IDEA International Collaborative Group Study is a prospective Phase III summary analysis study, which includes 6 studies aimed at exploring whether the duration of dual adjuvant chemotherapy can be reduced from 6 months to 3 months for patients with stage III and high-risk Stage II colon cancer. Recently, Timothy J. Iveson of University Hospital of Southampton, and his colleagues published the latest data from the IDEA study on J Clin Oncol. The results suggest that 3-month capecitabine and oxaliplatin (CAPOX) may be the treatment options for some high-risk stage II colon cancer patients [1].
Oxaliplatin plus fluorouracil has been shown to improve the efficacy of adjuvant chemotherapy in patients with colon cancer [2-4]. The first two studies included patients with stage II and stage III colon cancer: in the MOSAIC study, 40% of patients were in stage II, while in the NSABP CO-07 study, 28% were in stage II [2,3]. Based on these studies, adjuvant treatment for 6 months using FOLFOX protocol ( fluorouracil , foliote, oxaliplatin ) or CAPOX protocol (capecitabine and oxaliplatin) became the standard treatment for stage III colon cancer. However, it has been recognized that oxaliplatin can lead to significant accumulation and persistent neurotoxicity, so a prospective international collaborative group study of the IDEA (International Duration Evaluation of Adjuvant Chemotherapy) was conducted, which included six studies conducted in 11 countries around the world, aiming to explore whether the duration of adjuvant chemotherapy can be shortened from 6 months to 3 months for patients with stage III and high-risk stage II colon cancer to reduce toxicity without affecting efficacy. Previous research results on stage III colon cancer have been published [5].
Recently, adjuvant chemotherapy for high-risk stage II patients with bowel cancer has changed, and single-drugicil is usually given. For patients with stage II and III colon cancer, although the risk ratio (HR) of oxaliplatin to improve disease-free survival (DFS) is similar [2], for high-risk stage II colon cancer, the addition of oxaliplatin on the basis of fluorouracil did not improve the overall survival (OS) of patients [6]. Of the 6 studies studied by IDEA International Collaborative Group, 4 studies included high-risk patients with stage II disease. This paper summarizes and analyzes the data of high-risk stage II bowel cancer patients in four studies jointly conducted by IDEA.
analysis included 3273 high-risk stage II bowel cancer patients. These patients received either FOLFOX regimen (38% of patients) or CAPOX (62% of patients) and were randomly assigned for 3-month or 6-month treatment, depending on the choice of the doctor or patient. The primary endpoint was disease-free survival (DFS), and the results satisfie non-inferiority (NI) if the bilateral 80% CI of DFS hazard ratio (HR) (3 months vs. 6 months) estimated by the stratified Cox model is less than 1.2. To achieve 80% of the effectiveness, a total of 542 DFS events were needed to determine NI.
Figure 1. Consort flow chart (cited from published article)
efficacy results
- 5 DFS data
mITT research population Kaplan-Meier diagram of DFS is shown in Figure 2. A total of 553 DFS events were observed, exceeding the 542 DFS events required to achieve 80% effectiveness. Among high-risk patients with stage II bowel cancer, the 5-year DFS in the 3-month treatment group was 80.7%, and the 5-year DFS in the 6-month treatment group was 83.9% (HR=1.17, 80% CI: 1.05~1.31).
Figure 2. Kaplan-Meier estimates of DFS in mITT study population (cited from published article)
study overall did not show non-inferiority of the 3-month regimen (P=0.39), but here we see the same treatment effect as stage III bowel cancer. The results of the stage III bowel cancer analysis were originally published at the 2017 ASCO Annual Meeting and were published in the New England Journal of Medicine in 2018. The latest analysis is similar to those in stage III colon cancer patients. In stage III colon cancer patients, the non-inferiority of 3-month adjuvant chemotherapy has not been confirmed. However, the CAPOX regimen was non-inferiority compared with the 6-month group (HR 0.95; 95% CI: 0.85~1.06), while the FOLFOX regimen showed no non-inferiority compared with the 6-month group. This result is surprising.
- Subgroup analysis
Subgroup analysis was performed according to four variables: chemotherapy regimen (CAPOX vs. FOLFOX), T stage (T4 vs. T1-3), hypodifferentiated tumor (yes or no), and insufficient lymph node dissection (Figure 3).In the subgroup analysis of high-risk stage II colon cancer, chemotherapy regimen was the only subgroup with significant differences in treatment time. The HR of the CAPOX group was 1.02 (80%CI: 0.88~1.17), and the HR of the FOLFOX group was 1.41 (80%CI: 1.18~1.68). The 5-year disease-free survival rate for CAPOX treatment for 3 months was 81.7%, while the 6-month survival rate was 82.0%. This is only a 0.3% difference. After adjusting for multiple comparison factors, the results did not achieve statistical significance of non-inferiority. Figure 4 shows the Kaplan-Meier curves for CAPOX and FOLFOX (80%CI and 95%CI cases).
Figure 3. Forest graph of preset subgroup analysis (cited from published articles)
Figure 4. Kaplan-Meier curves of CAPOX and FOLFOX (80% CI and 95% CI) (cited from published articles)
- Effect of high-risk factors on DFS
Researchers used data from three studies with high-risk factors to conduct an exploratory analysis of the impact of high-risk factors on DFS. The results showed that patients with two or more risk factors had significantly worse DFS than patients with only one risk factor (74.8% vs. 87.3%); the prognosis of high-risk stage II T4 colon cancer patients is worse than that of T3 colon cancer patients. Clinicians can begin to use this data to help make treatment decisions.
- Adverse Events
The patients randomly assigned to the 6-month treatment group had significantly more adverse events than those in the 3-month treatment group, especially diarrhea, peripheral neuropathy, hand and foot syndrome, and mucositis. Among patients treated with 3-month and 6-month treatment, grade II peripheral neuropathy was 13% and 36%, respectively. If peripheral neuropathy reaches this level, it usually lasts for a long time and significantly affects the quality of life.
Given that the difference in disease-free survival of CAPOX for 3 months and 6 months of treatment is very small, and the toxicity is significantly smaller during the 3 month of treatment, it is possible to consider using 3 months of CAPOX in patients with high-risk stage II colon cancer.
For the FOLFOX regimen, the 5-year DFS rate for 3 months was 79.2%, while the 6-month DFS rate was 86.5%. Since chemotherapy is poor at 3 months and chemotherapy is significantly more toxic, for the FOLFOX regimen, neither chemotherapy time is recommended.
Summary
6-month CAPOX regimen is an option for high-risk stage II colon cancer. The latest analysis from the IDEA study showed that for patients with high-risk stage II colon cancer, the CAPOX regimen showed no non-inferiority in the overall study population of 3 months vs. 6 months (5-year DFS rate was 80.7% vs. 83.9% respectively); the continued effect of adjuvant chemotherapy depends on the chemotherapy regimen, and adjuvant chemotherapy was more toxic, which is consistent with the analysis results in patients with stage III colon cancer. In addition, the prognosis of patients with stage T4 or high-risk stage II colon cancer with two or more risk factors is even worse.
Therefore, 3-month CAPOX regimen adjuvant treatment can be considered an option for some high-risk stage II colon cancer patients.
For patients with high-risk stage II colon cancer, the dosage of oxaliplatin is a problem, and clinicians now have a choice. If you want to give oxaliplatin only for 3 months, you can consider giving CAPOX regimen to these patients; if you decide not to give oxaliplatin, you can choose to have capecitabine or fluorouracil. Since there is no data on the duration of the regimen, the authors recommend that treatment be performed for 6 months.
In addition, stage T4 colon cancer or stage II high-risk patients with two or more risk factors can gain more benefits from oxaliplatin treatment. If the decision is made to administer oxaliplatin plus fluorouracil to the patient, a 3-month CAPOX regimen can be selected instead of a 6-month monotherapy fluorouracil.
Reference
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. Iveson TJ, Sobrero AF, Yoshino T, et al. Duration of adjuvant doublet chemotherapy (3 or 6 months) in patients with high-risk stage II colorectal cancer. J Clin Oncol.2021;39:631-641.
5. Grothey A, Sobrero AF, Shields AF, et al: Duration of adjuvant chemotherapy for stage III colon cancer. N Engl J Med 378:1177-1188, 2018.
6. Tournigand C, Andre T, Bonnetain F, et al: Adjuvant therapy with fluorouracil and oxaliplatin in stage II and elderly patients (between ages 70 and 75 years) with colon cancer: Subgroup analyzes of the Multicenter International Study of Oxaliplatin, Fluorouracil, and Leucovorin in the Adjuvant Treatment of Colon Cancer trial. J Clin Oncol 30:3353-3360, 2012.
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