Prognostic variables in low and high risk stage III colon cancers treated in two adjuvant chemotherapy trials.
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ABSTRACT: Background
Stratification of patients with stage III colon cancer into low (T1-3N1) and high (T4 and/or N2) risk groups is used to guide the duration of adjuvant chemotherapy. We determined the relative contribution of clinical and molecular features to survival by risk group.Materials & methods
Stage III colon cancer (N = 5337) patients from two adjuvant trials of FOLFOX ± cetuximab [N0147 (Alliance), PETACC-8] were risk grouped, then subgrouped by clinical features and molecular variables [KRAS and BRAF/mismatch repair (MMR) combined variable]. Distributions of disease-free survival (DFS), overall survival (OS), and survival after recurrence (SAR) were estimated. In multivariable Cox models, backward elimination was performed for analysis of candidate predictors of outcomes. Relative contributions of model-selected variables to outcomes by risk group were calculated using χ2.Results
Among low risk tumours, mutant KRAS and male gender were significantly associated with poorer OS multivariately. In high risk tumours, significantly poorer OS was observed for right sidedness and for mutant KRAS and BRAFV600E/pMMR, subgroups. Specifically, BRAFV600E/pMMR (OS: HR = 1.75; 95% CI: 1.36-2.24; Padj<.0001) and right- versus left-sidedness were associated with significantly poorer DFS, OS (HR = 1.56; 95% CI: 1.31-1.83; Padj<.0001), and SAR (HR = 1.64; 95% CI: 1.37-1.95; Padj<.0001). Poor prognosis of mutant KRAS for DFS and OS was similar among risk groups. BRAF/MMR and sidedness were associated with poorer SAR in both low and high risk tumours. Age, gender, and KRAS were the top three relative contributors to DFS and OS among low risk tumours; sidedness ranked first for DFS and OS, and second to BRAF/MMR for SAR among high risk tumours.Conclusion
Sidedness and BRAF/MMR contributed the most to survival outcomes among high risk tumours and should be interpreted in the context of risk group.
SUBMITTER: Sinicrope FA
PROVIDER: S-EPMC7855426 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundAmong patients with resected colon cancer, black patients have worse survival than whites. We investigated whether disparities in survival and related endpoints would persist when patients were treated with identical therapies in controlled clinical trials.MethodsWe assessed 14,611 patients (1218 black and 13,393 white) who received standardized adjuvant treatment in 12 randomized controlled clinical trials conducted in North America for resected stage II and stage III colon cancer between 1977 and 2002. Individual patient data on covariates and outcomes were extracted from the Adjuvant Colon Cancer ENdpoinTs (ACCENT) database. The endpoints examined in this meta-analysis were overall survival (time to death), recurrence-free survival (time to recurrence or death), and recurrence-free interval (time to recurrence). Cox models were stratified by study and controlled for sex, stage, age, and treatment to determine the effect of race. Kaplan-Meier estimates were adjusted for similar covariates to control for confounding. All statistical tests were two-sided.ResultsBlack patients were younger than whites (median age, 58 vs 61 years, respectively; P < .001) and more likely to be female (55% vs 45%, respectively; P < .001). Overall survival was worse in black patients than whites (hazard ratio [HR] of death = 1.22, 95% confidence interval [CI] = 1.11 to 1.34, P < .001). Five-year overall survival rates for blacks and whites were 68.2% and 72.8%, respectively. When subsets defined by sex, stage, and age were analyzed, overall survival was consistently worse in black patients. Recurrence-free survival was worse in black patients than whites (HR of recurrence or death = 1.14, 95% CI = 1.04 to 1.24, P = .0045). Three-year recurrence-free survival rates in blacks and whites were 68.4% and 72.1%, respectively. In contrast, recurrence-free interval was similar in black and white patients (HR of recurrence = 1.08, 95% CI = 0.97 to 1.19, P = .15). Three-year recurrence-free interval rates in blacks and whites were 71.3% and 74.2%, respectively.ConclusionsBlack patients with resected stage II and stage III colon cancer who were treated with the same therapy as white patients experienced worse overall and recurrence-free survival, but similar recurrence-free interval, compared with white patients. The differences in survival may be mostly because of factors unrelated to the patients' adjuvant colon cancer treatment.
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Project description:BackgroundIdentifying optimal chemotherapy utilization rates can drive improvements in quality of care. We report a benchmarking approach to estimate the optimal rate of adjuvant chemotherapy (ACT) for stage III colon cancer.MethodsThe Ontario Cancer Registry and linked treated records were used to identify ACT utilization. Monte Carlo simulation was used to estimate the proportion of ACT rate variation that could be due to chance alone. The criterion-based benchmarking approach was used to explore whether socioeconomic or system-level factors were associated with ACT. We also used the "pared-mean" approach to identify a benchmark population of hospitals with the highest ACT rates.ResultsThe study population included 2801 patients; ACT was delivered to 66% (1861/2801). Monte Carlo simulation suggested that the observed component of variation (15.6%) in ACT rates was within the 95% CI (11.5%-17.3%) of what could be expected due to chance alone; the nonrandom component of ACT rate variation across hospitals was only 1.5%. There was no difference in hospital ACT rate by teaching status (P = .107), cancer center status (P = .362), or having medical oncology on site (P = .840). Unadjusted ACT rates varied across hospitals (range 44%-91%, P = .017). The unadjusted benchmark ACT rate was 81% (95%CI 76%-86%); utilization rate in non-benchmark hospitals was 65% (95%CI 63%-66%). However, after adjusting for case mix, the difference in ACT utilization between benchmark and non-benchmark populations was significantly smaller.ConclusionsWe did not find any system-level factors associated with the utilization of ACT. Our results suggest that the observed variation in hospital ACT rate is not significantly different from variation due to chance alone. Using the "pared-mean" approach may significantly overestimate optimal treatment rates if case mix is not considered.
| S-EPMC6745837 | biostudies-literature
Project description:BackgroundThe survival impact of multi-agent (MAC) compared with single-agent (SAC) adjuvant chemotherapy (AC) in elderly patients with stage III colon cancer (CC) remains controversial. The aim of this study was to compare survival outcomes of MAC and SAC in this population utilizing the National Cancer Database (NCDB).Patients and methodsPatients aged ≥70 years with pathological stage III CC diagnosed in 2004-2015 were identified in the NCDB. Univariate and multivariable analyses were conducted, and Kaplan-Meier analysis and Cox proportional hazard models were used to identify associations between MAC vs. SAC and overall survival (OS).ResultsAmong 41 707 elderly patients (≥70 years old) with stage III CC, about half (n = 20 257; 48.5%) received AC; the majority (n = 12 923, 63.8%) received MAC. The median age was 79 (range 70-90). The majority were female (n = 11 201, 55.3%), Caucasians (88%) and had moderately differentiated tumor grade (n = 12 619, 62.3%), tumor size >4 cm (11 785, 58.2%), and negative surgical margins (18 496, 91.3%). Low-risk stage III CC constituted 50.6% (n = 10 264) of the study population. High-risk stage III CC was associated with worse OS compared with low-risk disease (HR 0.35, 0.34-0.36, P < .001). Multi-agent chemotherapy was associated with a better 5-year OS compared with SAC (P < .001). High-risk stage III patients who received MAC vs. SAC had an OS of 4.2 vs. 3.4 years, respectively (P < .001). Low-risk stage III patients who received MAC vs. SAC had a median OS of 8.5 vs. 7 years (P < .001). In univariate and multivariable analyses, male sex, positive surgical margin, insurance and facility types, age, year of diagnosis, tumor size, and Charlson-Deyo score of >2 were associated with worse OS (P < .05).ConclusionsAny adjuvant chemotherapy has a trend of survival benefits. Multi-agent chemotherapy seems to have an enhanced benefit in the 70-75 age group. Multi-agent chemotherapy seemed to have similar efficacy as SAC in those aged >76 years.
| S-EPMC9438921 | biostudies-literature
Project description:Importance:The prognostic impact of DNA mismatch repair (MMR) status in stage III colon cancer patients receiving FOLFOX (folinic acid, fluorouracil, and oxaliplatin) adjuvant chemotherapy remains controversial. Objective:To determine the association of MMR status with disease-free survival (DFS) in patients with stage III colon cancer treated with FOLFOX. Design, Setting, and Participants:The evaluated biomarkers for MMR status were determined from prospectively collected tumor blocks from patients treated with FOLFOX in 2 open-label, phase 3 randomized clinical trials: NCCTG N0147 and PETACC8. The studies were conducted in general community practices, private practices, and institutional practices in the United States and Europe. All participants had stage III colon adenocarcinoma. They were enrolled in NCCTG N0147 from February 2004 to November 2009 and in PETACC8 from December 2005 to November 2009. Interventions:Patients in the clinical trials were randomly assigned to receive 6 months of chemotherapy with FOLFOX or FOLFOX plus cetuximab. Only those patients treated with FOLFOX alone were included in the present study. Main Outcomes and Measures:Association of MMR status with DFS was analyzed using a stratified Cox proportional hazards model. Multivariable models were adjusted for age, sex, tumor grade, pT/pN stage, tumor location, ECOG (Eastern Cooperative Oncology Group) performance status, and BRAF V600E mutational status. Results:Among 2636 patients with stage III colon cancer treated with FOLFOX, MMR status was available for 2501. Of these, 252 (10.1%) showed deficient MMR status (dMMR; 134 women, 118 men; median age, 59 years), while 2249 (89.9%) showed proficient MMR status (pMMR; 1020 women, 1229 men; median age, 59 years). The 3-year DFS rates in the dMMR and pMMR groups were 75.6% and 74.4%, respectively. By multivariate analysis, patients with dMMR phenotype had significantly longer DFS than those with pMMR (adjusted hazard ratio, 0.73; 95% CI, 0.54-0.97; P?=?.03). Conclusions and Relevance:The deficient MMR phenotype remains a favorable prognostic factor in patients with stage III colon cancer receiving FOLFOX adjuvant chemotherapy. Trial Registration:clinicaltrials.gov Identifier: NCT00079274 for the NCCTG N0147 trial and EudraCT identifier: 2005-003463-23 for the PETACC8 trial.
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Project description:BackgroundThe benefit of chemotherapy in colon cancer patients is well documented but depends largely on whether patients complete the planned treatment regimen. We evaluated predictors of early discontinuation (EDChemo) and dose reduction of chemotherapy, especially the role of adverse treatment effects, in stage III patients who received adjuvant chemotherapy.MethodsStage III colon cancer patients who were diagnosed in 2003-2014 and recruited into a population-based study in Germany and received FOLFOX [5-fluorouracil (5-FU), leucovorin (LV), and oxaliplatin], capecitabine monotherapy (CapMono), or 5-FU/LV were included. We assessed determinants of EDChemo and dose reduction using multivariable logistic regression. Also, we estimated proportions of EDChemo and dose reduction that are attributable to adverse effects using attributable fractions.ResultsEDChemo and dose reduction rates were 52% and 17% for FOLFOX, 28% and 9% for CapMono, and 45% and 6% for 5-FU/LV, respectively. Predictors of EDChemo were low-grade tumor and treatment in a medium-volume hospital (for FOLFOX), obesity (for CapMono), and increasing age, T4 stage, and treatment in a medium-volume hospital (for 5-FU/LV). Adverse effects were particularly strongly associated with EDChemo and contributed to about 63%, 51%, and 32% of EDChemo of FOLFOX, CapMono, and 5-FU/LV, respectively. Of the various adverse effects, gastrointestinal events showed the strongest associations with EDChemo and accounted for about 7%, 26%, and 20% of EDChemo of FOLFOX, CapMono, and 5-FU/LV, respectively. Adverse effects were, moreover, a strong determinant of dose reduction and accounted for about 82% of all cases.ConclusionsEDChemo is common in stage III colon cancer patients receiving chemotherapy and more than half of the cases of EDChemo and dose reduction are due to adverse treatment effects. Further research should address the potential for reducing EDChemo and dose reduction rates by close monitoring of patients for early signs and enhanced management of adverse effects, especially gastrointestinal events.
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