FOLFOX or CAPOX in Stage II to III Colon Cancer: Efficacy Results of the Italian Three or Six Colon Adjuvant Trial

Sobrero, Alberto; Lonardi, Sara; Rosati, Gerardo; Bartolomeo, Maria Di; Ronzoni, Monica; Pella, Nicoletta; Scartozzi, Mario; Banzi, M.; Zampino, Maria Giulia; Pasini, Felice; Marchetti, Paolo; Cantore, Maurizio; Zaniboni, Alberto; Rimassa, Lorenza; Ciuffreda, Libero; Ferrari, Daris; Zagonel, Vittorina; Maiello, Evaristo; Barni, Sandro; Rulli, Eliana; Labianca, Roberto

doi:10.1200/jco.2017.76.2187

Cited by 63 publications

(70 citation statements)

References 12 publications

(9 reference statements)

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“…The TOSCA trial is an open‐label, phase III, multicenter noninferiority trial that randomized patients with high‐risk stage II or stage III CC to receive 3 or 6 months of FOLFOX‐4/CAPOX adjuvant chemotherapy (ChT). The trial failed to demonstrate a formal noninferiority of 3 months versus 6 months of treatment .…”

Section: Introductionmentioning

confidence: 98%

Impact of Metformin Use and Diabetic Status During Adjuvant Fluoropyrimidine-Oxaliplatin Chemotherapy on the Outcome of Patients with Resected Colon Cancer: A TOSCA Study Subanalysis

Vernieri

Galli

Ferrari³

et al. 2019

The Oncologist

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Background Type 2 diabetes mellitus (T2DM) is associated with increased risk of colon cancer (CC), whereas metformin use seems to be protective. However, the impact of metformin use on the risk of death or disease recurrence after radical surgery for CC remains uncertain. Materials and Methods This is a substudy conducted in patients with high‐risk stage II or stage III CC randomized in the TOSCA trial, which compared 3 versus 6 months of fluoropyrimidine‐oxaliplatin adjuvant chemotherapy. Objective of the study was to investigate the impact of metformin exposure during adjuvant chemotherapy on overall survival (OS) and relapse‐free survival (RFS). We also evaluated the impact of T2DM or metformin dosage on clinical outcomes. Results Out of 3,759 patients enrolled in the TOSCA trial, 133 patients with diabetes (9.2%) and 1,319 without diabetes (90.8%) were recruited in this study. After excluding 13 patients with diabetes without information on metformin exposure, 76 patients with T2DM (63.3%) were defined as metformin users and 44 (36.7%) as metformin nonusers. After a median follow‐up of 60.4 months, 26 (21.7%) patients relapsed and 16 (13.3%) died. Metformin use was neither associated with OS (adjusted hazard ratio [HR], 1.51; 95% confidence interval [CI], 0.48–4.77; p = .4781) nor with RFS (HR, 1.56; 95% CI, 0.69–3.54; p = .2881). Similarly, we found no association between T2DM or metformin dosage and OS or RFS. Conclusions Metformin use and T2DM did not impact on OS or RFS in patients with resected CC treated with adjuvant fluoropyrimidine‐oxaliplatin chemotherapy. Larger studies and longer follow‐up are required to clarify the potential efficacy of metformin in improving the prognosis of patients with CC. Implications for Practice The role of the antidiabetic drug metformin in colon cancer prevention and treatment is highly debated. While low‐dose metformin reduced the incidence of colorectal adenomas in two prospective studies, its effect in patients with already established colon cancer remains unclear. In this study, the potential impact of metformin on the survival of resected colon cancer patients who received adjuvant chemotherapy was investigated in the context of the TOSCA study. We did not find any association between metformin use or dosages and patient survival. Prospective studies are required to draw definitive conclusions about metformin impact on colon cancer recurrence and survival.

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Section: Introductionmentioning

confidence: 98%

Impact of Metformin Use and Diabetic Status During Adjuvant Fluoropyrimidine-Oxaliplatin Chemotherapy on the Outcome of Patients with Resected Colon Cancer: A TOSCA Study Subanalysis

Vernieri

Galli

Ferrari³

et al. 2019

The Oncologist

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“…The primary end point was relapse-free survival (RFS), defined as the time from the date of randomization up to the date of the first relapse or death from any cause. At the primary analysis, 5 the trial failed to formally show non-inferiority of 3 versus 6 months of treatment to the predefined margin of 20% relative increase. However, in the low risk population (pN1 disease), the 3 months was similar to the 6-months duration in term of RFS.…”

Section: Tosca Trial Overviewmentioning

confidence: 99%

Khorana score and thromboembolic risk in stage II–III colorectal cancer patients: a post hoc analysis from the adjuvant TOSCA trial

et al. 2020

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Background: The risk of venous thromboembolic events (VTE) during adjuvant chemotherapy for colorectal cancer (CRC) is unknown. We aim to evaluate if the Khorana score (KS) can predict this risk, and if it represents a prognostic factor for overall survival (OS) through a post hoc analysis of the phase III TOSCA trial of different durations (3- versus 6-months) of adjuvant chemotherapy. Methods: A logistic regression model was used to test the associations between the risk of VTE and the KS. The results are expressed as odds ratios (OR) with 95% confidence intervals (95% CI). To assess the effect of the KS on OS, multivariable analyses using Cox regression models were performed. The results are expressed as hazard ratios (HR) with 95% CI. Results: Among 1380 CRC patients with available data, the VTE risk ( n = 72 events: 5.2%) was similar in the two duration arms (5.5% versus 4.9%), with 0.2% of patients belonging to the high-risk KS group. Rates of VTE were similar in the low- and intermediate-risk groups (4.8% versus 6.4%). KS did not represent an independent predictive factor for VTE occurrence. Chemotherapy duration was not associated with VTE risk. In addition, KS was not prognostic for OS in multivariate analysis (HR: 0.92, 95% CI, 0.63–1.36; p = 0.6835). Conclusions: The use of the KS did not predict VTEs in a low–moderate thromboembolic risk population as CRC. These data did not support the use of KS to predict VTE during adjuvant chemotherapy, and suggest that other risk assessment models should be researched.

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“…Our ndings from population-based cancer registry data con rmed that higher chemotherapy RDI was needed in high-risk stage III colon cancers, compared with low-risk cancers, and are consistent with the conclusions from six randomized, phase 3 clinical trials conducted by the International Duration Evaluation of Adjuvant Therapy (IDEA) collaboration, which found that 6 months of FOLFOX particularly bene ted high-risk stage III colon cancers. These clinical trials evaluated whether 3 months of FOLFOX or CAPOX is non-inferior to 6 months of therapy in the rate of disease-free survival at 3 years [4,9,32,33]. Results from a pooled analysis of six trials showed that in stage III colon cancer patients treated with FOLFOX, 6-month therapy had a higher rate of disease-free survival than 3-month therapy, particularly in the high-risk group [9].…”

Section: Discussionmentioning

confidence: 99%

“…FOLFOX (Oxaliplatin, uorouracil aka 5-FU, and leucovorin) is one of the standard adjuvant therapies commonly administered [2][3][4].…”

Section: Introductionmentioning

confidence: 99%

Impact of relative dose intensity of FOLFOX adjuvant chemotherapy on risk of death among stage III colon cancer patients

Zhou

Thompson²,

Lin

et al. 2020

Preprint

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Background: Clinical trials have suggested high-risk (T4 and/or N2) and low-risk (T1-T3 and N1) stage III colon cancer patients might need different doses of FOLFOX to reserve a similar survival probability. Observational studies have investigated the effect of relative dose intensity (RDI) of FOLFOX on cancer survival for patients with stage III colon cancer, but nonetheless, the studies focused on very specific populations, and none performed stratified analysis by risk profiles. This study aims to identify the optimal RDI of FOLFOX administered for high-risk and low-risk stage III colon cancer patients. Methods: Data on 407 eligible patients, diagnosed with stage III colon cancer in 2011 who received FOLFOX, were collected by the eight population-based cancer registries for a CDC National Program of Cancer Registries (NPCR) project focused on Comparative Effectiveness Research. We employed Kaplan-Meier method, cumulative incidence function (CIF), Multivariable Cox model and Fine-Gray competing risks model to explore Optimal RDI defined as the lowest RDI administered without significant differences in either overall or cause-specific death. Results: Among the 168 high-risk patients, the optimal RDI cut-off point was 70% where there was no statistically significant difference in overall mortality (HR=1.59; 95% CI: 0.69-3.66) and cause-specific mortality (HR=1.24; 95% CI: 0.42-3.64) when RDI<70% vs. RDI≥70%, adjusting for sociodemographic and clinical covariates. When the RDI cut-off was lower than the optimal one (<55% vs. ≥55%, <60% vs. ≥60%, or <65% vs. ≥65%), the overall mortality was significantly statistically different between the two groups of each comparison. Among the 239 low-risk patients, none of the evaluated cut-offs were associated with statistically significant differences in overall and cause-specific mortalities between comparison groups. The lowest RDI we assessed was 45%, HR=0.80; 95% CI: 0.24-2.73 for the overall mortality and HR=0.53; 95% CI: 0.06-4.95 for the cause-specific mortality, when RDI<45% vs. RDI≥45%. Conclusions: To best utilize health care resources while maintaining efficacy, RDI can be maintained at a minimum of 70% for high-risk stage III colon cancer patients. For low-risk patients, we found that RDI as low as 45% did not significantly affect the risk of death.

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FOLFOX or CAPOX in Stage II to III Colon Cancer: Efficacy Results of the Italian Three or Six Colon Adjuvant Trial

Cited by 63 publications

References 12 publications

Impact of Metformin Use and Diabetic Status During Adjuvant Fluoropyrimidine-Oxaliplatin Chemotherapy on the Outcome of Patients with Resected Colon Cancer: A TOSCA Study Subanalysis

Impact of Metformin Use and Diabetic Status During Adjuvant Fluoropyrimidine-Oxaliplatin Chemotherapy on the Outcome of Patients with Resected Colon Cancer: A TOSCA Study Subanalysis

Khorana score and thromboembolic risk in stage II–III colorectal cancer patients: a post hoc analysis from the adjuvant TOSCA trial

Impact of relative dose intensity of FOLFOX adjuvant chemotherapy on risk of death among stage III colon cancer patients

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