Background
Since the MOSAIC trial, the standard of care for patients with resected stage III colon cancer has been treatment with 6 months of adjuvant FOLFOX (fluorouracil/leucovorin/oxaliplatin) chemotherapy.1–3 In this patient population, the addition of oxaliplatin to 5-FU confers a 5% improvement in 3-year disease-free survival (DFS) benefit and an 8% increase in 10-year overall survival (OS).4 However, oxaliplatin is associated with significant treatment-related adverse effects (trAEs), including neutropenia, thrombocytopenia, and permanent peripheral neuropathy, that may limit the clinical benefits of FOLFOX chemotherapy.5
Given the need to balance survival outcomes with toxicity, the IDEA collaboration aimed to evaluate the efficacy of a shorter duration of adjuvant chemotherapy. Six concurrent multicenter randomized phase III trials were conducted across 12 countries, comparing 3 versus 6 months of adjuvant fluoropyrimidine-based chemotherapy (FOLFOX or CAPOX [capecitabine/oxaliplatin]).6 The primary endpoint was DFS, and noninferiority was met if the upper limit of the 2-sided 95% confidence interval of the hazard ratio (HR) was not greater than 1.12.6 Although the study failed to meet its primary endpoint (HR, 1.07; 95% CI, 1.00–1.15), the results of the exploratory subgroup analysis have suggested potential practice changes in the prescribing of adjuvant chemotherapy. Among patients with low-risk colon cancer (T1–3 and N1 disease), 3 months of therapy was noninferior to 6 months (HR, 1.01; 95% CI, 0.90–1.12), with 3-year DFS of 83.1% versus 83.3%, respectively.6 However, among patients with high-risk disease (T4 or N2 or both), DFS favored 6 months over 3 months of treatment (HR, 1.12; 95% CI, 1.03–1.23), which translated to an absolute difference in 3-year DFS of 1.7% (64.4% vs 62.7%, respectively).6 Although the study was not designed to compare treatment regimens, in subsequent analysis, 3 months of CAPOX was noninferior to 6 months of CAPOX (3-year DFS, 75.9% vs 74.8%; HR, 0.95; 95% CI, 0.85–1.06), whereas 6 months of FOLFOX was superior to 3 months of FOLFOX (3-year DFS, 73.6% vs 76.0%; HR, 1.16; 95% CI, 1.06–1.26). In the updated analysis reporting 5-year OS outcomes, 6 months of chemotherapy resulted in a 0.4% higher 5-year OS rate compared with 3 months of chemotherapy (82.8% vs 82.4%).7 The noninferiority of 3 versus 6 months of chemotherapy in terms of OS was not confirmed in the overall population (HR, 1.02; 95% CI, 0.95–1.11; noninferiority P=.058) or in any of the subgroups examined.
When evaluating safety outcomes of the IDEA collaboration, lower rates of trAEs, including diarrhea, neutropenia, thrombocytopenia, mucositis, fatigue, and hand–foot syndrome, were observed with 3 months compared with 6 months of adjuvant chemotherapy. The incidence of grade ≥2 neurotoxicity was significantly lower among patients who received 3 months of therapy, regardless of treatment regimen (FOLFOX, 16.6% vs 47.7%; CAPOX, 14.2% vs 44.9%).6 Despite not establishing noninferiority of 3 months of adjuvant therapy in the overall population, the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Colon Cancer include the recommendation of 3 to 6 months of adjuvant chemotherapy based on risk stratification.8 This recommendation acknowledges the need to minimize risk of trAEs when expected survival benefits from a longer duration of therapy are nominal.
In our study, we aimed to evaluate prescribing practice patterns, including planned adjuvant treatment regimen and duration, before the abstract presentation of the IDEA collaboration in June 2017 and after full article publication in March 2018.6 Given the results of the IDEA collaboration, we hypothesized that CAPOX use would increase and that shorter planned duration of therapy would be more prevalent over the study period.
Patients and Methods
Analysis Population
Patients seen at Mayo Clinic (including all 3 sites and health systems) and the Emory University Health System were included. Patients’ electronic health records were first filtered based on the following criteria: (1) ICD-9 or ICD-10 codes for colon cancers; (2) diagnosis date of January 1, 2016, or later; and (3) receipt of oxaliplatin within the health system. After filtering, candidate records were further reviewed by the investigators to ensure that patients included in this study were diagnosed with stage III colon cancer and received adjuvant chemotherapy with either CAPOX or FOLFOX. Patients who received the first dose of chemotherapy between January 1, 2016, and January 31, 2021, were included in the analysis. Patients’ demographic and disease characteristics, treatment details (including chemotherapy regimen, intended duration, and dose reductions), trAEs, recurrence status, last disease evaluation date, mortality status, and last follow-up date were extracted from medical records (by D.J. Walden, S. King, J.J. Larson, C.R. Griswold, B.E. Ueberroth, B. Patel, A. Draper, P. Raman) and stored in a REDCap database. Institutional Review Board exempt status was granted for both institutions (Mayo Clinic and Emory University).
Outcomes
Outcomes of interest included chemotherapy regimen prescribed (CAPOX vs FOLFOX); planned therapy duration (3 vs 6 months); and the overall treatment strategy—that is, the combination of chemotherapy and duration (3 months of CAPOX, 6 months of CAPOX, 3 months of FOLFOX, and 6 months of FOLFOX).
Statistical Analyses
Baseline clinical characteristics were compared between patients receiving CAPOX and those receiving FOLFOX. Continuous variables were presented as medians with interquartile percentiles, whereas categorical variables were expressed as counts and percentages. Univariate comparisons were performed using Wilcoxon rank-sum tests for continuous variables and Pearson chi-square tests for categorical variables. The Cochran-Armitage test for trend was used when comparing the prescribing percentage over time. To visually evaluate the prescribing pattern over time, a simple moving average (with a window of 180 days) was used to create the prescribing percentage and graphed against the date of first therapy dose. Logistic regression with logit link and generalized logit link was used for multivariable analysis with binary outcomes (ie, chemotherapy of choice and therapy duration) and 4-level categorical outcome (ie, treatment strategy), respectively. The therapy initiation day (defined as the date of first therapy dose minus January 1, 2016) was used as the dependent variable in the model. To aid interpretability, the therapy initiation day was scaled to calendar quarter; therefore, the odds ratio (OR) should be interpreted as “per calendar quarter increase.” Covariates included in the multivariable models were age, sex, race, ECOG performance status, and risk group. The risk group included 2 categories: low risk was defined as T1–3/N1 tumor, and high risk was defined as either T4 or N2 tumor. Subgroup analysis was performed by incorporating an interaction term between the dependent variable and the subgroup of interest in the multivariable logistic model. The likelihood ratio test was used to test the significance of the interaction term. A P<.05 was considered statistically significant, except for interaction terms, for which P<.10 was considered statistically significant. Raw P values are reported without multiple comparison adjustments. All statistical analyses were performed using R statistical software (version 4.0.3; R Foundation for Statistical Computing).
Results
A total of 399 patients with stage III colon cancer were included (Figure 1); 126 (31.6%) had a planned chemotherapy duration of 3 months, and 273 (68.4%) had a planned chemotherapy duration of 6 months. Patient characteristics were compared between planned therapy durations (Table 1). White patients and those with high-risk cancers (T4 or N2 or both) were more likely to receive 6 months of therapy (Table 1). Patient characteristics were also compared between chemotherapy of choice (supplemental eTable 1, available with this article at JNCCN.org) and treatment strategy (supplemental eTable 2). Patients with high-risk cancers were more likely to receive FOLFOX (supplemental eTable 1). No other statistically significant differences were observed for race and risk group.
Analysis population.
Abbreviations: CAPOX, capecitabine/oxaliplatin; FOLFOX, fluorouracil/leucovorin/oxaliplatin.
Citation: Journal of the National Comprehensive Cancer Network 21, 8; 10.6004/jnccn.2023.7028
Analysis population.
Abbreviations: CAPOX, capecitabine/oxaliplatin; FOLFOX, fluorouracil/leucovorin/oxaliplatin.
Citation: Journal of the National Comprehensive Cancer Network 21, 8; 10.6004/jnccn.2023.7028
Analysis population.
Abbreviations: CAPOX, capecitabine/oxaliplatin; FOLFOX, fluorouracil/leucovorin/oxaliplatin.
Citation: Journal of the National Comprehensive Cancer Network 21, 8; 10.6004/jnccn.2023.7028
Patient Characteristics by Planned Duration of Chemotherapy
Three months of therapy duration was rarely prescribed (5.6%) before IDEA abstract presentation (June 4, 2017) and became almost as common as 6 months of therapy duration after full manuscript publication (March 29, 2018; 45.2%), revealing a significant increasing trend (P<.001) (Table 2). CAPOX was prescribed in 14.0% of patients before IDEA abstract presentation, and rates increased significantly to 48.0% after IDEA full manuscript publication (P<.001) (Table 2). The prescribing patterns of different treatment strategies (ie, chemotherapy regimen and duration combination) over the different time periods are shown in Table 2, where a decrease in FOLFOX for 6 months (82.2% before IDEA abstract presentation and 42.1% after full article publication) and an increase in CAPOX for 3 months (1.9% before IDEA abstract presentation and 35.3% after full article publication) were observed (P<.001).
Prescribing Patterns Over Time
The prescribing pattern changes for chemotherapy regimen and duration as a function of the date of the first dose are shown in Figure 2. CAPOX was more likely to be prescribed over time compared with FOLFOX (multivariable adjusted odds ratio [aOR], 1.16; 95% CI, 1.11–1.21; P<.001). Similarly, the likelihood of prescribing 3 months of therapy increased over the study period (aOR, 1.19; 95% CI, 1.14–1.26; P<.001). Comparing 3 months of CAPOX with 6 months of FOLFOX, 3 months of CAPOX use steadily increased over time (aOR, 1.28; 95% CI, 1.20–1.37; P<.001).
Prescription pattern changes over time by (A) chemotherapy, (B) planned therapy duration, and (C) treatment strategy (combination of chemotherapy and therapy duration). The 2 vertical dashed lines indicate IDEA collaboration abstract presentation at the 2017 ASCO Annual Meeting (June 2–6, 2017) and the full manuscript publication (March 29, 2018). The gray zones indicate the interval from the first US patient diagnosed with COVID-19 to the first stay-at-home order (California).
Abbreviations: CAPOX, capecitabine/oxaliplatin; FOLFOX, fluorouracil/leucovorin/oxaliplatin.
Citation: Journal of the National Comprehensive Cancer Network 21, 8; 10.6004/jnccn.2023.7028
Prescription pattern changes over time by (A) chemotherapy, (B) planned therapy duration, and (C) treatment strategy (combination of chemotherapy and therapy duration). The 2 vertical dashed lines indicate IDEA collaboration abstract presentation at the 2017 ASCO Annual Meeting (June 2–6, 2017) and the full manuscript publication (March 29, 2018). The gray zones indicate the interval from the first US patient diagnosed with COVID-19 to the first stay-at-home order (California).
Abbreviations: CAPOX, capecitabine/oxaliplatin; FOLFOX, fluorouracil/leucovorin/oxaliplatin.
Citation: Journal of the National Comprehensive Cancer Network 21, 8; 10.6004/jnccn.2023.7028
Prescription pattern changes over time by (A) chemotherapy, (B) planned therapy duration, and (C) treatment strategy (combination of chemotherapy and therapy duration). The 2 vertical dashed lines indicate IDEA collaboration abstract presentation at the 2017 ASCO Annual Meeting (June 2–6, 2017) and the full manuscript publication (March 29, 2018). The gray zones indicate the interval from the first US patient diagnosed with COVID-19 to the first stay-at-home order (California).
Abbreviations: CAPOX, capecitabine/oxaliplatin; FOLFOX, fluorouracil/leucovorin/oxaliplatin.
Citation: Journal of the National Comprehensive Cancer Network 21, 8; 10.6004/jnccn.2023.7028
The prescribing pattern changes over time in specific subgroups of interest are shown in Figure 3. No differences in adoption of CAPOX were seen across the subgroups examined (Figure 3A). There were no differences in adoption of 3 months of therapy in most of the subgroups (Figure 3B), except race, where the transition toward prescribing 3 months of chemotherapy was adopted significantly earlier in Black patients (aOR, 1.55; 95% CI, 1.17–2.05) than in white patients (aOR, 1.19; 95% CI, 1.13–1.26; P=.034 for interaction). Similarly, there were no differences in use of treatment strategy (ie, chemotherapy and duration combination) in most subgroups (Figure 3C), except race (P=.092 for interaction), where the adoption of 3 months of CAPOX was faster in Black patients (aOR, 1.63; 95% CI, 1.18–2.25) than in white patients (aOR, 1.30; 95% CI, 1.21–1.40). Interestingly, the adoption of 3 months of CAPOX was similar in patients with low-risk cancer (aOR, 1.27; 95% CI, 1.17–1.37) and those with high-risk cancer (aOR, 1.31; 95% CI, 1.16–1.47).
Prescription pattern changes over time in subgroups of interest. Odds ratios predicting receipt of (A) CAPOX versus FOLFOX and (B) 3-month planned duration versus 6-month planned duration of therapy, and (C) treatment strategy versus 6-month FOLFOX.
Abbreviations: CAPOX, capecitabine/oxaliplatin; FOLFOX, fluorouracil/leucovorin/oxaliplatin.
aOdds ratio is interpreted as the odds of receiving the regimen and duration indicated compared with the odds of receiving FOLFOX for 6 months per calendar quarter increase.
bLow risk: T1–3 and N1; high risk: T4 or N2.
Citation: Journal of the National Comprehensive Cancer Network 21, 8; 10.6004/jnccn.2023.7028
Prescription pattern changes over time in subgroups of interest. Odds ratios predicting receipt of (A) CAPOX versus FOLFOX and (B) 3-month planned duration versus 6-month planned duration of therapy, and (C) treatment strategy versus 6-month FOLFOX.
Abbreviations: CAPOX, capecitabine/oxaliplatin; FOLFOX, fluorouracil/leucovorin/oxaliplatin.
aOdds ratio is interpreted as the odds of receiving the regimen and duration indicated compared with the odds of receiving FOLFOX for 6 months per calendar quarter increase.
bLow risk: T1–3 and N1; high risk: T4 or N2.
Citation: Journal of the National Comprehensive Cancer Network 21, 8; 10.6004/jnccn.2023.7028
Prescription pattern changes over time in subgroups of interest. Odds ratios predicting receipt of (A) CAPOX versus FOLFOX and (B) 3-month planned duration versus 6-month planned duration of therapy, and (C) treatment strategy versus 6-month FOLFOX.
Abbreviations: CAPOX, capecitabine/oxaliplatin; FOLFOX, fluorouracil/leucovorin/oxaliplatin.
aOdds ratio is interpreted as the odds of receiving the regimen and duration indicated compared with the odds of receiving FOLFOX for 6 months per calendar quarter increase.
bLow risk: T1–3 and N1; high risk: T4 or N2.
Citation: Journal of the National Comprehensive Cancer Network 21, 8; 10.6004/jnccn.2023.7028
Discussion
The IDEA collaboration aimed to determine whether 3 months of adjuvant chemotherapy was noninferior to 6 months. Although the prespecified noninferiority margin was not met, exploratory (post hoc) subgroup analyses revealed several clinically relevant findings. Notably, in patients with low-risk disease, 3 months of therapy was noninferior to 6 months of therapy. However, in those with high-risk disease, 6 months of therapy was superior to 3 months, where the observed clinical benefit was a 1.7% improvement in 3-year DFS (64.4% vs 62.7%).6 When examining the differences between treatment regimens, 3 months of CAPOX was noninferior to 6 months of CAPOX in all patients (3-year DFS, 75.9% vs 74.8%), whereas noninferiority was not proved in high-risk patients (HR, 1.02; 95% CI, 0.89–1.17). For patients who received FOLFOX, 6 months of FOLFOX was found to be superior to 3 months of FOLFOX in all patients (3-year DFS, 76% vs 73.6%) and in those with high-risk disease (3-year DFS, 64.7% vs 61.5%) but was not superior in low-risk disease (HR, 1.10; 95% CI, 0.96–1.26). Our study aimed to evaluate whether prescribing practices of adjuvant chemotherapy in patients with resected stage III colon cancer changed over time, incorporating patients treated before and after the initial presentation of the IDEA collaboration data at ASCO in June 2017 and subsequent full article publication in March 2018.
Since the IDEA collaboration, we observed significant changes in prescribing patterns with an increase in the prescribing of CAPOX (Table 2, Figure 2) and shorter duration of adjuvant chemotherapy (3 vs 6 months). Several factors likely contributed to the increased use of CAPOX. In patients with low-risk disease, this was probably attributable to the findings from the exploratory (post hoc) subgroup analysis of the IDEA collaboration demonstrating noninferiority. In addition, for patients with high-risk disease, we report a decrease in prescribing FOLFOX for 6 months (82.2% to 42.1%) in favor of CAPOX. We noted an earlier adoption of 3 months of chemotherapy among Black patients than in white patients. One consideration may be racial and ethnic differences in the incidence of capecitabine-related toxicities9; however, the findings are limited to the small number of Black patients in our study.
An additional consideration that may have impacted CAPOX prescribing patterns was COVID-19, where the increased use of adjuvant CAPOX was intended in part to reduce the frequency of possible patient exposures and decrease patient volume in the infusion center. However, recent data suggest that capecitabine use did not significantly change across gastrointestinal malignancies during this time period.10,11
Despite the observed changes in prescribing patterns, FOLFOX was still used more frequently than CAPOX (52.0% vs 48.0%) by January 31, 2021. CALBG/SWOG 80702, the one US-based trial included in the IDEA collaboration, used adjuvant FOLFOX chemotherapy exclusively12; difficulties extrapolating results of CAPOX use to a US-based practice site may account for the limited CAPOX use in this setting. Survey-based studies that evaluated prescribing trends suggest that the preference for FOLFOX is confined to the United States, with 75% of prescribers from Europe/Asia prescribing CAPOX but 75% of American prescribers preferentially using FOLFOX in the adjuvant treatment of colon cancer.13 The US preference for FOLFOX is associated with the improved tolerability of 5-FU over capecitabine. A retrospective trial comparing fluoropyrimidine tolerability in the United States, East Asia, and the rest of the world revealed that US patients tolerate capecitabine the poorest, with the highest incidence of grade 3 gastrointestinal adverse effects (37%) compared with East Asia (8%) and the rest of the world (23%). In addition, grade ≥3 palmar-plantar erythrodysesthesia occurs more frequently in US patients (11% vs 1% East Asia vs 5% rest of the world), as do other serious trAEs (23% vs 5% vs 16%, respectively).14 The observed difference in tolerability is likely related to the prevalence of folate supplementation in US-based diets compared with Europe/Asia, resulting in a higher baseline serum folate level.15 Folate stabilizes the interaction between the prodrug intermediate fluorodeoxyuridine monophosphate to thymidylate synthase, the enzyme responsible for conversion to the active drug 5-FU. In vitro and clinical data suggest that serum folate concentrations are associated with increased toxicity with fluoropyrimidines.16,17 Numerous studies evaluating patients with colorectal cancer identified pretreatment serum folate levels as an independent predictor for grade 3 toxicity, possibly leading to dosing modifications or discontinuation.18,19
Notable changes in treatment duration have been seen since the initial IDEA abstract presentation and subsequent publication. In our analysis, only 5.6% of patients received 3 months of adjuvant therapy prior to IDEA, increasing to 28.2% after the abstract presentation and to 45.2% after the full article publication. A similar change in use of 6 months’ duration of adjuvant chemotherapy was seen, decreasing from 94.4% before IDEA collaboration abstract presentation to 71.8% after abstract presentation and 54.8% after full article publication. Most of this reduction is attributable to the 6 months of FOLFOX subgroup, which decreased from 82.2% before to 42.1% after the IDEA collaboration. Furthermore, an increase in 3 months’ duration of adjuvant chemotherapy was primarily due to increased use of CAPOX, which increased from 1.9% to 35.3% before and after the IDEA collaboration, respectively (Table 2).
Here we report the first retrospective analysis of real-world prescribing trends after the publication of the IDEA collaboration across 4 US academic medical centers. Prior studies evaluating changes in prescribing practices since the IDEA collaboration have been confined to survey-based approaches, many of which were performed within 6 months of the ASCO presentation.20,21 Our findings suggest that providers are now prescribing shorter durations of therapy and with an increase in CAPOX use, particularly in patients with low-risk disease; a similar trend was seen in other recent studies.13,22,23 Additional prospective trials evaluating outcomes in high-risk patients receiving 3 months CAPOX versus 3 months of CAPOX followed by 3 months of capecitabine versus 6 months of CAPOX would be of value to determine the relative benefit of such strategies in this at-risk population. KCSG CO09-07, a randomized phase III noninferiority trial, compared 3 and 6 months of oxaliplatin with 6 months of fluoropyrimidine in patients with high-risk stages II and III colorectal cancer, with the primary endpoint of DFS.23 Similarities in 3-year DFS were observed in the 6-month (83.7%) and 3-month (84.7%) arms, with an HR of 0.953 (95% CI, 0.769–1.180), which was within the noninferiority margin, suggesting noninferior outcomes with 3 months of oxaliplatin compared with 6 months of capecitabine. One limitation of these findings was that the study population was limited to one country and may not be reflective of Western patients.
Limitations of our study include the lack of multiple comparison control, the retrospective nature, and the practice setting, given that all participating sites in our study are academic medical centers. No multiple comparison control was performed because the goal was to identify practice patterns rather than hypothesis testing. Providers at academic medical centers may be aware of pivotal data prior to full publication and adopt practice changes sooner than those practicing in community settings; thus, our study may not accurately reflect the majority of prescribing practices in the United States. Our planned follow-up study will evaluate clinical outcomes in resected stage III colon cancer with adjuvant chemotherapy, including clinical outcomes associated with oxaliplatin discontinuation in a US-based patient population.
Conclusions
Despite the IDEA collaboration failing to demonstrate noninferiority of 3 months’ duration of adjuvant therapy compared with 6 months, the findings have influenced practice prescribing patterns, favoring CAPOX and a shorter duration of planned adjuvant treatment.
References
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