Adjuvant Chemotherapy for Stage II Colon Cancer

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.[1] 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.

Early Trials

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).[5] 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.[10] 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.