Adjuvant Chemotherapy in Colon Cancer: Ageism or Appropriate Care?

In 1990, Moertel et al reported that fluorouracil-based adjuvant chemotherapy prolongs survival in patients with high-risk colon cancer. More recently, three large adjuvant colon cancer studies have refined adjuvant drug combinations by demonstrating that the addition of oxaliplatin improves the chance of cure. The Multicenter International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer (MOSAIC) trial included 2,246 patients and showed that the addition of oxaliplatin to a fluorouracil/ leucovorin regimen improved 5-year disease-free survival rates from 67.4% to 73.3% and improved 6-year overall survival rates from 76% to 78.5%. In addition, the National Surgical Adjuvant Breast and Bowel Project (NSABP) C-07 trial included 2,407 patients and tested a combination of oxaliplatin, fluorouracil, and leucovorin against a combination of fluorouracil and leucovorin. The combination of oxaliplatin, fluorouracil, and leucovorin yielded an improvement in 3-year disease-free survival from 71.8% to 76.1% and an improvement in 4-year disease-free survival from 67% to 73.2%. In addition, in the XELOX in Adjuvant Colon Cancer Treatment (XELOXA) trial, 1886 patients were randomly assigned to oxaliplatin and capecitabine (XELOX) versus a fluorouracil and leucovorin regimen. The former yielded an improvement in 3-year disease-free survival from 66.5% to 70.9% and an improvement in 5-year overall survival from 74.2% to 77.6%. Such reports have culminated in the designation of 6 months of one of these oxaliplatin-based regimens as the current standard of care for patients with stage III colon cancer and for patients with high-risk stage II disease. But has this designation of the standard of care led to the routine use of oxaliplatin-based chemotherapy in the appropriate adjuvant settings? In other words, have the three clinical trials described truly been practice changing? Spurred on by such category one evidence, Abrams et alsought to answer these questions and, as a result, provide important insights in the article that accompanies this editorial. Examining 2,560 patients from the IntelliDose (IntrinsiQ, Burlington, MA) ordering system during the past six and a half years, these investigators observed that such clinical trial evidence does appear to modify clinical practice: by the year 2007, oxaliplatin-based combinations represented 90% of adjuvant chemotherapy administered to patients with stage III disease; and by 2008, these combinations represented 79% of adjuvant chemotherapy in patients with stage II disease. In addition, more than 70% of patients completed most of the planned therapy. These observations should be heartening to the oncology community at large, because they show that well-done clinical trials can and truly do change clinical practice. Now for the more difficult question: what can be said about the 10% of patients who did not initiate oxaliplatin-based adjuvant chemotherapy and the approximately 30% who completed fewer than 3 months of adjuvant therapy? Abrams et al observed several factors directly associated with the omission of oxaliplatin in postoperative chemotherapy, including but not limited to older age, poorer performance status, and stage II disease. They revealed that 93.6% of patients younger than age 50 years had received an oxaliplatin-based regimen; 41.5% of those age 80 years or older had received such chemotherapy; and a gradual decline in these percentages occurred with each increasing decade between these age groups (P .001). Focusing on the roughly 30% of all patients who stopped adjuvant chemotherapy after less than 3 months, Abrams et al found several factors that were directly associated with this premature discontinuation, including but not limited to older age (again) and the use of an oxaliplatin regimen. With respect to this first factor, 23.5% of patients younger than age 50 years received fewer than 3 months of chemotherapy; 38.9% of those age 80 years or older received a shorter duration of treatment; and a gradual increase in these percentages was observed between these age groups by increasing decades (P .001). Taken together, these findings might lead one to consider a variety of conclusions, not the least of which is that some older patients with colon cancer appear to receive less chemotherapy in the adjuvant setting. What is it about chemotherapy in the elderly? Why is it that, with the initiation of oxaliplatin-based adjuvant treatment for colon cancer and the continuation of adjuvant chemotherapy in general, older patients are prescribed less? Although definitive answers remain elusive, a few facts pertinent to the elderly merit mention. First, in contrast to the high-level evidence derived from trials conducted in the general population, similar evidence is sparse among older patients with colon cancer. In general, adjuvant trials have not focused on the elderly. Despite the fact that colon cancer has become a disease of the elderly and despite the observation that trials designed for elderly patients seem to accrue relatively well, no adjuvant trial for the elderly is underway to our knowledge. Thus, it is currently impossible for oncologists to use high-level evidence when considering options specific to older patients with colon cancer in the adjuvant setting, because little exists. Of incidental note, in the metastatic disease setting, such evidence will likely emerge in the future with the opening of C81002/N0949. Second, although secondary analyses suggest that chemotherapy regimens that exclusively or almost exclusively include a fluoropyrimidine confer a survival advantage among older patients, conclusions from similar analyses of oxaliplatin-based adjuvant trials have been contradictory and confusing, providing little direction to practicing oncologists. For example, secondary analyses of the MOSAIC and NSABP C-07 trials suggest that adding oxaliplatin to an adjuvant regimen does not yield significantly greater benefit among older patients, a conclusion shared by analyses from the Adjuvant Colon Cancer End Points (ACCENT) database. In contrast, a reanalysis of the smaller XELOXA trial, referred to above and results from the Surveillance, Epidemiology, and End Results (SEER) database suggest benefit in the elderly with the addition of oxaliplatin to a Editorials