The role of biomarker in later-line treatment for metastatic colorectal cancer.
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ABSTRACT:
SUBMITTER: Kawakami T
PROVIDER: S-EPMC10186531 | biostudies-literature | 2023 Apr
REPOSITORIES: biostudies-literature
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The role of biomarker in later-line treatment for metastatic colorectal cancer.
Kawakami Takeshi T Yamazaki Kentaro K
Journal of gastrointestinal oncology 20230324 2
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Project description:The treatment of metastatic colorectal cancer (mCRC) has evolved considerably in the last decade, currently allowing most mCRC patients to live more than two years. Monoclonal antibodies targeting the epidermal growth factor receptor (EGFR) and vascular endothelial growth factor play an important role in the current treatment of these patients. However, only antibodies directed against EGFR have a predictive marker of response, which is the mutation status of v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS). Cetuximab has been shown to be effective in patients with KRAS wild-type mCRC. The CRYSTAL study showed that adding cetuximab to FOLFIRI (regimen of irinotecan, infusional fluorouracil and leucovorin) significantly improved results in the first-line treatment of KRAS wild-type mCRC. However, results that evaluate the efficacy of cetuximab in combination with oxaliplatin-based chemotherapy in this setting are contradictory. On the other hand, recent advances in the management of colorectal liver metastases have improved survival in these patients. Adding cetuximab to standard chemotherapy increases the response rate in patients with wild-type KRAS and can thus increase the resectability rate of liver metastases in this group of patients. In this paper we review the different studies assessing the efficacy of cetuximab in the first-line treatment of mCRC.
| S-EPMC3989957 | biostudies-literature
Project description:BackgroundColorectal cancer is one of the tumors with the highest morbidity and mortality rates in China and the world. Regorafenib is a targeted drug for standard third-line treatment of metastatic colorectal cancer (mCRC). Regorafenib monotherapy has shown certain efficacy in the elderly population, but more robust evidence is needed. The aim of this study was to evaluate the dosing characteristics, prognosis, and safety of regorafenib monotherapy in elderly Chinese patients with mCRC.MethodsThis retrospective study comprised elderly patients (aged ≥60 years) with mCRC who received regorafenib monotherapy as a third-line or above treatment in 10 hospitals from August 2017 to June 2020. We analyzed the association between different dosing regimens and prognosis. The primary endpoint was overall survival (OS), and other endpoints included progression-free survival (PFS) and adverse events (AEs).ResultsIn total, 203 patients were included in the analysis. The median PFS was 3.88 months [95% confidence interval (CI): 3.48-5.65], and the median OS was 10.1 months (95% CI: 8.94-12.1). There was no significant difference in the survival curves between the different dosage groups. The multivariate Cox analysis showed a significant benefit in OS in the high final daily dose group (120-160 mg/day) [hazard ratio (HR): 0.45, 95% CI: 0.25-0.84, P=0.01], which was further confirmed by the propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) analysis. No significant association was found between the initial daily dose and prognosis. Nor was any significant association found between PFS and drug dosage. Subsequently, an age subgroup analysis was conducted using 70 years as the cut-off value. In those aged <70 years, the application of higher final doses (120-160 mg/day) was significantly associated with the prolongation of OS compared to a final dose of 80 mg/day [HR (95% CI): 0.38 (0.16-0.91), P=0.03], and the prolongation of OS was predominantly observed in the 120 mg/day dose group [HR (95% CI): 0.24 (0.09-0.67), P=0.006]. Besides, we observed a statistically insignificant increase in the incidence of AEs in the higher dose group compared to the lower dose group.ConclusionsRegorafenib monotherapy was shown to be efficacious in the elderly population, but further evidence is needed for guidance. Based on our multicenter real-world investigation, the final daily dose was significantly associated with OS. For those aged <70 years, maintaining the final dose at 120 mg/day may have prognostic advantages. The suggested medication protocol requires validation through comprehensive clinical trials.
| S-EPMC11565098 | biostudies-literature
Project description:BackgroundPrimary tumor location (PTL) is an important prognostic and predictive factor in the first-line treatment of metastatic colorectal cancer (mCRC). Although regorafenib (REG) and trifluridine/tipiracil (FTD/TPI) have been introduced recently, the clinical impact of PTL in these treatments is not well understood.Materials and methodsWe retrospectively evaluated patients with mCRC who were registered in a multicenter observational study (the REGOTAS study). The main inclusion criteria were Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-2, refractory or intolerant to fluoropyrimidines, oxaliplatin, irinotecan, angiogenesis inhibitors, anti-epidermal growth factor receptor therapy (if RAS wild-type), and no prior use of REG and FTD/TPI. The impact of PTL on overall survival (OS) was evaluated using Cox proportional hazard models based on baseline characteristics.ResultsA total of 550 patients (223 patients in the REG group and 327 patients in the FTD/TPI group) were included in this study, with 122 patients with right-sided tumors and 428 patients with left-sided tumors. Although the right-sided patients had significantly shorter OS compared with the left-sided patients by univariate analysis (p = 0.041), a multivariate analysis revealed that PTL was not an independent prognostic factor (hazard ratio, 0.95; p = 0.64). In a subgroup analysis, the OS was comparable between the REG and FTD/TPI groups regardless of PTL (p for interactions = 0.60).ConclusionsIn the present study, PTL is not a prognostic and predictive factor in patients with mCRC under later-line REG or FTD/TPI therapy.
| S-EPMC8239287 | biostudies-literature
Project description:Colorectal cancer represents an important oncological challenge both for its incidence, which makes it an important health problem, and for its biological complexity, which has made clinical results very difficult in terms of outcome for this category of patients. To date these diseases should not be treated as a single entity but it is necessary to distinguish colorectal cancers based on characteristics that nowadays are essential to have greater therapeutic benefits. These include the sideness of the disease, the state of microsatellites, the presence of prognostic and predictive mutations of response to treatments currently available in clinical practice, which are associated with new therapeutic targets. The greatest challenge in the future will be to circumvent the resistance mechanisms that make this disease very difficult to treat with good long-term results by studying effective combination treatments with a good toxicity profile. Once such combinations or targeted treatments are consolidated, it will be desirable to shift the best therapies to the first line treatment to make them immediately accessible to the patient. It will also be essential to refine the selection of patients who can benefit from these treatments.
| S-EPMC10614157 | biostudies-literature
Project description:The approval of targeted therapies for metastatic colorectal cancer (mCRC) has led to important improvements in patient outcomes. However, it is still necessary to increase individualisation of treatments based on tumour genetic profiles to optimise efficacy, while minimising toxicity. As such, there is currently great focus on the discovery and validation of further biomarkers in mCRC, with many new potential prognostic and predictive markers being identified alongside developments in patient molecular profiling technologies. Here, we review data for validated and emerging biomarkers impacting treatment strategies in mCRC. We completed a structured literature search of the PubMed database to identify relevant publications, limiting for English-language publications published between 1 January 2014 and 11 July 2018. In addition, we performed a manual search of the key general oncology and CRC-focused congresses to identify abstracts reporting emerging mCRC biomarker data, and of ClinicalTrials.gov to identify ongoing clinical trials investigating emerging biomarkers in mCRC and/or molecular-guided clinical trials. There is solid evidence supporting the use of BRAF status as a prognostic biomarker and DYPD, UGT1A1, RAS, and microsatellite instability as predictive biomarkers in mCRC. There are a number of emerging biomarkers that may prove to be clinically relevant in the future to have prognostic (HPP1 methylation), predictive (HER3, microRNAs, anti-angiogenic markers, and CRC intrinsic subtypes), or both prognostic and predictive values (HER2, CpG island methylator phenotype, tumour mutational load, gene fusions, and consensus molecular subtypes). As such, new biomarker-led treatment strategies in addition to anti-epidermal growth factor receptor and anti-angiogenetic treatments are being explored. Biomarkers that are not recommended to be tested in clinical practice or are unlikely to be imminently clinically relevant for mCRC include thymidylate transferase, ERCC1, PIK3CA, and PTEN. We highlight the clinical utility of existing and emerging biomarkers in mCRC and provide recommended treatment strategies according to the biomarker status. An update on ongoing molecular-guided clinical trials is also provided.
| S-EPMC6728290 | biostudies-literature
Project description:Since its approval for the first-line treatment of metastatic colorectal cancer (mCRC), bevacizumab has become a standard treatment option in combination with chemotherapy for patients with mCRC. Bevacizumab has demonstrated efficacy in combination with a number of different backbone chemotherapy regimens, and its widespread use has introduced several important questions regarding the selection and optimization of bevacizumab-based treatment regimens, its use in various patient populations, and the identification of associated adverse events. This review discusses the results of several phase II and phase III clinical trials, as well as large observational studies, to address the use of bevacizumab in the treatment of patients with mCRC in the first-line setting.
| S-EPMC3336830 | biostudies-other
Project description:PurposeBiologic agents have achieved variable results in relapsed metastatic colorectal cancer (mCRC). Systematic meta-analysis was undertaken to determine the efficacy of biological therapy.MethodsMajor databases were searched for randomised studies of mCRC after first-line treatment comparing (1) standard treatment plus biologic agent with standard treatment or (2) standard treatment with biologic agent with the same treatment with different biologic agent(s). Data were extracted on study design, participants, interventions and outcomes. Study quality was assessed using the MERGE criteria. Comparable data were pooled for meta-analysis.ResultsTwenty eligible studies with 8225 patients were identified. The use of any biologic therapy improved overall survival with hazard ratio (HR) 0.87 (95% confidence interval (CI) 0.82-0.91, P<0.00001), progression-free survival (PFS) with HR 0.71 (95% CI 0.67-0.74, P<0.0001) and overall response rate (ORR) with odds ratio (OR) 2.38 (95% CI 2.03-2.78, P<0.00001). Grade 3/4 toxicity was increased with OR 2.34. Considering by subgroups, EGFR inhibitors (EGFR-I) in the second-line setting and anti-angiogenic therapies (both in second-line and third-line and beyond settings) all improved overall survival, PFS and ORR. EGFR-I in third-line settings improved PFS and ORR but not OS.ConclusionsThe use of biologic agents in mCRC after first-line treatment is associated with improved outcomes but increased toxicity.
| S-EPMC4453848 | biostudies-literature
Project description:ObjectiveTo evaluate the efficacy and safety of regorafenib monotherapy or in combination with immune-checkpoint inhibitor while treating Chinese patients with metastatic colorectal cancer (mCRC): a real-world study.MethodsThe data of patients with metastatic colorectal cancer who received regorafenib-containing regimen as the third or later line treatment at ten Chinese hospitals from Aug 2017 to Jun 2020 were retrospectively analyzed, including dosing details, survival data as well as adverse events. Survival analysis was further performed for patients administrated with regorafenib monotherapy and combined with an immune-checkpoint inhibitor based on Kaplan-Meier and Cox regression methods. The primary endpoint was overall survival.ResultsA total of 537 patients were included with a median age of 61, among whom 376 received regorafenib monotherapy and 245 received regorafenib combined with immune-checkpoint inhibitors. The clinicopathological characteristics of the two groups at baseline were mainly balanced. No significant difference in progression-free survival (PFS) was observed in patients receiving regorafenib monotherapy or combination therapy (3.8 vs. 5.5 months, p = 0.170). In contrast, patients receiving combination therapy had a more prolonged overall survival (OS) than those receiving regorafenib monotherapy (13.5 vs. 10.0 months, p = 0.001). The treatment regimen and regorafenib dosage were significant prognostic factors in the multivariate analysis. Significant benefits in PFS and OS were achieved in KRAS mutant and anti-angiogenesis treatment-naïve subgroups receiving combination therapy compared to monotherapy. No apparent increase was recorded in treatment-related adverse events in patients receiving combination therapy.ConclusionRegorafenib plus an immune-checkpoint inhibitor has already been a widely adopted strategy in the later-line treatment for mCRC in the real world. The combination therapy yielded a significantly prolonged overall survival than regorafenib alone, with a manageable safety profile in Chinese patients, and warrants further investigation.Trial registrationClinicalTrials.gov Identifier: NCT04835324. Registered 6th April 2021.
| S-EPMC10763390 | biostudies-literature
Project description:ImportanceAmong patients with metastatic colorectal cancer (mCRC), data are limited on disparate biomarker testing and its association with clinical outcomes on a national scale.ObjectiveTo evaluate the socioeconomic and demographic inequities in microsatellite instability (MSI) and KRAS biomarker testing among patients with mCRC and to explore the association of testing with overall survival (OS).Design, setting, and participantsThis cohort study, conducted between November 2022 and March 2024, included patients who were diagnosed with mCRC between January 1, 2010, and December 31, 2017. The study obtained data from the National Cancer Database, a hospital-based cancer registry in the US. Patients with mCRC and available information on biomarker testing were included. Patients were classified based on whether they completed or did not complete MSI or KRAS tests.ExposureDemographic and socioeconomic factors, such as age, race, ethnicity, educational level in area of residence, median household income, insurance type, area of residence, facility type, and facility location were evaluated.Main outcomes and measuresThe main outcomes were MSI and KRAS testing between the date of diagnosis and the date of first-course therapy. Univariable and multivariable logistic regressions were used to identify the relevant factors in MSI and KRAS testing. The OS outcomes were also evaluated.ResultsAmong the 41 061 patients included (22 362 males [54.5%]; mean [SD] age, 62.3 [10.1] years; 17.3% identified as Black individuals, 78.0% as White individuals, 4.7% as individuals of other race, with 6.5% Hispanic or 93.5% non-Hispanic ethnicity), 28.8% underwent KRAS testing and 43.7% received MSI testing. A significant proportion of patients had Medicare insurance (43.6%), received treatment at a comprehensive community cancer program (40.5%), and lived in an area with lower educational level (51.3%). Factors associated with a lower likelihood of MSI testing included age of 70 to 79 years (relative risk [RR], 0.70; 95% CI, 0.66-0.74; P < .001), treatment at a community cancer program (RR, 0.74; 95% CI, 0.70-0.79; P < .001), rural residency (RR, 0.80; 95% CI, 0.69-0.92; P < .001), lower educational level in area of residence (RR, 0.84; 95% CI, 0.79-0.89; P < .001), and treatment at East South Central facilities (RR, 0.67; 95% CI, 0.61-0.73; P < .001). Similar patterns were observed for KRAS testing. Survival analysis showed modest OS improvement in patients with MSI testing (hazard ratio, 0.93; 95% CI, 0.91-0.96; P < .001). The median (IQR) follow-up time for the survival analysis was 13.96 (3.71-29.34) months.Conclusions and relevanceThis cohort study of patients with mCRC found that older age, community-setting treatment, lower educational level in area of residence, and treatment at East South Central facilities were associated with a reduced likelihood of MSI and KRAS testing. Highlighting the sociodemographic-based disparities in biomarker testing can inform the development of strategies that promote equity in cancer care and improve outcomes for underserved populations.
| S-EPMC11227072 | biostudies-literature
Project description:BackgroundThis trial evaluated the feasibility and efficacy of combined sorafenib and irinotecan (NEXIRI) as second- or later-line treatment of patients with KRAS-mutated metastatic colorectal cancer (mCRC), who had progressed after irinotecan-based chemotherapy.MethodsIn Phase I, in a 3+3 dose escalation schedule, patients received irinotecan (125, 150 or 180 mg m(-2) every 2 weeks), in combination with 400 mg sorafenib b.d. The primary end point was the maximum-tolerated dose of irinotecan. In Phase II, the primary end point was disease control rate (DCR). Secondary end points were progression-free survival (PFS), overall survival (OS) and toxicity.ResultsPhase I included 10 patients (median age 63 (49-73)); no dose-limiting toxicity was seen. In Phase II, 54 patients (median age 60 (43-80) years) received irinotecan 180 mg m(-)(2) every 2 weeks with sorafenib 400 mg b.d. Nine patients (17%) remained on full-dose sorafenib. The DCR was 64.9% (95% CI, 51-77). Median PFS and OS were 3.7 (95% CI, 3.2-4.7) and 8.0 (95% CI, 4.8-9.7) months, respectively. Toxicities included Grade 3 diarrhoea (37%), neutropenia (18%), hand-foot syndrome (13%) and Grade 4 neutropenia (17%).ConclusionThe NEXIRI regimen showed promising activity as second- or later-line treatment in this heavily pretreated mCRC population (ClinicalTrials.gov NCT00989469).
| S-EPMC3950852 | biostudies-literature