Adjuvant Chemotherapy in the Treatment of Colon Cancer
ADJUVANT CHEMOTHERAPY IN STAGE III COLON CANCER
Postoperative adjuvant chemotherapy is the standard of care for patients with stage III disease. In the 1960s, infusional fluorouracil was first used to treat inoperable colon cancer.78,79 After encouraging results, the agent was used both intraluminally and intravenously as an adjuvant therapy for patients undergoing resection with curative intent; however, only modest benefits were described.80,81 The National Surgical Adjuvant Breast and Bowel Project (NSABP) C-01 trial (Table 3) was the first study to demonstrate a benefit from adjuvant chemotherapy in colon cancer. This study randomly assigned patients with stage II and III colon cancer to surgery alone, postoperative chemotherapy with fluorouracil, semustine, and vincristine (MOF), or postoperative bacillus Calmette-Guérin (BCG). DFS and OS were significantly improved with MOF chemotherapy.82 In 1990, a landmark study reported on outcomes after treatment of 1296 patients with stage III colon cancer with adjuvant fluorouracil and levamisole for 12 months. The combination was associated with a 41% reduction in risk of cancer recurrence and a 33% reduction in risk of death.83 The NSABP C-03 trial (Table 3) compared MOF to the combination of fluorouracil and leucovorin and demonstrated improved 3-year DFS (69% versus 73%) and 3-year OS (77% versus 84%) in patients with stage III disease.84 Building on these outcomes, the QUASAR study (Table 3) compared fluorouracil in combination with one of levamisole, low-dose leucovorin, or high-dose leucovorin. The study enrolled 4927 patients and found worse outcomes with fluorouracil plus levamisole and no difference in low-doseversus high-dose leucovorin.85 Levamisole fell out of use after associations with development of multifocal leukoencephalopathy,86 and was later shown to have inferior outcomes versus leucovorin when combined with fluorouracil.87,88 Intravenous fluorouracil has shown similar benefit when administered by bolus or infusion,89 although continuous infusion has been associated with lower incidence of severe toxicity.90 The efficacy of the oral fluoropyrimidine capecitabine has been shown to be equivalent to that of fluorouracil.91
Fluorouracil-based treatment remained the standard of care until the introduction of oxaliplatin in the mid-1990s. After encouraging results in the metastatic setting,92,93 the agent was moved to the adjuvant setting. The MOSAIC trial (Table 3) randomly assigned patients with stage II and III colon cancer to fluorouracil with leucovorin (FULV) versus FOLFOX given once every 2 weeks for 12 cycles. Analysis with respect to stage III patients showed a clear survival benefit, with a 10-year OS of 67.1% with FOLFOX chemotherapy versus 59% with fluorouracil and leucovorin.94,95 The NSABP C-07 (Table 3) trial used a similar trial design but employed bolus fluorouracil. More than 2400 patients with stage II and III colon cancer were randomly assigned to bolus FULV or bolus fluorouracil, leucovorin, and oxaliplatin (FLOX). The addition of oxaliplatin significantly improved outcomes, with 4-year DFS of 67% versus 71.8% for FULV and FLOX, respectively, and a HR of death of 0.80 with FLOX.59,96 The multicenter N016968 trial (Table 3) randomly assigned 1886 patients with stage III colon cancer to adjuvant capecitabine plus oxaliplatin (XELOX) or bolus fluorouracil plus leucovorin (FU/FA). The 3-year DFS was 70.9% versus 66.5% with XELOX and FU/FA, respectively, and 5-year OS was 77.6% versus 74.2%, respectively.97,98
,In the metastatic setting, additional agents have shown efficacy, including irinotecan,99,100 bevacizumab,101,102 cetuximab,103,104 and regorafenib.105 This observation led to testing of these agents in earlier stage disease. The CALGB 89803 trial compared fluorouracil, leucovorin, and irinotecan to fluorouracil with leucovorin alone. No benefit in 5-year DFS or OS was seen.106 Similarly, infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI) was not found to improve 5-year DFS as compared to fluorouracil with leucovorin alone in the PETACC-3 trial.107 The NSABP C-08 trial considered the addition of bevacizumab to FOLFOX. When compared to FOLFOX alone, the combination of bevacizumab to FOLFOX had similar 3-year DFS (77.9% versus 75.1%) and 5-year OS (82.5% versus 80.7%).108 This finding was confirmed in the Avant trial.109 The addition of cetuximab to FOLFOX was equally disappointing, as shown in the N0147 trial110 and PETACC-8 trial.111 Data on regorafenib in the adjuvant setting for stage III colon cancer is lacking; however, 2 ongoing clinical trials, NCT02425683 and NCT02664077, are each studying the use of regorafenib following completion of FOLFOX for patients with stage III disease.
Thus, after multiple trials comparing various regimens and despite attempts to improve outcomes by the addition of a third agent, the standard of care per National Comprehensive Cancer Network (NCCN) guidelines for management of stage III colon cancer remains 12 cycles of FOLFOX chemotherapy. Therapy should be initiated within 8 weeks of surgery. Data are emerging to support a short duration of therapy for patients with low-risk stage III tumors, as shown in an abstract presented at the 2017 American Society of Clinical Oncology annual meeting. The IDEA trial was a pooled analysis of 6 randomized clinical trials across multiple countries, all of which evaluated 3 versus 6 months of FOLFOX or capecitabine and oxaliplatin in the treatment of stage III colon cancer. The analysis was designed to test non-inferiority of 3 months of therapy as compared to 6 months. The analysis included 6088 patients across 244 centers in 6 countries. The overall analysis failed to establish noninferiority. The 3-year DFS rate was 74.6% for 3 months and 75.5% for 6 months, with a DFS HR of 1.07 and a confidence interval that did not meet the prespecified endpoint. Subgroup analysis suggested noninferiority for lower stage disease (T1–3 or N1) but not for higher stage disease (T4 or N2). Given the high rates of neuropathy with 6 months of oxaliplatin, these results suggest that 3 months of adjuvant therapy can be considered for patients with T1–3 or N1 disease in an attempt to limit toxicity.112
CASE PRESENTATION 2
A 57-year-old woman presents to the emergency department with fever and abdominal pain. CT of the abdomen and pelvis demonstrates a left-sided colonic mass with surrounding fat stranding and pelvic abscess. She is taken emergently for left hemicolectomy, cholecystectomy, and evacuation of pelvic abscess. Pathology reveals a 5-cm adenocarcinoma with invasion through the visceral peritoneum; 0/22 lymph nodes are involved. She is given a diagnosis of stage IIC and referred to medical oncology for further management. Due to her young age and presence of high-risk features, she is recommended adjuvant therapy with FOLFOX for 6 months.
