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New Developments in the Adjuvant Therapy of Stage II Colon Cancer

New Developments in the Adjuvant Therapy of Stage II Colon Cancer

ABSTRACT: While adjuvant chemotherapy has proven benefit in stage III colon cancer, its role for stage II colon cancer remains unclear. This article reviews data regarding adjuvant therapy in stage II colon cancer. We will discuss factors to consider in assessing the risk of recurrence in stage II disease. We will also outline considerations regarding adjuvant therapy in older patients.

Colon cancer is estimated to have accounted for 106,100 new cancer cases and 49,920 cancer-related deaths in 2009.[1] Over half of these new diagnoses and deaths occur in individuals age 70 and older.[2] The probability of developing colon cancer increases with advancing age from less than 1% in the first 4 decades of life to nearly 5% in the seventh decade of life [2]. Nearly 40% of these older individuals are diagnosed with stage II disease [2]. While the overall 5-year survival rate for individuals 75 and older is 67% for all stages of colon cancer, survival of those aged 70 to 79 diagnosed with stage II (T3 or T4, N0, M0) colon cancer is 77% (low-grade disease) or 70% (high-grade disease).[2,3]

The benefit of adjuvant chemotherapy after surgery for stage III colon cancer is well established.[4,5] However, the role of chemotherapy in patients with stage II disease not as well established and has been a source of debate over the past 2 decades. While the percentage of stage II colon cancer patients of any age that receive adjuvant therapy after surgery is unknown, one study found that 27% of 65- to 75-year-old Medicare beneficiaries received chemotherapy for stage II disease.[6] This article will outline the evidence for chemotherapy in stage II colon cancer and review risk assessments for colon cancer recurrence, with a focus on older patients.

Treatment Efficacy—Fluoropyrimidine Monotherapy

Early studies in adjuvant colon cancer enrolled patients with stage II and III disease.[7-11] The North Central Cancer Treatment Group (NCCTG) and subsequently the Eastern Cooperative Oncology Group (ECOG) compared the administration of fluorouracil (5-FU) and levamisole with observation in the adjuvant setting.[10,11] The NCCTG trial enrolled 401 patients with stage II or III colon cancer and demonstrated a 31% reduction in recurrence rate for patients with stage III disease who received fluorouracil and levamisole.[10] In the larger ECOG trial of 1,296 patients, adjuvant fluorouracil and levamisole reduced the risk of recurrence by 41% (P = .0001) and the risk of death by 33% (P = .006) compared with surgery alone in patients with stage III disease.[11] In contrast, no meaningful benefit was noted in the subset of patients with stage II disease.

TABLE 1

Pooled Analyses of Randomized Clinical Trials of Fluoropyrimidine Adjuvant Therapy for Stage II Colon Cancer

Multiple pooled analyses that included these and other studies have led to mixed findings regarding the benefit of adjuvant therapy in stage II patients (see Table 1). The International Multicenter Pooled Analysis of Colon Cancer Trials (IMPACT) group conducted two pooled analyses evaluating the impact of fluorouracil and high-dose leucovorin compared to observation following resection of colon cancer that failed to show a survival benefit for patients with stage II disease.[8,12] Both analyses failed to show a statistically significant benefit in disease-free survival for stage II patients.

The National Surgical Adjuvant Breast and Bowel Project (NSABP) conducted pooled analysis of individual patient data of the effect of adjuvant fluoropyrimidine-based regimens for stage II and III disease in NSABP studies C-01, C-02, C-03, and C-04.[13,14] Of the 3,820 patients enrolled, 41% had stage II (26% of those with high-risk features) and 56% were ≥ 60 years old. Cumulative odds of death demonstrated survival benefit for both stage II (0.70) and stage III (0.82) patients. Treatment effect was similar for stage II patients regardless of presence of high-risk features (low-risk: cumulative odds of death = 0.68; 95% confidence interval [CI] = 0.50–0.92; P = .01; high risk: cumulative odds of death = 0.80; 95% CI = 0.55–1.17; P = .26).

Gill and colleagues conducted a pooled analysis of 3,302 patients from seven randomized adjuvant trials, including 1,440 patients with stage II disease and 1,864 patients ≥ 60 years old.[3] Adjuvant therapy led to a 4% absolute 5-year disease-free survival (DFS) benefit (76% vs 72%; P = .05) and no overall survival (OS) benefit (81% vs 80%; P = .11). For patients 70 to 79 years old, both DFS and OS appeared to be increased among those receiving adjuvant therapy, although the statistical significance of the apparent absolute difference is not described.[3]

In a systematic review of stage II colon cancer patients in 37 clinical trials and 11 meta-analyses on behalf of the Cancer Care Ontario Program in Evidence-Based Care, no OS benefit was noted for adjuvant therapy (N = 4,187, relative risk [RR] of death 0.87, 95% CI = 0.75–1.01; P = .07).[15] An updated pooled analysis of data from 1980 until 2007 noted a 17% reduction in risk of recurrence or death with the use of adjuvant therapy in stage II disease (pooled relative risk ratio = 0.83; 95% CI = 0.75–0.92) without a significant difference in OS (RR = 0.96; 95% CI = 0.88–1.05).[16]

The Adjuvant Colon Cancer Endpoints (ACCENT) Group reported on a collection of individual patient data from 18 trials (20,898 patients with 33% stage II) testing fluorouracil-based adjuvant therapy in stage II or III colon cancer.[17] At 8 years, the OS among stage II colon cancer patients receiving adjuvant chemotherapy was 72.2% compared to 66.8% in those who had surgery alone (P = .026).

The largest randomized clinical trial evaluating treatment of individuals with stage II colon cancer was conducted in the United Kingdom by the Quick And Simple And Reliable (QUASAR) Collaborative Group.[18] In one of the two cohorts of the study, patients who were deemed by their oncologist to have a low risk of cancer recurrence and in whom the indication for chemotherapy was uncertain (ie, mainly stage II cancers) were randomized to a fluoropyrimidine regimen or placebo.[19] The baseline characteristics of the 3,239 patients enrolled were as follows: 71% colon cancer, 29% rectal cancer, 91% stage II disease with 8% stage III, and < 1% stage I. Individuals 70 and older accounted for 20% of each treatment arm. All patients enrolled were included in intention-to-treat analyses with the primary endpoint of overall survival. The relative risk of dying from any cause with chemotherapy vs observation was 0.82 (95% CI = 0.70–0.95). When considering cancer recurrences, the relative risk of recurrence with chemotherapy vs observation was 0.78 (95% CI = 0.67–0.91). When limited to stage II colon cancer patients only, the relative risks for overall mortality (0.86, 95% CI = 0.66–1.12) and recurrence (0.82, 95% CI = 0.63–1.08) are similar to the overall population but not statistically significant.

In QUASAR, while limited by sample size, the point estimates for overall mortality (relative risk 1.02, 95% CI = 0.70–1.48) and recurrence (relative risk 1.13, 95% CI = 0.74–1.75) in patients greater than 70 years old suggests a lack of benefit in elderly patients. This is in contrast to a pooled analysis of seven randomized adjuvant trials (40% with stage II disease) by Sargent et al demonstrating similar OS benefit and decreased time to cancer recurrence for patients ≥ 70 receiving adjuvant chemotherapy compared to their younger counterparts [20]. This pooled analysis, however, included patients with stage II and stage III colon cancer.

Treatment Efficacy—Combination Therapy

TABLE 2

Randomized Clinical Trials of Adjuvant Therapy for Stage II Colon Cancer: Combination Therapy

Two clinical trials have been initiated to evaluate oxaliplatin (Eloxatin) and a fluoropyrimidine in the adjuvant treatment of colon cancer, both enrolling stage II and III patients [21,22]. Both trials demonstrated statistically significant DFS benefit with the addition of oxaliplatin to a fluoropyrimidine in the overall cohort, with one reaching statistical significance in OS (see Table 2 for trial details).

In the Multicenter International Study of Oxaliplatin/Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer (MOSAIC), a phase III study of 2,246 patients with stage II or III colon cancer randomized to receive infusional fluorouracil and leucovorin (LV5FU2) plus or minus oxaliplatin, 40% of patients had stage II disease. The latest report from MOSAIC was published when the last enrolled patient had 5 years of follow-up for DFS and 6 years of OS.[21] While DFS was statistically significant for the overall cohort and stage III subset, the 5-year DFS among stage II patients was 83.7% and 79.9% in the FOLFOX4 and LV5FU2 groups, respectively (hazard ratio [HR] = 0.84, 95% CI = 0.62–1.14; P = .26). Similarly, 6-year OS was 86.9% and 86.8%, respectively (HR = 1.00, 95% CI = 0.70–1.41; P = .99). While the investigators did not report results of the stage II patients by age, the DFS benefit appeared limited to those under the age of 65 in exploratory analyses of those with stage III disease.

The NSABP randomized 2,407 patients (one-third were ≥ 65 and nearly one-third had stage II disease) to a weekly fluorouracil and leucovorin regimen with or without every-other-week oxaliplatin.[22] While the overall cohort achieved a statistically significant DFS benefit, with a 34-month follow-up and dose intensity of at least 85%, no statistically significant DFS benefit was shown for older patients or those with stage II disease.

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