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

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 infusion every other week, +/− a 2-hour infusion of oxaliplatin.^3,4 (This regimen, oxaliplatin, 5-FU, and LV, given every other week with a two-day ambulatory infusion of 5-FU, is known as ‘FOLFOX.’) Five-year disease-free survival (DFS) was 73.3% in the group receiving FOLFOX versus 67.4% in the group receiving 5-FU/LV (p = .003). Six-year overall survival (OS) rates were 72.9% for the FOLFOX arm versus 68.7% for the 5-FU/LV arm (p = .023). All of the benefits from oxaliplatin in this trial were limited to patients with stage III; when oxaliplatin was added to the treatment regimen of patients with stage II disease—including those with one or more high-risk features⁵—no improvement in OS was observed. Nevertheless, the results established FOLFOX as the standard in treatment for stage III colon cancer.

The most common side effect of oxaliplatin is peripheral sensory neurotoxicity. This manifests as numbness, tingling, sensitivity to cold, and loss of fine motor coordination because of numbness. Other negative side effects are diarrhea, fatigue, myelosuppression, nausea, and vomiting. Current antiemetic regimens of HT3 antagonists, such as ondansetron or related agents plus dexamethasone, are extremely effective in controlling the nausea and vomiting. However, long-term cumulative neuropathy is a major concern. Patients receiving FOLFOX in the MOSAIC trial suffered a 12.5% incidence of grade 3 sensory neuropathy, and also showed high levels of persistent grade 1 and 2 neuropathy. This demonstrates what is known as a “coasting effect,” in that the neuropathy may peak as late as 3 to 4 months after the last dose of oxaliplatin—due to the very long (50 days) half-life of the elemental platinum. At the time of their one-year follow-up, 1.3% had persistent grade 3 neuropathy. However, 30% of those receiving oxaliplatin had some degree of residual neurotoxicity 1 year following the end of treatment; 15% had residual neurotoxicity after 4 years of follow-up (essentially permanent).

The NSABP C-07 trial evaluated the addition of oxaliplatin to a weekly treatment schedule of 5-FU/LV via brief intravenous bolus injection (instead of infusion). Stage II or III colon cancer patients (n = 2407; 71% stage III) were randomly assigned to 6 months of weekly bolus 5-FU/LV with or without oxaliplatin; administered on weeks 1, 3, and 5 of every 8-week cycle, this is known as the “FLOX” regimen.⁶ Five-year DFS in the FLOX arm was 69.4%; DFS in the 5-FU/LV arm was 64.2% (HR 0.82, p = 0.002). For stage III patients, 5-year DFS improved by 6.6%: from 57.8% to 64.4%. However, after a median follow-up of 8 years, this trial demonstrated no statistically significant survival benefit when oxaliplatin was added to the treatment regimen, and so FLOX is considered an option only when preferred regimens such as FOLFOX or CapeOx (discussed below) cannot be given for logistical reasons. In stage II patients treated with FLOX, virtually no benefit in OS was seen. Stage III patients showed a 2.7% improvement in median OS (73.8 vs. 76.5 years) when oxaliplatin was added, with a p value of borderline significance (p = 0.052). The weekly bolus schedule of 5-FU/LV in this study did cause significant toxicity: 5% of patients receiving FLOX and 3% of those receiving 5-FU/LV required hospitalization for diarrhea and dehydration.

Capecitabine and uracil + tegafur (UFT), both oral fluoropyrimidines, have demonstrated equivalence to parenteral 5-FU/LV in the adjuvant setting. (UFT is not available commercially in the United States.) In a study comparing capecitabine with the bolus daily × 5 Mayo Clinic 5-FU/LV schedule, noninferiority was demonstrated.⁷ Similar results were shown in the NSABP C-06 trial for oral UFT + oral LV.⁸ However, 5-FU/LV alone is no longer the standard regimen in the adjuvant setting.

In a more recent phase III trial involving 1866 patients, a combination of oral capecitabine plus intravenous oxaliplatin (CapeOx) was compared with intravenous 5-FU/LV.⁹ Three-year DFS was 70.9% in the CapeOx arm versus 66.5% in the 5-FU/LV arm. The difference in OS at 5 years favored the CapeOx arm, but does not appear to be statistically significant (p = 0.15486) at this time; follow-up continues. No comparison of FOLFOX to CapeOx has been (or will be) undertaken in the adjuvant setting; in order to be adequately powered, such a study would have to enroll more than 10,000 patients. Nevertheless, comparisons in the metastatic setting have shown that the efficacy of FOLFOX and CapeOx is quite similar.¹⁰ Thus, it is reasonable to regard FOLFOX or CapeOx as being equally acceptable in the adjuvant treatment of colon cancer. However, the convenience of parenteral FOLFOX versus parenteral + oral CapeOx is debatable. The CapeOx regimen includes oral capecitabine as well as intravenous oxaliplatin, which places significant responsibility on the patient to follow a complicated medication schedule. For this reason, CapeOX is appropriate therapy only for highly motivated and reliable patients, or for patients with competent, involved caregivers who can be counted on to ensure that medications are taken correctly.

Negative Trials

The drugs irinotecan, bevacizumab, and cetuximab have all demonstrated anticancer activity in the metastatic setting. However, none have shown any benefit in the adjuvant setting. Therefore, these three agents should not be used in treating anything but stage IV disease.

Irinotecan

Irinotecan, a topoisomerase I inhibitor, has shown important antitumor activity in patients with metastatic colon cancer. However, its efficacy is a matter of some debate. A randomized phase III trial of 1200 patients receiving a weekly bolus 5-FU/LV with or without irinotecan demonstrated no clinical benefit to irinotecan. Instead, higher rates of early death and serious, life-threatening (grades 3 and 4) neutropenia were seen in the irinotecan-inclusive arm of the study.¹¹ Similar results were observed in studies of irinotecan with twice-weekly 48-hour infusions of 5-FU/LV (FOLFIRI). Likewise, two European studies of combination irinotecan + 48-hour infusion showed no benefit.^12,13 Another report on 5-FU/LV +/− irinotecan following resection of colorectal liver metastases also failed to show any benefit.¹³

Bevacizumab

In a phase III trial of irinotecan, 5-FU, and LV +/− bevacizumab in patients with metastatic colon cancer, those receiving bevacizumab had a 4.7-month median survival benefit. Subsequently, the NSABP conducted a 2673-patient randomized trial comparing FOLFOX to FOLFOX + bevacizumab in patients with stage II and III disease.¹⁴ Although there was an early trend toward improved DFS at 1¼ year, any advantage in DFS had vanished by 3 years. There was no statistically significant improvement in either DFS or OS, nor was there any improvement in the stage III subset (OS in stage III patients: HR 1.0, p = 0.99). Another trial randomized 3451 patients with stage II and III colon cancer (2867 with stage III disease) to one of three arms: FOLFOX, FOLFOX + bevacizumab, or CapeOx + bevacizumab.¹⁵ The results of this study, too, were negative: when bevacizumab was added to treatment, no benefit was observed. Bevacizumab did not improve DFS; in fact, there was a trend toward decreased OS in the FOLFOX + bevacizumab and CapeOx + bevacizumab arms, compared to the FOLFOX control arm. As such, there is no role for the use of bevacizumab in the adjuvant treatment of stage II or III colon cancer.