FOLFOX and FLOX regimens for the adjuvant treatment of resected stage II and III colon cancer.
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ABSTRACT:
SUBMITTER: Sharif S
PROVIDER: S-EPMC2588473 | biostudies-literature | 2008 Nov
REPOSITORIES: biostudies-literature
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FOLFOX and FLOX regimens for the adjuvant treatment of resected stage II and III colon cancer.
Sharif Saima S O'Connell Michael J MJ Yothers Greg G Lopa Samia S Wolmark Norman N
Cancer investigation 20081101 9
The MOSAIC trial showed that the use of adjuvant oxaliplatin and an infusional regimen of 5-FU/LV in the treatment of stage II/III colon cancer improved disease-free survival (DFS). The NSABP's C-07 trial evaluated the addition of oxaliplatin to a weekly Roswell Park regimen of bolus 5-FU/LV and found a similar improvement in DFS. The benefit of oxaliplatin appears to be independent of the 5-FU/LV regimen used. This paper reviews the efficacy and toxicities of these two regimens and is meant to ...[more]
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Project description:BackgroundWe evaluated the impact of 3 months of mFOLFOX6 adjuvant chemotherapy or surgery alone in comparison with 6 months of mFOLFOX6 on disease-free survival (DFS) in deficient mismatch repair (dMMR) colon cancer (CC) patients.MethodsThis retrospective study identified a cohort of patients with high-risk stage II and III dMMR CC who underwent curative surgery between May 2011 and July 2019. DFS was compared using the Kaplan-Meier survival methods and Cox proportional hazards models. Propensity-score matching was performed to reduce imbalance in baseline characteristics.ResultsA total of 242 dMMR CC patients were identified; 66 patients received 6 months of mFOLFOX6, 87 patients received 3 months of mFOLFOX6, and 89 patients were treated with surgery alone. The 3-year DFS rate was 72.8% in 3-month therapy group and 86.1% in 6-month therapy group, with a hazard ratio (HR) of 2.78 (95CI%, 1.18 to 6.47; P= 0.019). The difference in DFS between surgery alone group and 6-month therapy group was also observed but was nonsignificant (HR= 2.30, 95%CI, 0.99 to 5.38; P=0.054). The benefit of 6-month therapy in DFS compared with 3-month therapy group was pronounced for patients with stage III (HR=2.81, 95%CI, 1.03 to 7.67; P=0.044) but not for high-risk stage II patients. Propensity score matched analysis confirmed a DFS benefit in the 6-month therapy group.ConclusionThis study suggested that a 6-month duration of mFOLFOX6 adjuvant chemotherapy in dMMR CC patients may be associated with improved DFS compared with 3-month therapy, particularly in patients with stage III. The observational nature of the study implies caution should be taken in the interpretation of these results.
| S-EPMC7747753 | biostudies-literature
Project description:BackgroundMethylation levels of long interspersed nucleotide elements (LINE-1) are representative of genome-wide methylation status and crucial in maintaining genomic stability and expression. Their prognostic impact on colon cancer patients receiving adjuvant chemotherapy has not been well established. We evaluated the association between LINE-1 methylation status and clinicopathologic features and postoperative oncological outcomes in stage III colon cancer patients.Materials and methods129 UICC stage III colon cancer patients who had received radical resection and FOLFOX adjuvant chemotherapy were enrolled. Global methylation was estimated by analyzing tumor LINE-1 methylation status using bisulfite-polymerase chain reaction (PCR) and pyrosequencing assay. Demographics, clinicopathological data, and postoperative outcomes were recorded by trained abstractors. Outcome measurements included postoperative recurrence and disease-free survival. Univariate, multivariate, and survival analyses were conducted to identify prognostic factors of oncological outcomes.ResultsThe LINE-1 methylation of all 129 patients was measured on a 0-100 scale (mean 63.3; median 63.7, standard deviation 7.1), LINE-1 hypomethylation was more common in patients aged 65 years and above (61.7%±7.6% vs. 64.6±6.4, p=0.019) and those with post-therapeutic recurrence (61.7±7.4 vs 64.3±6.7, p=0.041). Considering risk adjustment, LINE-1 hypomethylation was found to be an independent risk factor of post-therapeutic recurrence (Adjusted OR=14.1, p=0.012). Kaplan-Meier analysis indicated that patients in the low methylation group had shorter period of disease free survival (p=0.01). In a stratified analysis that included 48 patients with post-therapeutic recurrence, it was found that those who experienced shorter period of disease free survival (?6 months) appeared to have lower LINE-1 methylation levels than patients who reported of recurrence after 6 months (56.68±15.75 vs. 63.55±7.57, p=0.041).ConclusionThere was a significantly greater risk of early postoperative recurrence and a shorter period of disease-free survival in Stage III colon cancer patients exhibiting LINE-1 hypomethylation status after being treated with radical resection and FOLFOX chemotherapy.
| S-EPMC4412676 | biostudies-literature
Project description:Cancer stem cell (CSC) and ATP-binding cassette (ABC) transporters are associated with treatment resistance and outcomes of patients with cancer. The present study investigated the prognostic implications of pre-therapeutic expression of ABC transporters and CSC markers in patients with colon cancer (CC) who received adjuvant 5-fluorouracil, leucovorin and oxaliplatin combination therapy (FOLFOX-4). The immunohistochemical expression of 3 ABC transporters, including ABC subfamily C member 2 (ABCC2), ABCC3 and ABC subfamily G member 2 (ABCG2), and 3 CSC markers, including sex determining region Y-box 2 (SOX2), leucine-rich repeat-containing G protein-coupled receptor 5 and aldehyde dehydrogenase 1, were determined in 164 CC tissues from patients with stage III CC, who underwent postoperative FOLFOX-4 chemotherapy. The association between the protein expression and patients' prognoses was statistically analyzed. ABCG2 was associated with favorable overall survival rate (OS; P=0.001), and ABCC2, ABCG2 and SOX2 were associated with increased disease-free survival rate (DFS; P=0.001, 0.002 and 0.013, respectively). In multivariate analyses, ABCG2 was an independent prognostic factor for OS [hazard ratio (HR)=2.877; P=0.046], and ABCC2 and SOX2 were independent prognostic factors for DFS (HR=2.831; P=0.014; HR=2.558, P=0.020, respectively). ABCC2, ABCG2 and SOX2 may be promising prognostic markers for patients with CC receiving FOLFOX-4 therapy.
| S-EPMC6507487 | biostudies-literature
Project description:BackgroundSince 2004, a regimen of 6 months of treatment with oxaliplatin plus a fluoropyrimidine has been standard adjuvant therapy in patients with stage III colon cancer. However, since oxaliplatin is associated with cumulative neurotoxicity, a shorter duration of therapy could spare toxic effects and health expenditures.MethodsWe performed a prospective, preplanned, pooled analysis of six randomized, phase 3 trials that were conducted concurrently to evaluate the noninferiority of adjuvant therapy with either FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CAPOX (capecitabine and oxaliplatin) administered for 3 months, as compared with 6 months. The primary end point was the rate of disease-free survival at 3 years. Noninferiority of 3 months versus 6 months of therapy could be claimed if the upper limit of the two-sided 95% confidence interval of the hazard ratio did not exceed 1.12.ResultsAfter 3263 events of disease recurrence or death had been reported in 12,834 patients, the noninferiority of 3 months of treatment versus 6 months was not confirmed in the overall study population (hazard ratio, 1.07; 95% confidence interval [CI], 1.00 to 1.15). Noninferiority of the shorter regimen was seen for CAPOX (hazard ratio, 0.95; 95% CI, 0.85 to 1.06) but not for FOLFOX (hazard ratio, 1.16; 95% CI, 1.06 to 1.26). In an exploratory analysis of the combined regimens, among the patients with T1, T2, or T3 and N1 cancers, 3 months of therapy was noninferior to 6 months, with a 3-year rate of disease-free survival of 83.1% and 83.3%, respectively (hazard ratio, 1.01; 95% CI, 0.90 to 1.12). Among patients with cancers that were classified as T4, N2, or both, the disease-free survival rate for a 6-month duration of therapy was superior to that for a 3-month duration (64.4% vs. 62.7%) for the combined treatments (hazard ratio, 1.12; 95% CI, 1.03 to 1.23; P=0.01 for superiority).ConclusionsAmong patients with stage III colon cancer receiving adjuvant therapy with FOLFOX or CAPOX, noninferiority of 3 months of therapy, as compared with 6 months, was not confirmed in the overall population. However, in patients treated with CAPOX, 3 months of therapy was as effective as 6 months, particularly in the lower-risk subgroup. (Funded by the National Cancer Institute and others.).
| S-EPMC6426127 | biostudies-literature
Project description:The advantage of adjuvant chemotherapy (ACT) for treating Stage III colon cancer patients is well established and widely accepted. However, many patients with Stage III colon cancer do not receive ACT. Moreover, there are controversies around the effectiveness of ACT for Stage II patients. We investigated the administration of ACT and its association with overall survival in resected Stage II (overall and stratified by low-/high-risk) and Stage III colon cancer patients in three European countries including The Netherlands (2009-2014), Belgium (2009-2013) and Sweden (2009-2014). Hazard ratios (HR) for death were obtained by Cox regression models adjusted for potential confounders. A total of 60244 resected colon cancer patients with pathological Stages II and III were analyzed. A small proportion (range 9-24%) of Stage II and over half (range 55-68%) of Stage III patients received ACT. Administration of ACT in Stages II and III tumors decreased with higher age of patients. Administration of ACT was significantly associated with higher overall survival in high-risk Stage II patients (in The Netherlands (HR; 95%CI?=?0.82 (0.67-0.99), Belgium (0.73; 0.59-0.90) and Sweden (0.58; 0.44-0.75)), and in Stage III patients (in The Netherlands (0.47; 0.43-0.50), Belgium (0.46; 0.41-0.50) and Sweden (0.48; 0.43-0.54)). In Stage III, results were consistent across subgroups including elderly patients. Our results show an association of ACT with higher survival among Stage III and high-risk Stage II colon cancer patients. Further investigations are needed on the selection criteria of Stages II and III colon cancer patients for ACT.
| S-EPMC6002808 | biostudies-literature
Project description:In patients with high risk stage II and stage III colon cancer (CC), curative surgery followed by adjuvant FOLFOX-4 chemotherapy has become the standard of care. However, for 20 to 30% of these patients, the current curative treatment strategy of surgical excision followed by adjuvant chemotherapy fails either to clear locoregional spread or to eradicate distant micrometastases, leading to disease recurrence. Preoperative chemotherapy is an attractive concept for these CCs and has the potential to impact upon both of these causes of failure. Optimum systemic therapy at the earliest possible opportunity may be more effective at eradicating distant metastases than the same treatment given after the delay and immunological stress of surgery. Added to this, shrinking the primary tumor before surgery may reduce the risk of incomplete surgical excision, and the risk of tumor cell shedding during surgery.PRODIGE 22--ECKINOXE is a multicenter randomized phase II trial designed to evaluate efficacy and feasibility of two chemotherapy regimens (FOLFOX-4 alone and FOLFOX-4 + Cetuximab) in a peri-operative strategy in patients with bulky CCs. Patients with CC deemed as high risk T3, T4 and/or N2 on initial abdominopelvic CT scan are randomized to either colectomy and adjuvant chemotherapy (control arm), or 4 cycles of neoadjuvant chemotherapy with FOLFOX-4 (for RAS mutated patients). In RAS wild-type patients a third arm testing FOLFOX+ cetuximab has been added prior to colectomy. Patients in the neoadjuvant chemotherapy arms will receive postoperative treatment for 4 months (8 cycles) to complete their therapeutic schedule. The primary endpoint of the study is the histological Tumor Regression Grade (TRG) as defined by Ryan. The secondary endpoints are: treatment strategy safety (toxicity, primary tumor related complications under chemotherapy, peri-operative morbidity), disease-free and recurrence free survivals at 3 years, quality of life, carcinologic quality and completeness of the surgery, initial radiological staging and radiological response to neoadjuvant chemotherapy, and the correlation between histopathological and radiological response. Taking into account a 50% prevalence of CC without RAS mutation, accrual of 165 patients is needed for this Phase II trial.NCT01675999 (ClinicalTrials.gov).
| S-EPMC4497499 | biostudies-literature
Project description:Comparison the mRNA expression profiles of 101 CRC tissues to those from matched 35 non-neoplastic colon mucosal tissues from patients with stage III CRCs treated with FOLFOX adjuvant chemotherapy in each molecular subtype. Gene expression–based subtyping is widely accepted as a relevant source of disease stratification. Results provide important information of molecular marker genes for molecular classification.
2017-05-31 | GSE83889 | GEO
Project description:Individualizing adjuvant chemotherapy is important in patients with advanced colorectal cancers (CRCs), and the ability to identify molecular subtypes predictive of good prognosis for stage III CRCs after adjuvant chemotherapy could be highly beneficial. We performed microarray-based gene expression analysis on 101 fresh-frozen primary samples from patients with stage III CRCs treated with FOLFOX adjuvant chemotherapy and 35 matched non-neoplastic mucosal tissues. CRC samples were classified into four molecular subtypes using nonnegative matrix factorization, and for comparison, we also grouped CRC samples using the proposed consensus molecular subtypes (CMSs). Of the 101 cases, 80 were classified into a CMS group, which shows a 79% correlation between the CMS classification and our four molecular subtypes. We found that two of our subtypes showed significantly higher disease-free survival and overall survival than the others. Group 2, in particular, which showed no disease recurrence or death, was characterized by high microsatellite instability (MSI-H, 6/21), abundant mucin production (12/21), and right-sided location (12/21); this group strongly correlated with CMS1 (microsatellite instability immune type). We further identified the molecular characteristics of each group and selected 10 potential biomarker genes from each. When these were compared to the previously reported molecular classifier genes, we found that 31 out of 40 selected genes were matched with those previously reported. Our findings indicate that molecular classification can reveal specific molecular subtypes correlating with clinicopathologic features of CRCs and can have predictive value for the prognosis for stage III CRCs with FOLFOX adjuvant chemotherapy.
| S-EPMC5503619 | biostudies-literature
Project description:Objective: To determine the efficacy of pembrolizumab relative to other treatments used in stage III melanoma by conducting a systematic literature review (SLR) and network meta-analysis (NMA). Methods: A SLR was conducted to identify randomized clinical trials (RCTs) evaluating approved adjuvant treatments including interferon-containing regimens, BRAF-inhibitors, and PD-L1 inhibitors in stage III melanoma patients. Relative treatment effects for recurrence-free survival (RFS) were synthesized with Bayesian NMA models that allowed for hazard ratios (HRs) to vary over time. Results: Included studies formed a connected network of evidence composed of eight trials. In high-risk stage III patients, the HR for pembrolizumab vs observation decreased significantly over time with the superiority of pembrolizumab over observation becoming statistically meaningful before 3 months. By 9 months, the HR for pembrolizumab vs observation was statistically significantly lower than the HR for most other treatments vs observation, with the exception of ipilimumab and biochemotherapy due to overlapping 95% credible intervals. In BRAF + patients, pembrolizumab was statistically significantly better than observation after 3 months. The HR for both BRAF-inhibitors vs observation increased significantly over time and pembrolizumab was statistically superior to both BRAF-inhibitors after 15 months. Conclusions: Pembrolizumab results in statistically significantly improved RFS compared to all competing regimens after 9 months, except ipilimumab and biochemotherapy, for the adjuvant treatment of stage III melanoma. However, point estimate HRs vs observation for pembrolizumab are much lower than those for ipilimumab. In BRAF + patients, the advantage of pembrolizumab versus competing interventions increases over time with respect to RFS.
| S-EPMC6713115 | biostudies-literature
Project description:BackgroundThe tumour-stroma ratio (TSR) has proven to be an independent prognostic factor in colon cancer.MethodsHaematoxylin eosin tissue slides of patients from the AVANT trial were microscopically scored for TSR and categorised as stroma -low or stroma -high. Scores were correlated to the primary and secondary endpoint disease-free survival (DFS) and overall survival (OS).ResultsPatients with stroma-high tumours (N = 339, 28%) had a significantly shorter DFS (p < 0.001) compared to stroma-low tumours (N = 824, 68%). In the bevacizumab-FOLFOX-4 arm, DFS was significantly shorter compared to FOLFOX-4 in stroma-low tumours, with a hazard ratio (HR) of 1.94 (95% CI 1.24-3.04; p = 0.004). In stroma-high tumours a trend for better DFS was seen in bevacizumab-FOLFOX-4 vs. FOLFOX-4 (HR 0.61 (95% CI 0.35-1.07; p = 0.08)). For bevacizumab-XELOX vs. FOLFOX-4, this was not seen (stroma-low HR 1.07 (95% CI 0.64-1.77; p = 0.80); stroma-high HR 0.78 (95% CI 0.47-1.30; p = 0.35)). OS showed the same pattern for bevacizumab-FOLFOX-4 vs. FOLFOX-4 with a HR of 2.53 (95% CI 1.36-4.71; p = 0.003) for stroma-low and HR 0.50 (95% CI 0.22-1.14; p = 0.10) for stroma-high tumours. For bevacizumab-XELOX vs. FOLFOX-4, HR 1.13 (95% CI 0.55-2.31; p = 0.74) for stroma-low tumours and HR 0.74 (95% CI 0.37-1.51; p = 0.41) for stroma-high tumours.ConclusionsThis exploratory analysis suggests a significantly shorter DFS and OS in stroma-low tumours with addition of bevacizumab to intravenous oxaliplatin-based chemotherapy, contrary to stroma-high tumours, where a beneficial trend is observed.
| S-EPMC6048031 | biostudies-literature