Oxaliplatin-based chemotherapy (FOLFOX [folinic acid, fluorouracil, oxaliplatin] or XELOX [oxaliplatin, capecitabine; also called CAPOX]) for 6 months is the current standard for adjuvant therapy of stage III colon cancer patients with good performance status. However, these regimens are associated with significant toxicities, including myelosuppression, diarrhea, and oxaliplatin-induced, cumulative, dose-dependent neurotoxicity. A reduced duration of adjuvant therapy, which would reduce overall toxicity while maintaining overall clinical efficacy, would be optimal. The goal of the International Duration Evaluation of Adjuvant (IDEA) study was to evaluate the noninferiority of 3-month compared with 6-month adjuvant oxaliplatin-based treatment in stage III colon cancer using a prospectively designed pooled analysis of 6 concurrently conducted phase III randomized trials. Herein, we review the findings of the IDEA study and discuss the optimal duration of oxaliplatin-based adjuvant chemotherapy using patient-based risk factors.
Colorectal cancer is the third most common cancer and the second leading cause of cancer death in the United States. Approximately 140,250 new cases of colorectal cancer will be diagnosed in 2018 in the US, and nearly 50,630 patients will die from this disease. Colorectal cancer is also a significant global public health issue, with 1.2 million cases diagnosed and 600,000 associated deaths each year. At the time of initial diagnosis, nearly 40% of colorectal cancer patients present with localized disease. Five-year survival rates vary with the stage at initial diagnosis, reflecting the risk of cancer recurrence after curative surgical resection of the primary tumor.
A significant proportion of stage III colon cancer patients who undergo potentially curative surgical resection develop disease recurrence secondary to clinically occult micrometastatic disease present at the time of surgery. Adjuvant chemotherapy administered after curative surgical resection has the potential to eradicate micrometastatic disease, thereby increasing the chance of cure. The clinical benefits of adjuvant chemotherapy, with respect to prolonging overall survival (OS), have been clearly demonstrated in stage III colon cancer.[4,5] For nearly 15 years, oxaliplatin-based chemotherapy for 6 months, with FOLFOX (folinic acid, fluorouracil [5-FU], oxaliplatin) or XELOX (capecitabine, oxaliplatin; also called CAPOX), has been the standard adjuvant treatment for stage III colon cancer patients who have good performance status and are able to tolerate aggressive combination chemotherapy. However, the administration of oxaliplatin-containing adjuvant chemotherapy for 6 months is associated with several important toxicities, including myelosuppression, gastrointestinal toxicity in the form of mucositis and/or diarrhea, and neurotoxicity. In particular, the oxaliplatin-induced, cumulative, dose-dependent neurotoxicity, which is usually manifested as a peripheral sensory neuropathy, can be a significant issue for patients. A reduced duration of adjuvant oxaliplatin-containing chemotherapy, assuming it maintained the efficacy of adjuvant treatment, would be preferable to reduce overall toxicity and cumulative neurotoxicity.
The International Duration Evaluation of Adjuvant (IDEA) chemotherapy collaboration was a global collaborative effort to evaluate the noninferiority of 3-month vs 6-month oxaliplatin-based adjuvant chemotherapy in patients with stage III colon cancer using a prospectively designed, pooled analysis of 6 concurrently conducted phase III randomized trials.[6,7] We review the recent findings of the IDEA study and discuss the optimal duration of oxaliplatin-based adjuvant chemotherapy for stage III colon cancer patients.
The Role of Fluoropyrimidines and Oxaliplatin in the Adjuvant Treatment of Stage III Colon Cancer
The fluoropyrimidine 5-FU has been the cornerstone of systemic chemotherapy for the management of early-stage and metastatic CRC for over 60 years. The combination of 5-FU and the reduced folate leucovorin (LV) continues to be the main backbone of adjuvant chemotherapy for patients with early-stage colon cancer. The benefit of adjuvant 5-FUâ€“based chemotherapy in stage III colon cancer was established in 1988 by the National Surgical Adjuvant Breast and Bowel Project (NSABP) in the NSABP C-01 trial. This study showed that adjuvant chemotherapy with MOF (5-FU, semustine, and vincristine) conferred a significant disease-free survival (DFS) and OS benefit when compared with surgery alone. Over the next 30 years, 5-FU chemotherapy evolved from schedules involving bolus administration to infusional schedules of 5-FU and leucovorin (LV) in which 5-FU is infused over a period of 46 hours. [10-15] Moreover, the infusional 5-FU and LV regimen (LV5FU2) developed by de Gramont and colleagues in France was adopted as the standard backbone regimen for many subsequent adjuvant combination trials, including the MOSAIC trial.[14,15]
Capecitabine is an oral fluoropyrimidine analog that offers increased convenience and potentially improved therapeutic benefit vs intravenous 5-FU chemotherapy. Single-agent capecitabine was first approved as adjuvant therapy for stage III colon cancer in 2005, based on the results of the Xeloda in Adjuvant Colon Cancer Therapy (X-ACT) study, and this study provided the rationale for using capecitabine as a fluoropyrimidine backbone for combination regimens that included oxaliplatin and other cytotoxic agents.
Oxaliplatin is a third-generation diaminocyclohexane platinum agent, and three large randomized phase III clinical trials-MOSAIC, NSABP C-07, and NO16968 (XELOXA)-have documented the clear benefit of adding oxaliplatin to fluoropyrimidine-based adjuvant therapy in patients with stage III colon cancer.[18-22]
FOLFOX4 was approved by the US Food and Drug Administration in 2004 as a standard treatment regimen for adjuvant chemotherapy in patients with stage III colon cancer. However, most oncologists in the US prefer to use the modified FOLFOX6 (mFOLFOX6) regimen, where only the day 1 bolus 5-FU is administered along with a 46-hour infusion of 5-FU on days 1 and 2. This regimen is more convenient for the patient, and by eliminating the day 2 bolus 5-FU dose, the safety profile is improved; myelosuppression and gastrointestinal toxicities are reduced compared with the standard FOLFOX4 regimen.[23,24] While no clinical study has directly compared FOLFOX4 with mFOLFOX6, the European Society for Medical Oncology (ESMO) clinical practice guidelines and the US National Comprehensive Cancer Network (NCCN) recommend mFOLFOX6 as adjuvant chemotherapy for patients with stage III colon cancer.[25,26] To further reduce toxicity, in particular, the chemotherapy-associated myelosuppression, some clinicians prefer the mFOLFOX7 regimen. With this regimen, only the 46-hour infusion of 5-FU is administered on days 1 and 2, with complete elimination of bolus 5-FU.
To date, no clinical study has directly compared FOLFOX4 or any other FOLFOX regimen with CAPOX in the adjuvant setting. However, a cross-trial comparison suggests that CAPOX provides similar clinical benefit in terms of DFS and OS to that observed with FOLFOX4. As a result, CAPOX is now a standard treatment option for adjuvant chemotherapy in patients with stage III colon cancer.
Shorter Duration of Adjuvant Therapy
Since the initial reports by the NSABP and the North Central Cancer Treatment Group (NCCTG) in the late 1980s and early 1990s on the benefit of adjuvant chemotherapy for stage III colon cancer, there has been a dramatic evolution in the overall duration of adjuvant chemotherapy (Figure). In the NSABP C-01 study, which was the first study to document the clinical benefit of adjuvant chemotherapy in the late 1980s, the MOF regimen was administered for 18 months. INT-0035 was the next important study, in which 5-FU/levamisole was administered for a total of 12 months.[10-15] In all of the adjuvant studies subsequently conducted by the NSABP, 48 weeks was selected as the treatment duration. Haller and colleagues from the US GI Intergroup conducted the landmark INT-0089 study, and concluded that 6 months of 5-FU/LV was equivalent to 12 months of 5-FU plus levamisole. The NCCTG, in collaboration with the National Cancer Institute of Canada, confirmed that 6 months of 5-FU and LV yielded clinical benefit equivalent to 12 months of 5-FU/LV plus levamisole. In Europe, André et al conducted a randomized 2 × 2 factorial study comparing semimonthly infusional LV5FU2 with monthly 5-FU/LV and 24 vs 36 weeks of each adjuvant treatment in patients with stage II/III colon cancer. This study confirmed that semimonthly infusional LV5FU2 was associated with an improved safety profile as compared with monthly 5-FU/LV. Moreover, the clinical benefit was essentially the same for the two treatment groups and the two treatment durations, thus providing further evidence for 6 months as the standard duration for adjuvant therapy.
In the United Kingdom, Chau et al conducted an adjuvant therapy trial of 801 patients with stage II/III colorectal cancer to compare the clinical efficacy of 3-month protracted venous infusion (PVI) of 5-FU (300 mg/m2/d) vs 6-month standard-bolus 5-FU/LV. This trial is somewhat more complicated than the other adjuvant trials because it included patients with both early-stage colon cancer and rectal cancer. Despite the inclusion of rectal cancer patients, the chance of the 3-month treatment being inferior to the 6-month treatment was extremely low (P < .005). With respect to the specific clinical endpoints when comparing bolus 5-FU/LV and PVI 5-FU, the 5-year relapse-free survival (RFS) rates were 66.7% and 73.3%, respectively (P = .10), while the 5-year OS rates were 71.5% and 75.7%, respectively (P = .083). Although not statistically significant, both 5-year RFS and 5-year OS favored the shorter duration of 3 months of PVI 5-FU therapy. Of note, the 3-month PVI 5-FU regimen was associated with significantly reduced overall toxicities: less diarrhea, stomatitis, nausea/vomiting, alopecia, lethargy, and neutropenia compared with 6-month treatment (P < .0001). As noted, despite the inclusion of patients with both early-stage colon cancer and rectal cancer, this is a historically important study, since it provided the first direct evidence for the potential benefit of 3-month adjuvant chemotherapy in the setting of stage III colon cancer.
The IDEA Collaboration
The IDEA collaboration was an international collaboration of clinical investigators and statisticians from six randomized phase III trials: SCOT (Short Course Oncology Treatment), TOSCA (Three or Six Colon Adjuvant), CALGB/SWOG (Cancer and Leukemia Group B/Southwest Oncology Group) 80702, IDEA France, ACHIEVE, and HORG (Hellenic Oncology Research Group).[6,7] The study's objective was to evaluate the noninferiority of 3-month oxaliplatin-based adjuvant treatment vs 6-month treatment in patients with stage III colon cancer using a prospectively designed, pooled analysis of individual patient data from the six concurrently conducted phase III randomized trials (Table). A total of 12,834 patients were enrolled in this study, and the primary endpoint was 3-year DFS. After a median follow-up of 41.8 months, the 3-year DFS rates were 74.6% (95% CI, 73.5-75.7) in the 3-month therapy group and 75.5% (95% CI, 74.4-76.7) in the 6-month group. Based on statistical analysis of the modified intention-to-treat population for the entire cohort of patients from the 6 randomized clinical trials, noninferiority of 3-month to 6-month therapy was not confirmed (hazard ratio [HR], 1.07; 95% CI, 1.00-1.15; P [for noninferiority of 3-month therapy] = .11; P [for superiority of the 6-month therapy] = .045). However, it should be noted that the difference in 3-year DFS was only 0.9%. A subgroup analysis demonstrated that 3-month CAPOX was noninferior to 6-month CAPOX (HR, 0.95; 95% CI, 0.85-1.06), with 3-year DFS rates of 75.9% and 74.8%, respectively. In contrast to CAPOX, 6-month FOLFOX was superior to 3-month FOLFOX (HR, 1.16; 95% CI, 1.06-1.26; P [for superiority of 6-month therapy] = .001), with 3-year DFS rates of 76.0% and 73.6%, respectively.
A preplanned analysis was performed, stratifying patients on the basis of T and N stage. For patients with low-risk features (T1, T2, or T3 and N1), 3-month therapy with the combined treatments of CAPOX and FOLFOX was noninferior to 6-month therapy. The 3-year DFS rates were nearly identical: 83.1% and 83.3%, respectively (HR, 1.01; 95% CI, 0.90-1.12). However, patients with high-risk features (T4, N2, or both) experienced an improved 3-year DFS rate when treated with 6-month combined therapy. DFS rates for the 3-month and 6-month therapies were 62.7% and 64.4%, respectively (HR, 1.12; 95% CI, 1.03-1.23; P [for superiority] = .01). In patients with low-risk features (T1, T2, or T3 and N1), 3-month CAPOX therapy was noninferior to 6-month CAPOX therapy; the 3-year DFS rate was 85.0% vs 83.1%, respectively (HR, 0.85; 95% CI, 0.71-1.01). In contrast, in patients with high-risk features, 6-month FOLFOX therapy was superior to 3-month FOLFOX therapy; the 3-year DFS rate for the 3-month therapy was 61.5%, and for the 6-month therapy, 64.7% (HR, 1.20; 95% CI, 1.07-1.3).
The incidence of toxicities, including diarrhea, neutropenia, thrombocytopenia, nausea, mucositis, fatigue, and hand-foot syndrome, was significantly lower in the 3-month therapy group. Neurotoxicity of grade ≥ 2 during active therapy and in the month after treatment cessation was also substantially lower in the 3-month group (16.6% with FOLFOX and 14.2% with CAPOX) than in the 6-month group (47.7% with FOLFOX and 44.9% with CAPOX).
The IDEA study investigators concluded that noninferiority of 3-month therapy was not confirmed in the overall population of patients with stage III colon cancer receiving adjuvant therapy with FOLFOX or CAPOX. However, in patients treated with CAPOX, 3-month therapy was as effective as 6-month therapy, especially in patients with low-risk features (T1, T2, or T3 and N1). The results of the IDEA study provide strong evidence for individualization of the duration of adjuvant therapy of stage III colon cancer according to the specific adjuvant chemotherapy (CAPOX or FOLFOX) and tumor characteristics (low- vs high-risk features).
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