Original ResearchA new look at the International Duration Evaluation of Adjuvant therapy (IDEA) classification—Defining novel predictive and prognostic markers in stage III colon cancer
Introduction
Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer-related deaths in men and women combined in the United States [1], with nearly 75% of patients diagnosed with non-metastatic diseases (i.e. stage I, II or III). After curative surgery, it is a standard practice to consider doublet oxaliplatin-based adjuvant chemotherapy for stage III disease, although heterogeneity in disease recurrence risk exists. Moreover, patients treated with oxaliplatin are at risk of developing late-onset neuropathy, which may have a profound impact on quality of life, particularly that of cancer survivors. Previous reports demonstrated a correlation between oxaliplatin cumulative doses and both incidence and severity of neurotoxicity [2], [3]. Therefore, there is a need to risk stratify stage III colon cancer patients into different prognostic subgroups to allow a more rational selection of low-risk patients who may not require doublet chemotherapy and high-risk patients who may benefit the most from doublet chemotherapy.
The IDEA (International Duration Evaluation of Adjuvant therapy) pooled analysis presented at the 2017 American Society of Clinical Oncology meeting compared 3 to 6 months of adjuvant chemotherapy for stage III colon cancer. The overarching goal was to reduce chemotherapy-related toxicity, mainly oxaliplatin-induced neuropathy. In an unplanned post hoc analysis, patients were classified into low-risk (T1-3N1) and high-risk (T4 or N2) groups. In the overall population, shorter duration of adjuvant chemotherapy (FOLFOX/CAPOX) demonstrated a less than 1% difference in 3-year disease-free survival. Adjuvant CAPOX for 3 months showed non-inferiority to 6 months in disease-free survival among low- but not high-risk patients. These results led some opinion leaders to consider 3 months of adjuvant treatment as the new standard of care for low-risk stage III patients.
Several known prognostic and predictive factors were not included in the IDEA subgroup classification. Among these factors are primary tumour location (i.e. tumour sidedness), patient age and lymph node ratio (LNR).
Age may predict benefit from doublet adjuvant chemotherapy, although there is no consensus on this matter. Subset analyses of two large phase 3 studies, NSABP C-07 and MOSAIC, showed no benefit for the addition of oxaliplatin to 5-fluorouracil (5-FU) in CRC patients older than 70 years, an arbitrary age cut-point [4], [5]. However, a recent meta-analysis showed an improved outcome for doublet chemotherapy regardless of age [6].
The ratio of tumour-containing lymph nodes to the total number of lymph nodes removed has been suggested as a prognostic factor in some, but not all, studies [7], [8]. In addition, tumour sidedness is prognostic in stage III disease, as right-sided tumours have increased mortality relative to left-sided disease [9], [10], [11].
We speculated that IDEA risk classification combined with additional clinical and pathological parameters may further guide decision-making in the adjuvant setting, allowing omission of oxaliplatin in specific subpopulations. To our knowledge, there are no population-level data on the prognostic and predictive value of these factors when combined within the IDEA analysis defined risk groups. In this study, we used a nationwide oncology data set to examine the magnitude of survival differences between IDEA risk groups according to treatment intensity (doublet versus monotherapy), and by subgroups of age, LNR and sidedness.
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Data source and patient population
Our cohort was derived from the National Cancer Database (NCDB), a hospital-based cancer registry, from 2004 to 2014. The NCDB captures data on 70% of cancer diagnoses in the United States from >1400 hospitals with cancer programmes accredited by the American College of Surgeons' Commission on Cancer and American Cancer Society [12].
All individuals with pathological stage II (T3-4N0M0) and stage III (TanyN1-2M0) colon cancer who received adjuvant chemotherapy were identified. Similar to the
Patient characteristics
We identified 31,344 and 104,285 individuals with stage II and stage III colon cancer, respectively, treated with adjuvant chemotherapy. Among patients with stage III colon cancer, we identified 56,728 and 47,557 patients in the low and high IDEA risk groups, respectively. Patients in both risk groups had similar baseline characteristics, including age, sex, race and Charlson-Deyo comorbidity condition (Supplementary Table 1). Right-sided and poorly differentiated tumours were more prevalent in
Discussion
In this study, we demonstrate similar benefit for monotherapy versus doublet chemotherapy in both low and high IDEA risk groups using a nationwide oncology data set. However, IDEA low-risk patients older than 72 years did not appear to benefit from the addition of oxaliplatin to the adjuvant chemotherapy regimen. Both high LNR and right-sided tumours had worse prognosis irrespective of IDEA risk group.
The IDEA analysis suggested lack of benefit for continuing adjuvant chemotherapy for 6 months
Funding
None.
Conflict of interest statement
None declared.
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Cited by (5)
Preliminary tolerance analysis of adjuvant chemotherapy in older patients after resection of stage III colon cancer from the PRODIGE 34-FFCD randomized trial
2023, Digestive and Liver DiseaseCitation Excerpt :However, another study that retrospectively assessed four other trials, showed better DFS and overall survival (OS) in patients over 70 receiving oxaliplatin than in those treated with fluoropyrimidine alone after resection of stage III colon cancer [11]. Moreover, a large database analysis concluded that doublet chemotherapy was not superior to fluoropyrimidine monotherapy in patients over 72 years old with low-risk stage III colon cancer [12]. The tolerance of adjuvant oxaliplatin-based chemotherapy in older patients was not increased in selected patients 70 years and older, compared to younger patients in the pooled analysis of Haller et al. [11].
Benefit of Oxaliplatin in Stage III Colon Cancer According to IDEA Risk Groups: Findings from the ACCENT Database of 4934 Patients
2021, Clinical Colorectal CancerCitation Excerpt :Among individuals with IDEA high risk, those with T4 disease did not gain OS benefit from addition of oxaliplatin (HR of 0.95, 95% CI, 0.71-1.27). Of note, the present study also confirms our previously published results using a retrospective nationwide dataset suggesting that both low- and high-risk IDEA groups benefit from oxaliplatin addition.17 We further investigated the effect of oxaliplatin among subgroups of IDEA high-risk patients.
Is Radical Surgery Alone Enough in T1-3N1a Colon Cancer?
2020, Frontiers in OncologyMaking sense of adjuvant chemotherapy in colorectal cancer
2019, Journal of Gastrointestinal Oncology
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These authors contributed equally to the manuscript.