Elsevier

European Journal of Cancer

Volume 96, June 2018, Pages 105-110
European Journal of Cancer

Original Research
A new look at the International Duration Evaluation of Adjuvant therapy (IDEA) classification—Defining novel predictive and prognostic markers in stage III colon cancer

https://doi.org/10.1016/j.ejca.2018.03.022Get rights and content

Highlights

  • International Duration Evaluation of Adjuvant Therapy (IDEA) pooled analysis compared 3 to 6 months of adjuvant chemotherapy in stage III colon cancer.

  • IDEA risk classification per se does nor predict for benefit from doublet chemotherapy in stage III colon cancer.

  • Omission of oxaliplatin can be considered in IDEA low-risk patients older than 72 years.

Abstract

Background

The International Duration Evaluation of Adjuvant therapy (IDEA) pooled analysis 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. Patients were classified into low-risk and high-risk groups, suggesting that low-risk patients may be offered only 3 months of treatment. We aimed to evaluate the benefit of monotherapy versus doublet chemotherapy in low and high IDEA risk groups.

Methods

Using the National Cancer Database (2004–2014), we identified 56,728 low-risk and 47,557 high-risk individuals with stage III colon cancer, according to the IDEA classification. We used multivariate Cox regression to evaluate the magnitude of survival differences between IDEA risk groups, according to treatment intensity (doublet versus monotherapy). In a secondary analysis, we examined the prognostic and predictive value of subgroups of age, tumour sidedness and lymph node ratio (LNR).

Results

Low and high IDEA risk groups derived similar benefit from doublet adjuvant chemotherapy as compared with monotherapy, with hazard ratios (HRs) of 0.83 (95% confidence interval [CI] 0.79–0.86) and 0.80 (95% CI 0.78–0.83), respectively. The only subpopulations that did not benefit from doublet chemotherapy were low-risk patients older than 72 years (HR = 0.95, 95% CI 0.90–1.01) and high-risk patients older than 85 years (HR = 0.90, 95% CI 0.77–1.05). LNR and tumour sidedness were shown as additional prognostic, but not predictive, factors within the IDEA risk groups.

Conclusions

IDEA risk classification per se does not predict for treatment benefit from doublet chemotherapy in stage III colon cancer. However, omission of oxaliplatin can be considered in IDEA low-risk patients older than 72 years.

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.

Section snippets

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.

References (20)

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1

These authors contributed equally to the manuscript.

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