Dataset Information

Association Between Adjuvant Chemotherapy Duration and Survival Among Patients With Stage II and III Colon Cancer: A Systematic Review and Meta-analysis.

ABSTRACT:

Importance

The 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.

Objective

To 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 sources

Abstracts 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 selection

Studies 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 synthesis

This 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 measures

The 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.

Results

Twenty-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 relevance

Shortened durations of chemotherapy may reduce survival among patients with stage III colon cancer prescribed monotherapy but not a combination regimen.

SUBMITTER: Boyne DJ

PROVIDER: S-EPMC6537824 | 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: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.

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Project description:BackgroundChemotherapy is an established treatment for stage III colon cancer cases. Older age is known to be associated with less chemotherapy use in these patients, but there might be other relevant factors besides age that influence treatment administration. We summarized evidence on associations between comorbidity and adjuvant chemotherapy administration in stage III colon cancer patients in a systematic review and meta-analysis.MethodsWe searched the PubMed and Web of Science databases up to 2 June 2020 for studies on comorbidities and chemotherapy use in patients with stage III colon cancer. Summary odds ratios (OR) and 95% confidence intervals (95% CI) were estimated using random-effects models. Subgroup analyses according to year of colon cancer diagnosis, timing of comorbidity assessment, and geographical region were also conducted.ResultsThirty-three studies were included in this review, including 219,406 stage III colon cancer patients overall. Chemotherapy administration was 60.9% (95% CI: 56.9% to 64.9%), increasing from 57.1% before 2001 to 66.3% after 2010. There were inverse associations between comorbidities and chemotherapy administration. Compared with patients with Charlson comorbidity score 0, those with scores 1 (OR = 0.79, 95% CI = 0.72-0.87) and 2+ (OR = 0.49, 95% CI = 0.42-0.56) received chemotherapy less often. Among comorbidities, the strongest predictors of chemotherapy non-use were dementia (OR = 0.37, 95% CI = 0.33-0.54), followed by heart failure (OR = 0.44, 95% CI = 0.28-0.70) and stroke (OR = 0.56, 95% CI = 0.38-0.81).ConclusionsMerely 60% of stage III colon cancer patients receive chemotherapy. Comorbidities are strong predictors of chemotherapy non-use, but the association differs by comorbid condition and is strongest with dementia. Given the survival disadvantage of colon cancer patients with comorbidities, further evidence on the risk-benefit ratio of chemotherapy according to the type and severity of comorbidity and on the extent to which the survival disadvantage of comorbidity is explained by less use or lower tolerability of chemotherapy is needed to foster personalized medical care in these patients.