The Adjuvant Treatment of Stage III Colon Cancer: Might Less Be More?

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.

Introduction

Colorectal cancer is the third most common cancer and the second leading cause of cancer death in the United States.[1] 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.[1] Colorectal cancer is also a significant global public health issue, with 1.2 million cases diagnosed and 600,000 associated deaths each year.[2] At the time of initial diagnosis, nearly 40% of colorectal cancer patients present with localized disease.[1] 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.[3]

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.[8] The benefit of adjuvant 5-FU–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.[9] 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.[16] 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.[17]

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.[19] 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.[27] 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.[28] 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.[15] 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.[29] 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).[7]

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).

Shi and colleagues of the IDEA study presented the initial overall findings of the pooled analysis at the 2017 annual meeting of the American Society of Clinical Oncology.[6] The results from four of the six individual randomized clinical trials have since been published.[30-33] IDEA France was a phase III trial that randomized 2,010 patients with stage III colon cancer to either 3 or 6 months of modified FOLFOX 6 (mFOLFOX6; a regimen in which only the day 1 bolus 5-FU is administered along with a 46-hour infusion of 5-FU on days 1 and 2) or CAPOX.[30] As was the case for the overall analysis, the primary endpoint was DFS. The vast majority (90%) of patients received mFOLFOX6. Overall, the 3-month therapy group had a lower 3-year DFS rate than the 6-month therapy group (72% vs 76%; HR, 1.24; 95% CI, 1.05-1.46; P = .0112). For patients with high-risk features, 3-year DFS rates were 58% and 66% in the 3-month and 6-month therapy groups, respectively (HR, 1.44; 95% CI, 1.14-1.82). In contrast, for patients with low-risk features, the 3-year DFS rates were 81% and 83% in the 3-month and 6-month therapy groups, respectively (HR, 1.15; 95% CI, 0.89-1.49). The rate of neuropathy grade ≥ 2 at any time point was 36% (28% grade 2 and 8% grade ≥ 3) in the 3-month therapy group and significantly higher at 66% (41% grade 2 and 25% grade ≥ 3) in the 6-month therapy group (P < .001). After a median follow-up of 3.6 years, the rate of persistent residual neuropathy grade ≥ 2 was 2.5% (2% grade 2 and 0.5% grade ≥ 3) in the 3-month therapy group and 8% (6% grade 2 and 2% grade ≥ 3) in the 6-month therapy group (P < .001).

SCOT was a randomized, phase III noninferiority trial conducted in several European countries: 6,088 patients with high-risk stage II/III colon cancer were randomized to receive either 3 or 6 months of adjuvant CAPOX or FOLFOX.[31] However, the decision to treat with CAPOX or FOLFOX was made solely at the discretion of the treating physician. This was the largest of all of the six studies conducted as part of the IDEA collaboration and the largest randomized study conducted to date of adjuvant therapy for early-stage colon cancer. SCOT is significant in that it enrolled the largest number of patients treated with CAPOX. The results showed that 3-month adjuvant chemotherapy was noninferior to 6-month therapy in patients with stage III colon cancer, with the same 3-year DFS rate in both groups (HR, 1.015 ; 95% CI, 0.909-1.132). A post-hoc analysis of 3-year DFS for patients in the CAPOX group revealed that 3 months of CAPOX therapy was significantly noninferior to 6 months of therapy. The 3-year DFS was 76.9% in the 3-month therapy group vs 76.1% in the 6-month therapy group (HR, 0.944; 95% CI, 0.835-1.067; P [for noninferiority] = .002). The frequency of grade ≥ 3 toxicities was significantly higher in the 6-month than in the 3-month group (59% vs 36%; P < .0001): diarrhea (17% vs 12%; P = .033), neutropenia (14% vs 10%; P = .031), pain (6% vs 2%; P = .014), and hand-foot syndrome (5% vs 2%; P = .031). Peripheral neuropathy of grade ≥ 2 was significantly greater in the 6-month than in the 3-month therapy group (58% vs 25%). Peripheral neuropathy was also assessed using the patient-reported outcome FACT/GOG-Ntx4 questionnaire, which showed that peripheral neuropathy was worse in the 6-month group and persisted for at least 5 years. Quality of life was measured using well-established assessment tools, including European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30, QLQ-CR29, and EQ-5D-3L, and was found to be significantly worse for patients treated with 6 months of adjuvant chemotherapy compared with 3 months of treatment.

TOSCA, a phase III trial conducted in Italy, randomized patients with high-risk stage II or stage III colon cancer to 3- or 6-month therapy with FOLFOX4 or XELOX.[32] A total of 3,759 patients were enrolled (FOLFOX4 was given to 64% and XELOX to 36%), and 2,402 patients had stage III disease. In the overall study population (stage II and III disease), 3-year relapse-free survival (RFS) was 81.1% in the 3-month therapy group and 83.0% in the 6-month group (HR, 1.14; 95% CI, 0.99-1.32; P [for noninferiority] = .514). In patients with stage III colon cancer, 3-year RFS rates were 78.8% in the 3-month group and 78.7% in the 6-month group (3-year RFS difference, 0.1%; HR, 1.07; 95% CI, 0.91-1.26). Of note, in patients with high-risk stage II colon cancer, 3-year RFS rates were 85.5% in the 3-month group and 91.2% in the 6-month group (3-year RFS difference, 5.7%; HR, 1.41; 95% CI, 1.05-1.89; P [for superiority of 6 months of therapy] = .022). The rate of neuropathy grade ≥ 2 was 9.0% in the 3-month group and 31.0% in the 6-month group. TOSCA was not able to demonstrate noninferiority of 3-month oxaliplatin-based adjuvant treatment to 6-month therapy. However, the absolute difference in 3-year RFS was small (1.9%), and this difference was primarily driven by the difference in the stage II population, which accounted for about one-third of the study population (n for stage II = 1,254; n for stage III = 2,360).

ACHIEVE was a phase III trial conducted in Japan that randomized patients with stage III colon cancer to receive either 3- or 6-month mFOLFOX6 or CAPOX adjuvant chemotherapy.[33] A total of 1,313 patients were randomized (15% T1/T2, 57% T3, 28% T4, and 26% N2). The 3-year DFS rate was 79.5% in the 3-month group and 77.9% in the 6-month group (HR, 0.954; 95% CI, 0.758-1.201). Subgroup analysis revealed that the HR was 0.811 (95% CI, 0.532-1.236) in patients with low-risk features (T1-T3 and N1) and 1.066 (95% CI, 0.810-1.403) in patients with high-risk features (T4 or N2). HR was 1.065 (95% CI, 0.709-1.600) in patients treated with FOLFOX and 0.904 (95% CI, 0.684-1.195) in those treated with CAPOX. The frequency of grade ≥ 2 neurotoxicity was significantly lower in the 3-month therapy group than in the 6-month group (14% vs 36%; P < .001).

Consensus Recommendations

The IDEA clinical consensus recommends a risk-based approach in deciding on the duration of adjuvant therapy.[6,7] For patients with low-risk stage III colon cancer (T1-3, N1), 3 months of CAPOX adjuvant chemotherapy is appropriate. For patients with high-risk stage III colon cancer (T4 and/or N2 or other high-risk factors), 6 months of adjuvant therapy with CAPOX or FOLFOX is appropriate. The IDEA investigators concluded that the duration of therapy should be determined by tolerability of therapy, patient preference, assessment of recurrence risk, and specific treatment regimen (CAPOX vs FOLFOX).

The European Society for Medical Oncology 2017 annual meeting held a special session to review the IDEA findings. The discussants at this session concluded that the specific chemotherapy regimen and patient preference should be the main factors that determine treatment duration, with clinical risk factors, including T4 and/or nodal status, playing a less important role.[34] In general, CAPOX for 3 months should be recommended for low-risk disease, while CAPOX or FOLFOX for 6 months should be recommended for high-risk disease. No consensus recommendation was made concerning the role of 3-month CAPOX therapy for high-risk N2 disease.

In the United States, the most recent National Comprehensive Cancer Network guidelines recommend CAPOX for 3 months as the preferred regimen or FOLFOX for 3 to 6 months (with category 1 evidence for 6 months) for patients with low-risk stage III colon cancer (T1-3, N1).[26] For patients with high-risk stage III colon cancer (T4/N1-2 or any T4/N2), the preferred regimen should be CAPOX for 3 to 6 months (with category 1 evidence for 6 months) or FOLFOX for 6 months (category 1).

Controversies, Limitations, and Unresolved Issues

Several controversies are associated with the IDEA study, stemming from limitations inherent in the study. Perhaps the most important controversy involves the fact that the noninferiority of 3 months of oxaliplatin-based adjuvant therapy vs 6 months of oxaliplatin-based adjuvant therapy was not proven. This controversy is exacerbated by one of the major limitations of the IDEA study-namely, that this was a pooled analysis of six randomized clinical trials from different regions of the world. Each of these studies had a slightly different study design and involved a different patient population; moreover, each study used a different proportion of FOLFOX and CAPOX adjuvant chemotherapy. With regard to this latter point, it should be emphasized that patients were not specifically randomized between FOLFOX and CAPOX in any of the individual IDEA studies. Such a randomization of patients to FOLFOX vs CAPOX and to 3 vs 6 months of adjuvant therapy would have been ideal and would have made the subsequent statistical analyses much cleaner. Thus, while preplanned analyses revealed that the benefit of a 3-month duration of treatment was dependent on patient stratification and the specific treatment used, these conclusions lack the weight they might have had if patients had been randomly assigned to FOLFOX or CAPOX.

In addition to heterogeneity across the IDEA studies in terms of FOLFOX vs CAPOX therapy (which was based on physician choice), another significant limitation involves the relatively high degree of heterogeneity with respect to treatment compliance. For example, in the French study, 94% of the patients in the 3-month treatment arm received the full-length treatment, while only 78% of those in the 6-month arm received the full-length treatment; a similar difference in treatment compliance was observed between the 3-month arm and the 6-month arm in the Italian TOSCA study.

Finally, an ongoing debate involves the small absolute difference of 0.9% between the 3-month and 6-month treatment arms: 74.6% vs 75.5%. Although the predefined goal for statistical noninferiority was not met, is the absolute difference of < 1% worth an additional 3 months of chemotherapy, with its associated increased toxicity and potential impairment of quality of life?

There remain several unresolved issues associated with the IDEA study. These are as follows:

1. Should T4 and N2 patients be considered in the same tier with regard to risk of disease recurrence? The clinical data suggest that T4 disease may be a more powerful negative prognostic factor than N2 disease and that T4 patients benefit from 6 months of therapy. Further stratification of T4 disease to T4a and T4b may be required to more precisely identify patients at increased risk for recurrence.

2. What is the role of tumor sidedness in determining the optimal length of adjuvant therapy? This is an especially relevant issue given the recent findings from the SCOT trial on the effect of tumor sidedness.

3. Are there other tumor-specific biomarkers-such as microsatellite instability, gene expression profile and/or consensus molecular subtype status, BRAF and/or KRAS mutations, and quantification of in situ immune cell infiltrates in the tumor microenvironment-that might identify patients at high risk who would require 6 months of adjuvant therapy?

4. What is the optimal treatment duration for patients with high-risk stage II colon cancer? Of the six IDEA trials, only the SCOT and TOSCA trials included this specific patient population. The data from these two studies suggest that 6 months of therapy should be recommended, but this remains to be confirmed.

5. What is the optimal duration of therapy for elderly patients?

6. Is 6 months of therapy really necessary for both oxaliplatin and a fluoropyrimidine, whether it be oral capecitabine or intravenous 5-FU, or is it possible to treat with only 3 months of oxaliplatin followed by an additional 3 months of fluoropyrimidine monotherapy?

Conclusions

For nearly 15 years since the initial reporting of the MOSAIC study, oxaliplatin-based chemotherapy with either FOLFOX or CAPOX for 6 months has been the gold standard for stage III colon cancer patients who have good performance status and are able to tolerate more aggressive cytotoxic combination chemotherapy. However, the survival benefit with oxaliplatin-containing adjuvant chemotherapy for 6 months comes with significant toxicities. There are both acute short-term side effects, such as myelosuppression, diarrhea, and hand-foot syndrome, and chronic effects, such as peripheral sensory neuropathy. In particular, the cumulative, dose-dependent peripheral neuropathy impairs the ability to perform normal activities of daily living in a large majority of patients, and in some cases, this impairment can persist for years after completion of therapy. Other side effects, including myelosuppression, diarrhea, and/or mucositis, can also be problematic for patients and may adversely impact their overall quality of life.

Since the 1980s, there has been an ongoing evolution of the overall duration of adjuvant therapy. The very first effective adjuvant regimen, MOF, was administered for 18 months; now, the gold standards, FOLFOX and CAPOX, as well as fluoropyrimidine monotherapy, are administered for 6 months. The IDEA study goes one step further. The overall analysis of IDEA was not able to confirm the noninferiority of 3 months of oxaliplatin-containing adjuvant chemotherapy vs 6 months of therapy. However, it should be noted that the clinical benefit of 6 months of therapy, as determined by the primary endpoint of 3-year DFS, was only 0.9% higher than that of 3 months of therapy. Although this difference was statistically significant, the question remains whether a difference of < 1% is truly clinically meaningful. Moreover, subgroup analysis revealed that 3-month therapy with either CAPOX or FOLFOX was as effective as 6-month therapy, particularly in patients with low-risk features (T1, T2, or T3 and N1).

The IDEA study provides strong evidence for individualizing the duration of adjuvant therapy for patients with stage III colon cancer according to the type of adjuvant chemotherapy (CAPOX vs FOLFOX) and specific risk characteristics of the patient's disease (low-risk vs high-risk cancer). Given the nearly 13,000 patients enrolled in the IDEA study, further studies are needed to interrogate this impressively large clinical database and identify a potential biomarker and/or molecular signature that could more precisely identify the subset of patients who would truly benefit from 3 months of adjuvant chemotherapy and those who would require 6 months.

Finally, patient preferences must be factored into the decision-making process, and there are at least three areas where patient choice comes into play with adjuvant chemotherapy. The first issue for a patient to consider is whether to take an oral pill, as with capecitabine, or to receive intravenous chemotherapy with infusional 5-FU. The second and perhaps more relevant point is whether a patient is willing to be treated with 6 months of adjuvant chemotherapy, whether it be FOLFOX or CAPOX, in the hopes of gaining a 0.9% improvement in overall clinical benefit and weighing that against the potential for increased overall toxicity and negative impact on quality of life that are associated with longer treatment. The third and final issue relates to the potential pharmacoeconomic implications of being treated for an additional 3 months. Without question, an additional 3 months of chemotherapy comes with increased economic costs to both the overall healthcare system and the patient. Further studies will be needed to determine the financial impact of 3-month vs 6-month adjuvant chemotherapy, but as with clinical efficacy, safety profile, and quality of life, less chemotherapy may end up being more cost-effective to the individual patient as well as to the overall healthcare system.

Acknowledgement:This work was supported in part by National Cancer Institute grants P30 CA147904 and UM1 CA099168.

Financial Disclosure:The authors have no financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

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