ABSTRACT: The use of adjuvant chemotherapy following resection for all patients with stage III colon cancer is now part of the standard of care around the world. Recent trials have led to changes in the standard regimens, which now include the use of oxaliplatin (Eloxatin) for most patients with stage III colon cancer. The addition of oxaliplatin has resulted in a 23% reduction in the risk of recurrence compared with fluorouracil/leucovorin alone, with a small but statistically significant survival benefit. Unfortunately, no adequately powered trial has determined whether adjuvant chemotherapy is beneficial for stage II patients, and its use is much more controversial. Most investigators agree that adjuvant chemotherapy has some activity against stage II disease. However, its impact on progression-free and overall survival remains highly controversial. Despite the lack of data, there is growing acceptance of an informal classification system, which stratifies stage II patients by risk on the basis of clinical data, as a guide for deciding whether to use adjuvant therapy. The only phase III clinical trial for stage II patients currently ongoing in the United States uses molecular classification as the basis for patient randomization.
Adjuvant therapy is defined as any treatment administered after surgical resection of a primary tumor with the intent of improving the patient’s outcome by eliminating any occult, viable tumor cells that may have remained after surgery. For adjuvant chemotherapy to be considered in any disease, the agents used should effectively eradicate the type of tumor cells present in that disease, and the risk-to-benefit ratio for the adjuvant treatment must be favorable, since some, if not most, patients who receive adjuvant treatment are already cured by the surgical procedure. Recent declines in mortality rates from colorectal cancer in the United States have been attributed to the increased utilization of surveillance and improvements in adjuvant chemotherapy. However, colon cancer continues to be a leading cause of cancer death around the world.
The decision of whether to use adjuvant chemotherapy is based on a patient’s risk of recurrence, which is determined in large measure by the disease stage (Table 1) and the risk reduction expected with treatment. The now-standard TNM staging system is based on tumor penetration through the bowel wall (T) and the presence of regional lymph node (N) and distant metastases (M). Patients with stage I disease have a high probability of cure after resection, and adjuvant chemotherapy is unlikely to add much benefit. Adjuvant therapy is not an option for patients with stage IV (metastatic) cancer, although the term is frequently used to identify chemotherapy given after resection of localized metastasis. Therefore, only patients with stage II or III disease are generally considered eligible for adjuvant chemotherapy.
The use of adjuvant chemotherapy in colon cancer dates back to 1990, when it was demonstrated that fluorouracil (5-FU) and the antihelminthic agent levamisole improved overall survival after resection—a finding that was repeated in 1994 in a study combining 5-FU with leucovorin (LV). In 1998, 5-FU/LV was demonstrated to be superior to 5-FU/levamisole, resulting in the discontinuation of further levamisole use. In 2003, the combination of oxaliplatin (Eloxatin) and 5-FU/LV demonstrated greater benefit than 5-FU/LV alone, and the oral agent capecitabine (Xeloda) was later shown to be equivalent to intravenous 5-FU/LV. Current trials in stage III colorectal cancer are exploring the integration of capecitabine into combination regimens and the addition of monoclonal antibodies to adjuvant therapies.
However, despite decades of adjuvant trials with 5-FU, the question of whether adjuvant chemotherapy is beneficial in node-negative, stage II (T3/4, N0) colon cancer has not yet been answered. Patients with stage II disease represent approximately one-quarter of the patients diagnosed with colon cancer and have a good prognosis, with a 5-year survival rate of approximately 80%. This review addresses the current debate over the use of adjuvant chemotherapy in stage II colon cancer, describing relevant concepts for critiquing the available data in the literature and attempting to place the potential benefits in a framework appropriate for discussion with patients.
Efficacy of Adjuvant Chemotherapy in Stage II Colon Cancer
The benefit of adjuvant chemotherapy for stage III colon cancer has been established and refined over several decades of clinical trials. The relevant historical trials focusing on stage III patients have been extensively reviewed.[2-4] Despite the fact that patients with stage II disease have been included in many of these adjuvant trials, the benefit of chemotherapy after resection in these patients has still not been definitively established. The following review of the past 20 years of trials provides a background for understanding the current controversy in this field.
An early prospective trial of adjuvant therapy for colorectal cancer reported a significant benefit of short-term 5-FU for stage II patients, with a 5-year disease-free survival rate of 82% compared with 59% in patients who did not receive adjuvant chemotherapy (P < .02). However, the dramatic results of this small study have never been replicated, and subsequent trials have only added to the confusion.
The early National Surgical Adjuvant Breast and Bowel Project (NSABP) trials randomized patients to 5-FU–based regimens (semustine, vincristine, and 5-FU or preoperative portal vein infusion of 5-FU) vs observation, whereas later trials compared a 5-FU–plus–leucovorin arm to other 5-FU regimens (semustine, vincristine, and 5-FU or 5-FU and levamisole with or without leucovorin).[6-9] These trials were designed with a primary endpoint of overall survival in stage II/III patients, and subgroup analyses failed to show a statistically significant improvement in the outcomes of stage II patients treated with adjuvant chemotherapy .
One of the first studies to report data separately for stage II patients was the North Central Cancer Treatment Group (NCCTG) trial in which patients were randomized to observation or adjuvant treatment with levamisole or 5-FU and levamisole for 12 months. The investigators found a trend toward improved disease-free survival with adjuvant chemotherapy (59% vs 73% for observation vs 5-FU/levamisole, P = .10). However, overall survival in this small stage II cohort was unchanged with treatment.
GI Intergroup Trials
A subsequent trial conducted through the GI Intergroup evaluated the benefit of 5-FU/levamisole in both stage II and stage III patients. This trial enrolled 1,247 patients; however, it was underpowered to answer the question of benefit in stage II patients, as only 318 with this diagnosis were studied. When compared with patients randomized to observation alone, those receiving 5-FU and levamisole were part of a trend toward a reduced rate of recurrence (71% vs 79% for observation and 5-FU/levamisole, respectively, P = .10), with nearly identical overall survival in the final report.[11,12]
A second GI Intergroup trial explored adjuvant chemotherapy with 5-FU–based regimens in patients with high-risk stage II/III disease, with a goal of identifying the optimal chemotherapy modulator. Patients with high-risk stage II disease, which was defined by the presence of obstruction, perforation, or invasion of adjacent structures at the time of diagnosis, accounted for 20% of the study enrollment. The four arms of the study included combinations of 5-FU with and without leucovorin or levamisole. Despite the fact that no observation arm was included, the results in high-risk stage II patients were felt to be similar to those in historical controls.
QUASAR 1 Trial
The largest trial to date involving stage II patients is the Quick and Simple and Reliable (QUASAR) 1 study, which randomized colon and rectal cancer patients with an unclear indication for adjuvant chemotherapy to 5-FU and leucovorin or observation. Of the 3,239 patients enrolled, 92% had stage II disease. The primary endpoint of overall survival for all enrolled patients had not been reached at the time of the most recent abstract presentation of the study.
In the subset of stage II patients, there was a 3% to 4% absolute improvement in the 5-year overall survival rate (P = .04), with a similar 3% to 4% absolute improvement in the rate of disease recurrence (15.4% vs 19.1%, P = .004). However, this study included rectal cancer patients (29%), some of whom also received adjuvant or neoadjuvant radiation therapy. A subset analysis suggested that the majority of the benefit seen with adjuvant chemotherapy occurred in the stage II rectal cancer patients (recurrence rate of 20% vs 27%, P = .005) as opposed to the stage II colon cancer patients (17% vs 20%). It has been subsequently reported that only a minority of these patients had high-risk disease, characterized by a T4 primary tumor, lymphovascular invasion, or perineural invasion. Further results are expected when the study report is published.
MOSAIC and NSABP C-07 Trials
With the introduction of oxaliplatin into adjuvant regimens, an additional question of benefit for stage II patients has been raised. In the MOSAIC trial (Multicenter International Study of Oxaliplatin/5-FU/LV in the Adjuvant Treatment of Colon Cancer), 6 months of 5-FU/LV was compared to 6 months of 5-FU/LV with oxaliplatin (FOLFOX regimen). The primary endpoint of improved 3-year disease-free survival for stage II/III colon cancer patients was met. However, subset analysis of disease-free survival for stage II patients failed to demonstrate a benefit (absolute risk reduction of 3.8%, hazard ratio [HR] = 0.84, 95% confidence interval [CI] = 0.62–1.14), prompting the US Food and Drug Administration to limit approval of oxaliplatin to use in stage III colon cancer.
Limiting the analysis to high-risk stage II disease (defined as a T4 lesion, tumor perforation or obstruction, poorly differentiated tumor, venous invasion, or fewer than 10 lymph nodes analyzed) likewise did not demonstrate a statistically significant benefit for oxaliplatin (absolute risk reduction of 7.2%, HR = 0.74, 95% CI = 0.52–1.06). Recently updated 6-year overall survival results did not differ for stage II patients treated with 5-FU/LV or FOLFOX.
Similar results from the NSABP C-07 trial demonstrated an overall benefit for the addition of oxaliplatin to 5-FU/LV but failed to demonstrate an improvement in the stage II subset. Of note, in both trials above, the relative positive effect of adjuvant treatment on disease-free survival was similar for stage II and III patients, as denoted by comparable hazards ratios for the subgroups (Figure 1).
Capecitabine, an oral prodrug of 5-FU, has been shown to be equivalent to bolus 5-FU/LV in the adjuvant treatment of 1,987 stage III patients. To date, completed capecitabine adjuvant trials have not included stage II patients, although a study that included a capecitabine-and-oxaliplatin arm for high-risk stage II patients has completed enrollment.
5-FU Meta-analyses and Cohort Studies
Given the potential absolute benefit of 4% seen in the QUASAR study, a definitive trial to demonstrate a benefit for adjuvant chemotherapy for stage II patients would require 4,700 patients to be adequately powered. As a result, the question of benefit in this population lends itself to meta-analysis. Unfortunately, the meta-analyses performed thus far have also been discordant and controversial.
One of the initial meta-analyses combined the outcomes of 4,000 colorectal cancer patients who received portal vein infusion of 5-FU as adjuvant therapy and demonstrated a statistically significant reduction in the 5-year mortality rate despite no change in the incidence of subsequent liver metastases. This improved 5-year overall survival rate was also seen in the Dukes’ B subset of approximately 1,400 patients, with a 6% absolute risk reduction compared to observation alone. This did not, however, reach statistical significance, although Dukes’ B patients had the same relative risk reduction with treatment as was seen in Dukes’ C patients (18%).
These discrepant results were repeated in two meta-analyses published concurrently in the Journal of Clinical Oncology. The IMPACT B2 study (International Multicentre Pooled Analysis of B2 Colon Cancer Trials) evaluated five trials that had compiled individual patient data for modified Dukes’ B2 (T3/4, N0) patients. These patients were randomized to treatment with 5-FU and leucovorin or observation. A total of 998 patients were included in the analysis, with a 5.8-year follow-up period. The 5-year overall survival rate was 82% in patients treated with 5-FU/LV and 80% for observation alone, which represented a statistically nonsignificant difference. The hazard ratio at 5 years was 0.83 (90% CI = 0.72–1.07) for disease-free survival and 0.86 (90% CI = 0.68–1.07) for overall survival. The authors concluded that 5-FU/LV could not be recommended for routine use in stage II colon cancer patients.
The second of the two reports evaluated the benefit of adjuvant treatment in the NSABP C-01 through C-04 trials. Comparison of the more effective to less effective treatment arms in the four trials revealed a 30% reduction in mortality for stage II patients (P < .05), with a corresponding decrease in risk of recurrence. The mortality reduction in stage II patients occurred irrespective of the presence or absence of the adverse prognostic factors of obstruction, perforation, and invasion into adjacent structures. Although the stated intent of the analysis was to determine the benefit of chemotherapy in stage II disease, the combined analysis of trials without comparison arms was appropriately criticized as inadequate to fulfill that objective.
However, a second and arguably more instructive goal was to compare the efficacy of adjuvant therapy in stage II and III tumors, with the hypothesis that if the biology of these tumors is similar,the relative benefit of any given chemotherapy regimen should also be similar. This was indeed suggested by the results of the analysis, as the relative benefit of the more effective treatment arm in each trial was similar in stage II and III patients, with a trend towards a greater relative benefit for stage II patients.
A similar finding was reported in an analysis of a GI Intergroup/NCCTG study.[11,12] Evaluation of several prognostic factors failed to demonstrate any interactions with tumor stage in the multivariate analysis, again suggesting that the relative benefit of adjuvant treatment is the same for stage II and III patients.
A multivariate analysis of seven trials of adjuvant therapy for stage II/III colon cancer explored the benefits of adjuvant treatment. Univariate analysis of node-negative patients demonstrated a 4% absolute risk reduction in disease-free survival (HR = 0.83, P = .049). This approach, which adjusted for tumor stage, nodal status, and histologic grade, demonstrated a 35% reduction in the risk of recurrence (HR = 0.65; 95% CI = 0.58–0.73) and a 30% reduction in the risk of death (HR = 0.73; 95% CI = 0.63–0.79) with adjuvant chemotherapy.
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