In 2014 an estimated 96,830 new cases of colon cancer were diagnosed in the United States alone (National Cancer Institute: http://www.cancer.gov/types/colorectal). In developed countries, colon cancer is two to three times more common than rectal cancer, while in rural Asia and Africa the incidence is reversed. Interestingly, as diets Westernize in Asian cities, both the incidence of colorectal cancer in general and the relative incidence of colon versus rectal cancer in particular increase. Epidemiologic studies indicate a rising proportion of right-sided tumors in developed countries as well. This, too, is likely due to factors associated with diet and, possibly, environment. This chapter reviews the most current information on the systemic treatment of colon cancer.
The National Cancer Institute (NCI) Cooperative Intergroup Trial INT-0035, a study of fluorouracil plus levamisole (a veterinary antihelminthic agent previously thought to have immunomodulatory effects, but now known to be inactive in this regard) as adjuvant treatment for stage II and III colon cancer, was the first to definitively demonstrate a survival benefit for postoperative adjuvant chemotherapy in colon cancer. This study randomized over 900 patients to surgery alone versus surgery followed by a year of 5-fluorouracil (5-FU) plus levamisole. The results showed that patients in the 5-FU/levamisole group had an absolute reduction of 17% in recurrence or death within 5 years, compared to those treated with surgery alone; this represents a one-third risk reduction.1 Further studies demonstrated that the benefits of 6 months of chemotherapy were essentially equivalent to those obtained within 12 months. These studies also showed that 5-FU + leucovorin (LV) (folinic acid) was as active as 5-FU + levamisole or 5-FU + levamisole + LV. As a result, 6 months of adjuvant 5-FU became the established practice for all stage III patients. It should be noted that the stage II patients in INY-0035 showed no benefit from treatment. Therefore, it became standard practice to treat most stage III colon cancer patients with 6 months of 5-FU/LV.2 Treatment of stage II patients remains a controversial area, which will be discussed below.
Over the past two decades, several chemotherapeutic agents have been established as part of standard treatment for unresectable metastatic colorectal cancer. The assumption that activity in the metastatic setting would routinely translate into improved activity in the adjuvant setting has not panned out, however. To date, only oxaliplatin has shown any efficacy when added to adjuvant fluoropyrimidines.
Oxaliplatin, a platinum-based agent with essentially no renal or ototoxicity but with considerable neurotoxicity, demonstrates little anticancer effect on its own. However, it is active in combination with other drugs such as 5-FU/LV or capecitabine (an oral prodrug of 5-FU). In the MOSAIC (Multicenter International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer) trial, a total of 2246 patients (60% stage III, 40% stage II) were randomized to postoperative 5-FU/LV by 48-hour ...