Evidence-based appraisal of the upfront treatment for unresectable metastatic colorectal cancer patients.
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ABSTRACT:
SUBMITTER: Aprile G
PROVIDER: S-EPMC3870493 | biostudies-literature | 2013 Dec
REPOSITORIES: biostudies-literature
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Project description:Despite being one of the most frequently diagnosed cancers worldwide, prognosis of metastatic colorectal cancer (CRC) was poor. Development and introduction of biologic agents in treatment of patients with metastatic CRC have brought improved outcomes. Monoclonal antibodies directing epidermal growth factor receptors and vascular endothelial growth factor are main biologic agents currently used in treatment of metastatic CRC. Encouraged by results from many clinical trials demonstrating efficacy of those monoclonal antibodies, the combination therapy with those targeted agents and conventional chemotherapeutic agents has been established as the standard therapy for patients with metastatic CRC. However, emergency of resistance to those target agents has limited the efficacy of treatment, and strategies to overcome the resistance are now being investigated by newly developed biological techniques clarifying how to acquire resistance. Here, we introduce mechanisms of action of the biologic agents currently used for treatment of metastatic CRC and several landmark historical clinical studies which have changed the main stream of treatment. The mechanism of resistance to those agents, one of serious problems in treatment metastatic CRC, and ongoing clinical trials to overcome the limitations and improve treatment outcomes will also be presented in this review.
| S-EPMC4835624 | biostudies-literature
Project description:While surgery is the cornerstone treatment for early-stage colorectal cancer, chemotherapy is the first treatment option for metastatic disease when tumor lesions are frequently not fully resectable at presentation. Mortality from colon cancer has decreased over the past 30 years, but there is still a huge heterogeneity in survival rates that can be mainly explained by patient and tumor characteristics, host response factors, and treatment modalities. The management of unresectable metastatic colorectal cancer is a global treatment strategy, which applies several lines of therapy, salvage surgery, maintenance, and treatment-free intervals. The individualization of cancer treatment is based on the evaluation of prognostic factors for survival (serum lactate dehydrogenase level, performance status), and predictive factors for treatment efficacy [Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation status]. The available treatment modalities for metastatic colorectal cancer are chemotherapy (fluoropyrimidine, oxaliplatin, irinotecan), anti-angiogenic agents (e.g. bevacizumab), and anti-epidermal growth factor agents (cetuximab, panitumumab). The increasing number of active compounds dictates the strategy of trials evaluating these treatments either in combination or sequentially. Alternative outcomes that can be measured earlier than overall survival are needed to shorten the duration and reduce the size and cost of clinical trials.
| S-EPMC3296081 | biostudies-other
Project description:BackgroundThe aim of the study is to reveal the contribution of complete response (CR) to treatment to overall survival (OS) in patients with unresectable metastatic colorectal cancer. In addition, to evaluate progression-free survival (PFS) in patients who attained CR to treatment and to examine the clinicopathologic features of the patient group with CR.MethodsThis article is a retrospective chart review. Patients diagnosed with metastatic colorectal cancer were divided into two groups. The systemic treatment was compared with the patients who received a full response according to the Response Evaluation Criteria in Solid Tumors (RECIST1.1) and those who did not attain CR (progression partial response and stable response) in terms of both PFS and OS data, and the effect of attaining CR to treatment on prognosis was evaluated.ResultsA total of 222 patients were included in the study. 202 of 222 patients could be evaluated in terms of complete response. All data from their files were tabulated and analyzed retrospectively. The mean age of diagnosis of the study group was 60.13 ± 12.52 years. The total number of patients who attained CR to treatment was 31 (15.3%); 171 (84.6%) patients did not attain CR. Patients who had a CR had longer median PFS times than patients who did not have a CR (15.2 vs. 7.4 months, P<0.001). Patients who had CR had longer median survival times than patients who did not have a CR (39.2 vs. 16.9 months, P<0.001). In subgroup patients who underwent primary surgery, the number of patients who attained CR was statistically higher compared with the number of patients who did not attain CR (p<0.001). Complete response was less common in the presence of liver metastasis and bone metastasis (p = 0.041 and p = 0.046, respectively), had a negative prognostic effect. In other words, 89.1% of patients with liver metastasis, 100.0% of patients with bone metastasis, and 88.7% of those who died did not have a CR to the treatment. According to multivariate analysis, CR to treatment, primary surgery, first-line chemotherapy (combination compared with fluoropyrimidine), and no bone metastasis were found to be predictors for OS.ConclusionProviding CR with systemic treatment in patients with unresectable metastatic colorectal cancer (mCRC) contributes to prognosis. The primary resection in our secondary acquisitions from the study, the number of metastatic regions and the combination therapy regimens also contributed to the prognosis.
| S-EPMC8575296 | biostudies-literature
Project description:The loss of adhesion molecules is reported to be associated with tumor invasion and metastasis in numerous types of cancer. Epithelial (E)-cadherin is an important molecule for cell-to-cell adhesion, while cluster of differentiation (CD)44 is an important molecule for cell-to-extracellular matrix adhesion. The focus of the present study was to evaluate the significance of the expression of E-cadherin and CD44 in patients with the unresectable metastatic colorectal cancer (CRC) who are undergoing palliative chemotherapy. Formalin-fixed, paraffin-embedded samples were obtained from 49 patients who underwent primary tumor resection and who were receiving palliative chemotherapy for unresectable metastatic CRC. The expression of E-cadherin and CD44 was evaluated using immunohistochemistry. The expression of E-cadherin was not significantly associated with progression-free survival (PFS; P=0.2825) or overall survival (OS; P=0.6617). The expression of CD44 was not associated with PFS (P=0.4365), but it did exhibit a certain level of association with OS (P=0.0699). However, the combined low expression of E-cadherin and CD44 demonstrated a significant association with decreased PFS (P=0.0101) and OS (P=0.0009). The combined loss of E-cadherin and CD44 expression also led to a reduction in the objective response rate and disease control rate (P=0.0076 and P=0.0294, respectively). A univariate analysis indicated that the combined low expression of E-cadherin and CD44 (P=0.0474) and sex (P=0.0330) were significantly associated with decreased PFS, and multivariate analysis confirmed combined low expression of E-cadherin and CD44 as an independent risk factor for decreased PFS [hazard ratio (HR), 8.276; 95% confidence interval (CI), 1.383-43.311; P=0.0227]. Univariate and multivariate analyses also indicated that the combined low expression of E-cadherin and CD44 expression was a significant prognostic factor for poor OS (HR, 15.118; 95% CI, 2.645-77.490; P=0.0039). Therefore the current study suggests that the combined low expression of E-cadherin and CD44 is an effective independent predictor of decreased chemotherapeutic outcome and survival in patients with unresectable metastatic CRC.
| S-EPMC5494689 | biostudies-other
Project description:Microsatellite Instability (MSI) status is an established predictive biomarker for the treatment of the anti-programmed death 1 (PD-1) antibody. The current approach to determine the MSI status in tumours requires matched normal DNA. Some mononucleotide microsatellite markers are known to have few variant alleles in both Caucasians and Asians. Therefore, the length of these microsatellite makers is almost confined within the quasi-monomorphic variation range (QMVR). Considering the application of MSI testing for various types of cancers, a simple, sensitive and inexpensive method is desired. This study assessed the clinical utility of the QMVR for determining the MSI status in patients with unresectable metastatic colorectal cancer (mCRC). The study enrolled 435 patients with mCRC. The concordance of the MSI status in mCRC between the standard method using tumour DNA plus matched normal DNA and the testing method using only tumour DNA was evaluated. Eleven (2.5%) MSI-high cases were detected by both the standard and testing methods. The sensitivity and specificity of the testing method were both 100%, indicating complete concordance between the methods. Among the mononucleotide markers, three and two patients showed discordance for NR-21 and BAT-25, respectively. Results from MSI testing with normal tissue indicated that four of five patients had rare germline variants outside the QMVR. For BAT-26, NR-24 and MONO-27, all patients showed complete concordance. Using the QMVR, the MSI status of mCRC can be determined without matched normal DNA.
| S-EPMC6215873 | biostudies-literature
Project description:Systemic therapy is the standard care for patients with unresectable advanced colorectal cancer (CRC), but salvage surgery of metastatic disease should be considered in the case of adequate tumor shrinkage. Several drugs and combinations are now available for use in treating patients with advanced CRC, but the optimal sequence of therapy remains unknown. Moreover, the administration of antitumor therapy can be modulated by periods of maintenance or treatment breaks rather than delivered as full therapy until disease progression or unacceptable toxicity, followed by reintroduction of prior full therapy when required, before switching to other drugs. Consequently, randomized strategy trials are needed to define the optimal treatment sequences. Molecular testing for Kirsten rat sarcoma viral oncogene homolog (KRAS) and neuroblastoma RAS viral oncogene homolog (NRAS) is mandatory but not sufficient to select appropriate patients for epidermal growth factor receptor (EGFR) monoclonal antibody (MoAb) therapy.
| S-EPMC4406914 | biostudies-literature
Project description:BackgroundThe addition of bevacizumab (BEV) to standard doublet chemotherapy improves outcomes compared with chemotherapy alone in patients with metastatic colorectal cancer (mCRC). The OPAL study examined the effect of BEV+FOLFOXIRI followed by 5FU/LV and BEV maintenance on progression-free survival (PFS) in patients with previously untreated unresectable mCRC.MethodsEligible patients had histologically confirmed mCRC, ECOG performance status ⩽1 and were 18-70 years old. Patients received up to 12 cycles of FOLFOXIRI+BEV q2w (induction phase) followed by up to ⩽40 cycles of 5FU/LV+BEV q2w (maintenance phase). Median PFS was the primary end point; secondary end points included response, OS, secondary resection rate, safety and prognostic value of pharmacogenetic profiling.ResultsNinety-seven patients were enrolled. Of these, 90 received study medication and formed the safety population: 64 males; median age 58 (range 28-71) years; ECOG performance status 0/1 in 54%/46% patients; and liver only disease in 35 patients. Relative dose intensities were 79-85% for all four drugs. The incidence of adverse events (AEs) was as previously reported and there were no new safety signals. In total, 87 serious AEs occurred in 39 patients (43%). Median PFS was 11.1 months (95% CI 9.4-12.0) and did thus not meet the primary objective of 12 months. Median OS was 32.2 months (95% CI 22.6-36.9). Fifty-two patients were pharmacogenetically profiled.ConclusionsFOLFOXIRI+BEV was feasible in this molecularly unselected mCRC patient population, showing a high efficacy in terms of survival, overall response and secondary resection rate. Pharmacogenomic profiling revealed no clinically relevant marker.
| S-EPMC4578090 | biostudies-literature
Project description:ObjectiveCirculating tumour DNA (ctDNA) sequencing is increasingly used in the clinical management of patients with colorectal cancer. However, the genomic heterogeneity in ctDNA during treatments and its impact on clinical outcomes remain largely unknown.DesignWe conducted a prospective cohort study (NCT04228614) of 171 patients with unresectable metastatic colorectal cancer (mCRC) who underwent first-line treatment and prospectively collected blood samples with or without tumour samples from patients at baseline and sequentially until disease progression or last follow-up.ResultsThe RAS/BRAF alterations in paired baseline tissue and plasma samples from 63 patients displayed a favourable concordance (81.0%, 51/63). After a period of first-line treatment (median time between baseline and last liquid biopsy, 4.67 months), 42.6% (26/61) of RAS-mutant patients showed RAS clearance and 50.0% (5/10) of BRAF-mutant patients showed BRAF clearance, while 3.6% (3/84) and 0.7% (1/135) of patients showed new RAS or BRAF mutations in ctDNA. Patients with plasma RAS/BRAF clearance showed similar progression-free survival (PFS) and overall survival (OS) with patients who remained RAS/BRAF wild-type, while much better outcomes than those who remained RAS/BRAF mutant. Patients who gained new RAS/BRAF mutations showed similar prognosis as those who maintained RAS/BRAF mutations, and shorter PFS and OS than those who remained RAS/BRAF wild-type.ConclusionThis prospective, serial and large-scale ctDNA profiling study reveals the temporal heterogeneity of mCRC-related somatic variants, which should be given special attention in clinical practice, as evidenced by the finding that the shift in plasma RAS/BRAF mutational status can yield a drastic change in survival outcomes.
| S-EPMC9185813 | biostudies-literature
Project description:BackgroundThe impact of primary tumor resection (PTR) on the prognosis of unresectable metastatic colorectal cancer (mCRC) patients remains debatable. We aimed to develop several prognostic nomograms which could be useful in predicting whether patients might benefit from PTR or not.MethodsPatients diagnosed as mCRC without resected metastasis were identified from the Surveillance Epidemiology and End Results database and randomly assigned into two groups: a training cohort (6369 patients) and a validation cohort (2774 patients). Univariate and multivariable Cox analyses were performed to identify the independent predictors and construct nomograms that could independently predict the overall survival (OS) of unresectable mCRC patients in PTR and non-PTR groups, respectively. The performance of these nomograms was assessed by the concordance index (C-index), calibration curves, and decision curve analysis (DCA).ResultsBased on the result of univariate and multivariable Cox analyses, two nomograms were respectively constructed to predict the 1-year OS rates of unresectable mCRC patients when receiving PTR and not. The first one included age, gender, tumor grade, proximal colon, N stage, CEA, chemotherapy, radiotherapy, histology type, brain metastasis, liver metastasis, lung metastasis, and bone metastasis. The second nomogram included age, race, tumor grade, primary site, CEA, chemotherapy, brain metastasis, and bone metastasis. These nomograms showed favorable sensitivity with the C-index range of 0.700-0.725. The calibration curves and DCAs also exhibited adequate fit and ideal net benefits in prognosis prediction and clinical application.ConclusionsThese practical prognosis nomograms could assist clinicians in making appropriate treatment decisions to effectively manage the disease.
| S-EPMC7401291 | biostudies-literature
Project description:AimThe use of bevacizumab in combination therapy is an emerging trend in metastatic colorectal cancer treatment. However, the clinical value of different combination types remains under debate. Thus, a meta-analysis of randomized controlled trials (RCTs) comparing bevacizumab-based combination therapy with monotherapy (therapy that uses one type of treatment, such as chemotherapy or surgery alone, to treat metastatic colorectal cancer) was performed, aiming to evaluate the safety and efficacy of bevacizumab-based combination therapy and to find a more beneficial combination.MethodsWe searched for clinical studies that evaluated bevacizumab-based combination therapy in metastatic colorectal cancer. We extracted data from these studies to evaluate the relative risk (RR) of overall response rate (ORR) and grade 3/4 treatment-related adverse events (AEs), HRs of overall survival (OS), and progression-free survival (PFS).ResultsEight RCTs were identified (n=3,424). Treatments included combinations of bevacizumab and oxaliplatin, fluorouracil, and leucovorin (FOLFOX4), combinations of bevacizumab and capecitabine and oxaliplatin, combinations of bevacizumab and fluorouracil/leucovorin, combinations of bevacizumab and irinotecan, fluorouracil, and leucovorin (IFL), and combinations of bevacizumab and capecitabine. Bevacizumab-based combination therapy showed higher ORR (RR: 1.40; 95% CI: 1.10–1.78; P=0.005), PFS (HR: 0.64; 95% CI: 0.55–0.73; P=0.000), and OS (HR: 0.82; 95% CI: 0.73–0.92; P=0.001) values than monotherapy. However, higher grade 3/4 treatment-related AEs (RR: 1.27; 95% CI: 1.15–1.41; P=0.000) were observed in combination therapy than in monotherapy.ConclusionThis meta-analysis showed that the addition of IFL to bevacizumab better benefits PFS and safety. Adding FOLFOX4 was associated with better ORR and OS. The efficacy and safety of an IFL–bevacizumab–FOLFOX4 combination should be given greater weight in future clinical trials, guidelines, and clinical practice.
| S-EPMC6287670 | biostudies-other