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Effect of duration of adjuvant chemotherapy for patients with stage III colon cancer (IDEA collaboration): final results from a prospective, pooled analysis of six randomised, phase 3 trials.

ABSTRACT:

Background

A prospective, pooled analysis of six randomised phase 3 trials was done to investigate disease-free survival regarding non-inferiority of 3 months versus 6 months of adjuvant chemotherapy for patients with stage III colon cancer; non-inferiority was not shown. Here, we report the final overall survival results.

Methods

In this prospective, pooled analysis of six randomised phase 3 trials, we included patients with stage III colon cancer aged at least 18 years with an Eastern Cooperative Oncology Group performance status of 0-1 recruited between June 20, 2007, and Dec 31, 2015, across 12 countries in the CALGB/SWOG 80702, IDEA France, SCOT, ACHIEVE, TOSCA, and HORG trials, who started any treatment (modified intention-to-treat). Patients in all trials were randomly assigned to 3 months or 6 months of adjuvant fluorouracil, leucovorin, and oxaliplatin (FOLFOX) every 2 weeks or capecitabine and oxaliplatin (CAPOX) in different doses and methods every 3 weeks, at the treating physician's discretion. The primary endpoint was disease-free survival (time to relapse, secondary colorectal primary tumour, or death due to all causes), and overall survival (time to death due to all causes) was the prespecified secondary endpoint. The non-inferiority margin for overall survival was set as a hazard ratio (HR) of 1·11. Pre-planned subgroup analyses included regimen and risk group. Non-inferiority was declared if the one-sided false discovery rate adjusted (FDRadj) p value was less than 0·025.

Findings

With median follow-up of 72·3 months (IQR 72·2-72·5), 2584 deaths among 12 835 patients were observed. 5064 (39·5%) patients received CAPOX and 7771 (60·5%) received FOLFOX. 5-year overall survival was 82·4% (95% CI 81·4-83·3) with 3 months of therapy and 82·8% (81·8-83·8) with 6 months of therapy (HR 1·02 [95% CI 0·95-1·11]; non-inferiority FDRadj p=0·058). For patients treated with CAPOX, 5-year overall survival was 82·1% (80·5-83·6) versus 81·2% (79·2-82·9; HR 0·96 [0·85-1·08]); non-inferiority FDRadj p=0·033), and for patients treated with FOLFOX 5-year overall survival was 82·6% (81·3-83·8) and 83·8% (82·6-85·0; HR 1·07 [0·97-1·18]; non-inferiority FDRadj p=0·34). Updated disease-free survival results confirmed previous findings (HR 1·08 [95% CI 1·02-1·15]; non-inferiority FDRadj p=0·25). Data on adverse events were not further recorded.

Interpretation

Non-inferiority of 3 months versus 6 months of adjuvant chemotherapy for patients with stage III colon cancer was not confirmed in terms of overall survival, but the absolute 0·4% difference in 5-year overall survival should be placed in clinical context. Overall survival results support the use of 3 months of adjuvant CAPOX for most patients with stage III colon cancer. This conclusion is strengthened by the substantial reduction of toxicities, inconveniencies, and cost associated with a shorter treatment duration.

Funding

US National Cancer Institute.

SUBMITTER: Andre T

PROVIDER: S-EPMC7786835 | biostudies-literature |

REPOSITORIES: biostudies-literature

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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.).

Project description:BACKGROUND:The International Duration Evaluation of Adjuvant Chemotherapy (IDEA) collaboration aimed to evaluate whether 3 months of adjuvant chemotherapy are noninferior to 6 months. Our study objectives were to characterize medical oncologists' perspectives toward the results of the IDEA collaboration and to evaluate how IDEA impacted prescribing patterns of adjuvant FOLFOX and CAPOX in colon cancer. MATERIALS AND METHODS:A list of questions developed by four medical oncologists regarding IDEA results were formulated and distributed online to gastrointestinal medical oncologists globally. Descriptive statistics and chi-square tests were used to summarize information. RESULTS:Of 174 responses, 145 were complete and analyzed. Responses were obtained globally from South America (53%); the U.S. and Canada (28%); Europe, Australia, and New Zealand (12%); and Asia (7%). Most clinicians (98%) were aware of the IDEA study. Prior to IDEA, clinicians preferred FOLFOX over CAPOX (81% vs. 19%). Subsequent to IDEA, 55% of clinicians preferred CAPOX over FOLFOX (odds ratio, 5.0; 95% confidence interval, 3.0-8.5; p < .01 compared with pre-IDEA). Two thirds (68%) of responders tailored duration of adjuvant therapy based on risk stratification. Most oncologists (76%) were more willing to discontinue oxaliplatin early if toxicities develop after the results of IDEA. Half of responders (50%) found that IDEA increased their confidence in decision making for adjuvant treatment; 36% were unchanged, and 15% indicated decreased confidence. Less than half (48%) were comfortable communicating the study results and the concept of a noninferiority trial with patients. CONCLUSION:IDEA appears to have shifted clinician preference from FOLFOX to CAPOX for adjuvant therapy, and most clinicians now use a risk-stratified approach in determining duration of adjuvant therapy. Patient education resources may facilitate better communication of IDEA results to patients. IMPLICATIONS FOR PRACTICE:This global survey illustrates that most gastrointestinal medical oncologists now use a risk-stratified approach for determining the duration of adjuvant chemotherapy for stage III colon cancer. Clinicians are five times more likely to choose CAPOX over FOLFOX after the International Duration Evaluation of Adjuvant Chemotherapy (IDEA) collaboration results.

Project description:ImportanceSeveral real-world oncology studies have produced findings that contradict those from randomized clinical trials. Such disparities may be associated with methodological shortcomings.ObjectiveTo examine the association between a shortened duration of adjuvant chemotherapy among individuals with stage III colon cancer using real-world data.Design, setting, and participantsThis comparative effectiveness study included individuals diagnosed with stage III colon cancer between January 2004 and December 2015 who initiated adjuvant chemotherapy at oncology clinics within the province of Alberta, Canada. Patients were identified through record linkage of various administrative databases and were followed up until September 2017. Eligibility criteria were modeled after those used in the International Duration Evaluation of Adjuvant (IDEA) trial. A target trial emulation and naive observational analysis were conducted. Results from both cohorts were benchmarked against findings from the IDEA trial. Data analysis was conducted from March to December 2020.ExposureA shortened duration of adjuvant 5-fluorouracil/leucovorin plus oxaliplatin (FOLFOX) or capecitabine plus oxaliplatin (CAPOX) chemotherapy, defined as 3 to 5 months of treatment vs 6 months.Main outcomes and measuresOverall survival assessed via vital statistics. The per-protocol hazard ratio (HR) was estimated using a weighted pooled logistic regression model. Subgroup analyses were conducted by treatment regimen (ie, FOLFOX vs CAPOX) and cancer stage (ie, T1-3 and N1 vs T4 or N2).ResultsFrom an initial cohort of 3086 patients, 485 (16%) were eligible for inclusion in the target trial analysis. The median age was 59 years (range, 19-81 years), and 230 (47%) were women. The maximum follow-up was 11.6 years. Median overall survival was not reached. A total of 90 patients (19%) died. The 5-year Kaplan Meier overall survival estimate was 0.79 (95% CI, 0.75-0.84). Estimates from the trial emulation were similar to those from the IDEA trial. For example, a shortened duration of adjuvant chemotherapy was not associated with overall survival among patients prescribed CAPOX in the IDEA trial (HR, 0.96; 95% CI, 0.85-1.08) or in the trial emulation (HR, 0.96; 95% CI, 0.43-2.14). In contrast, the naive observational analysis suggested that a shortened duration of CAPOX was significantly associated with worse survival (HR, 3.33; 95% CI, 1.04-10.65).Conclusions and relevanceIn this study, the explicit emulation of a target trial better approximated results from an analogous well-conducted randomized clinical trial.

Project description:ImportanceThe results from the recent International Duration Evaluation of Adjuvant Therapy (IDEA) collaboration have led some clinicians to adopt shorter durations of adjuvant chemotherapy for patients with stage III colon cancer. The extent to which these findings are supported by other data is unknown.ObjectiveTo conduct a systematic review and meta-analysis of randomized and observational studies investigating the association between the duration of adjuvant chemotherapy and survival among individuals diagnosed as having stage II and III colon cancer (PROSPERO protocol CRD42018108711]).Data sourcesAbstracts published in English between 2003 and 2018 within the MEDLINE, Embase, CENTRAL, and CINAHL databases were reviewed by 2 authors. Also searched were conference proceedings and the indexes of high-impact oncology journals.Study selectionStudies were excluded if they did not present original data; focused on animal populations, on cancers in sites other than the colon, or on patients with stage 0, I, or IV disease; did not examine a 5-flourouracil-based monotherapy or combination therapy; or did not evaluate the association between treatment duration and survival. The search identified 2341 articles, from which 2 randomized trials and 20 observational studies were included in the meta-analysis.Data extraction and synthesisThis study followed the PRISMA and MOOSE reporting guidelines. The risk of bias was assessed by 2 authors using the Cochrane and Risk of Bias in Nonrandomized Studies of Interventions (ROBINS-I) tools. The results were synthesized using a random-effects model.Main outcomes and measuresThe primary and secondary outcomes were overall survival and disease-free survival, respectively. It was hypothesized a priori that 3 months of chemotherapy would be as effective as 6 months of chemotherapy.ResultsTwenty-two studies were included in the meta-analysis, representing 43 671 patients. The inclusion of patients with stage II disease or with rectal cancer was identified as a source of heterogeneity. After restricting the analysis to patients with stage III colon cancer, there was no association between the duration of chemotherapy and overall survival among studies involving FOLFOX (leucovorin calcium [folinic acid], fluorouracil, and oxaliplatin) or CAPOX (capecitabine plus oxaliplatin) regimens (hazard ratio [HR], 0.80; 95% CI, 0.58-1.09). Among studies focused exclusively on monotherapy, the standard 6-month regimen relative to a 3-month regimen was associated with improved survival (HR, 0.59; 95% CI, 0.52-0.68).Conclusions and relevanceShortened durations of chemotherapy may reduce survival among patients with stage III colon cancer prescribed monotherapy but not a combination regimen.

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.