles per group.
RESULTS: 703 patients initiated regorafenib during the study period, of whom 310 (44%) initiated before and 393 (56%) initiated after inclusion of ReDOS in NCCN Guidelines. After inclusion in the guidelines, the proportion of patients who received flexible dosing increased from 21% (n = 66/310) to 45% (n = 178/393), the proportion who received standard dosing decreased from 79% (n = 244/310) to 55% (n = 215/393), the proportion who initiated their third treatment cycle increased from 36% (n = 113/310) to 46% (n = 179/393), and the mean (standard deviation) number of treatment cycles increased from 2.6 (2.9) to 3.2 (3.1).
CONCLUSIONS: Following inclusion of ReDOS in NCCN Guidelines, real-world data suggest that US clinicians have markedly increased use of flexible dosing in clinical practice, potentially maximizing clinical benefits and safety outcomes for patients with metastatic CRC receiving regorafenib.

Numerous biomarkers that reflect host status have been identified for patients with metastatic colorectal cancer (mCRC). However, there has been a paucity of biomarker studies that comprehensively indicate body composition, nutritional assessment, and systemic inflammation status. The advanced lung cancer inflammation index (ALI), initially introduced as a screening tool for patients with non-small-cell lung cancer in 2013, emerges as a holistic marker encompassing all body composition, nutritional status, and systemic inflammation status. The index is calculated by the simple formula: body mass index × albumin value / neutrophil-to-lymphocyte ratio. Given its accessibility in routine clinical practice, the ALI has exhibited promising clinical utility in prognosticating outcomes for patients with multiple types of cancer. In this review, we focus on the significance of host status and the clinical applicability of the ALI in the treatment and management of patients with malignancies, including mCRC. We also suggest its potential in guiding the formulation of treatment strategies against mCRC and outline future perspectives.

BACKGROUND: KEYNOTE-177 demonstrated that immunotherapy was superior to chemotherapy for microsatellite-instability-high (MSI-high) metastatic colorectal cancer. Colorectal cancer with peritoneal metastases (CRPM) has a poorer prognosis than other metastatic sites, with an unclear role of immunotherapy. We evaluated trends in immunotherapy use and overall survival (OS).
METHODS: Patients with CRPM and MSI testing were identified in the National Cancer Database (2016-2020). We evaluated immunotherapy use by year and associated patient/hospital factors. OS was compared for immunotherapy versus chemotherapy, cytoreductive surgery (CRS), and immunotherapy plus CRS.
RESULTS: Among 15 322 CRPM patients, 7072 (46.2%) patients had documented MSI testing, with 819 (11.6%) MSI-high. Ninety-eight MSI-high patients received immunotherapy alone (12.3%), increasing from 0% in 2016 to 19.1% in 2020 (p < 0.01). On multivariable analysis, only higher comorbidity was associated with immunotherapy (OR: 2.83 [1.22-6.52]). Two-year OS with immunotherapy versus chemotherapy was 64.2% versus 54.1% (p < 0.05). In patients receiving CRS plus systemic therapy (N = 96), 2-year OS was 68.4%. Among patients who underwent immunotherapy and CRS versus immunotherapy alone, 2-year OS was 80.0% versus 60.0% (p = 0.14).
CONCLUSIONS: Immunotherapy was associated with significantly better survival compared to chemotherapy in MSI-high CRPM. Two-year OS with systemic + CRS was 68.4%. Despite its role in guiding treatment, MSI testing remains low for these patients.

UNASSIGNED: This systematic review and meta-analysis was to evaluate the relationship between body mass index (BMI) and the clinical outcomes in patients with metastatic colorectal cancer (mCRC) undergoing treatment with bevacizumab plus chemotherapy.
UNASSIGNED: The search for relevant literature was conducted across PubMed, Embase, Cochrane Library, and Web of Science, with the final search date being October 4, 2023. We utilized the weighted mean differences (WMDs), risk ratios (RRs), or Hazard ratios (HRs) as the metric for effect sizes, which were accompanied by 95% confidence intervals (CIs).
UNASSIGNED: A total of 9 studies were included for analysis. The results indicated that non-obese patients with mCRC undergoing treatment with bevacizumab experienced a reduced overall survival (OS) at the six-month compared to their obese counterparts (RR: 0.97, 95% CI: 0.94 to 1.00, p = 0.047). Furthermore, no significant differences in one-year, two-year, and five-year OS, as well as PFS and median OS, were observed between obese and non-obese mCRC patients undergoing treatment with bevacizumab plus chemotherapy.
UNASSIGNED: These findings suggest that obesity may play a role in the short-term OS of patients with mCRC undergoing bevacizumab treatment. The clinical implications of these findings underscore the importance of considering patients\' BMI in the context of mCRC care. This study may also help guide personalized treatment strategies and further research into the interplay between obesity, treatment efficacy, and patient survival in mCRC. However, further investigation is warranted to substantiate the findings of this study.

BACKGROUND: BRAF mutation has been recognized as a negative prognostic marker for metastatic colorectal cancer (mCRC), but these data are from common BRAF V600E-mutated mCRC. Combination therapy of BRAF inhibitor and anti-epidermal growth factor receptor (EGFR) antibody has been approved for BRAF V600E-mutated mCRC. However, BRAF non-V600 mutations are rare mutations, and their clinical behavior is not understood. Moreover, the BRAF K601E mutation is extremely rare in mCRC, and there have been no reports on its specific treatment.
METHODS: Herein, we report the case of a 59-year-old female with super aggressive mCRC with multiple metastases, which extended to whole body including mediastinal to abdominal lymph nodes, bones, pleura, and peritoneum. The companion diagnostics of tumor tissues showed RAS/BRAF wild-type without microsatellite instability. She received chemotherapy with mFOLFOX6 (oxaliplatin plus infusional 5-fluorouracil [5-FU] and leucovorin) plus panitumumab, following FOLFIRI (irinotecan plus infusional 5-FU and leucovorin) plus ramucirumab. For the next regimen selection, a comprehensive genomic profiling panel was performed and revealed a BRAF K601E mutation, which was not covered in the initial companion diagnostics. After disease progression, a combination of encorafenib, binimetinib, and cetuximab was selected as third-line chemotherapy. The serum levels of tumor markers were immediately decreased accompanied by improvements in pleural effusion and ascites. However, the disease progressed again, and best supportive care was done instead.
CONCLUSIONS: This case offers novel insights into the clinical behaviors of BRAF non-V600E-mCRC, potentially advancing personalized therapy for rare and aggressive cases.

Liquid biopsies can accurately identify molecular alterations in patients with colorectal cancer with high concordance with tissue analysis and shorter turnaround times. Circulating tumor (ct) DNA analysis can be used for diagnosing and monitoring tumor evolution in patients with metastatic colorectal cancer who are treated with EGFR inhibitors. In this article, we reported three clinical cases to illustrate the relevance of RAS mutations identified in ctDNA samples of patients with wild-type metastatic colorectal cancer who received an EGFR inhibitor plus chemotherapy as first-line treatment. The identification of RAS mutations in these patients is one of the most frequently identified mechanisms of acquired resistance. However, detecting a KRAS mutation via liquid biopsy can be caused by inter-tumor heterogeneity or it can be a false positive due to clonal hematopoiesis. More research is needed to determine whether ctDNA monitoring may help guide therapy options in metastatic colorectal cancer patients. We performed a literature review to assess the technologies that are used for analysis of RAS mutations on ctDNA, the degree of agreement between tissue and plasma and the importance of tissue/plasma discordant cases.