Duration of adjuvant therapy for stage III colon cancer: No longer one size fits all

In 1990, a National Institute of Health consensus conference concluded that adjuvant chemotherapy should be recommended to patients with stage III colon cancer after surgical resection to reduce the risk of recurrence and improve survival.¹ The initial trials that led to this conclusion tested 12 months of adjuvant fluoropyrimidine-based (either intravenous 5-FU or oral capecitabine) therapies; however, at least three trials demonstrated that six months of therapy was non-inferior to 12 months. ^{2 – 4}

Six months of therapy remained the standard for the subsequent decade of trials testing multidrug regimens that combine fluoropyrimidine with oxaliplatin, irinotecan, bevacizumab, or cetuximab. At least three trials showed improved disease-free survival (DFS) with the addition of oxaliplatin.^5-7 Although moving the bar on the cure rate was an important advancement, oxaliplatin led to additional toxicities, particularly long-lasting neuropathy that can affect patients for extended periods and can become permanent. Multiple trials to test supportive agents to reduce or prevent neuropathy were unsuccessful. Given that neuropathy from oxaliplatin is cumulative and dependent on total dose delivered, researchers have expressed great interest in testing shorter duration of therapy.

IDEA collaboration

The International Duration Evaluation of Adjuvant therapy (IDEA) collaboration included six trials to test three versus six months of adjuvant fluoropyrimidine and oxaliplatin (see Table 1).⁸ Based on data from the metastatic setting, the efficacy of FOLFOX (5-fluorouracil, leucovorin, and oxaliplatin) and of capecitabine and oxaliplatin (CAPOX) was assumed to be similar in the adjuvant setting.⁹ Balancing goals of minimizing relapse risk with reducing toxicity (particularly cumulative neuropathy), the international team agreed on a non-inferiority margin for disease relapse that allowed for up to 12 percent relative risk increase, when comparing three versus six months of adjuvant therapy. This margin for relapse practically translates to the fact that the upper limit of the 95 percent confidence interval (CI) of the hazard ratio (HR) needed to be less than 1.12.

Table 1. Trials included in IDEA collaboration

Over the span of nearly a decade, 12,834 patients from around the world were enrolled, treated, and followed in the IDEA collaboration on six randomized clinical trials.⁸ In June 2017, the results of non-inferiority were presented. As anticipated, toxicities were significantly less after three versus six months of therapy. Of particular interest, grade 2 or higher neuropathy rate was 16 percent versus 47 percent (p < 0.0001). When considering all patients randomized who received at least one dose of chemotherapy, the disease relapse HR comparing three versus six months of therapy was 1.07, with 95 percent CI of 1.00–1.15. Since the CI crossed 1.12, non-inferiority was not demonstrated.

IDEA results

Notably, several preplanned subgroup analyses also were presented. First, approximately 60 percent of patients received FOLFOX and approximately 40 percent received CAPOX across the six trials. For patients who received FOLFOX, three-year DFS was 73.6 percent versus 76 percent (three versus six months, HR 1.16 [95 CI 1.06–1.26]); these results suggest inferiority of three months of therapy when treated with FOLFOX. In contrast, and to the surprise of investigators given the data for metastatic disease, for patients who received CAPOX, three-year DFS was 75.9 versus 74.8 percent (three versus six months, HR 0.95 [95 CI 0.8–1.06]); this subgroup met the criteria for non-inferiority.⁸

Because patients were not randomized to FOLFOX versus CAPOX, it is impossible to conclude CAPOX is a more efficacious adjuvant regimen, but the interaction by regimen was significant (p = 0.0051) and thus if one chooses CAPOX as an adjuvant therapy, three months of therapy is non-inferior to six months. The biological rationale for this apparent difference by treatment regimen is unclear. Chance or bias by indication are possible reasons, but the difference in fluoropyrimidine dosing (more continuous with CAPOX) or total dosage of oxaliplatin in the initial month of the treatment also are possible explanations.

Additionally, subgroup analyses by T and N stage were presented. The initial analysis plan considered subgroup by T stage (T 1–2 versus T3 versus T4) and N stage (N1 versus N2). There were no statistically significant interactions by T stage (p = 0.36) or N stage (p = 0.44), though T4 tumors showed inferiority with three months of therapy compared with six months. However, higher-risk tumors (T4 or N2), which constituted 40 percent of the cohort, had a clinically meaningful worse three-year DFS (60 percent) as compared with better-risk tumors (T1–3, N1; 80 percent three-year DFS). When considering risk groups, the HR for three versus six months of therapy for patients with T1–3 N1 tumors was 1.10 (95 percent CI 0.90–1.12), whereas the HR for patients with T4 or N2 tumors was 1.12 (95 percent 1.03–1.23), suggesting non-inferiority with three months of therapy for better-risk tumors but inferiority for higher-risk tumors (see Table 2).

Table 2. DFS by regimen and T and N stage-based risk groups

Unanswered questions remain

The IDEA collaboration is the largest prospective effort in colon cancer conducted, demonstrating the feasibility of publicly funded international research. While the intention was to arrive at a simple answer of whether three months is sufficient or six months is necessary, stepping back, it is not surprising that it is more complicated because stage III colon cancer is not a single disease biologically.

Many unanswered questions remain, including how to apply these data to rectal cancer or stage II colon cancer, whether a mixed strategy of three months oxaliplatin-based therapy followed by three months of fluoropyrimidine only would be a better option, and the possibility of further refining prognostic features that can be considered to determine duration of therapy. Although IDEA will not answer all of these questions, many ongoing efforts seek to further classify phenotype and molecular markers to eventually develop a model that can be used to individualize the duration of adjuvant therapy for each stage III patient.

References

1. NIH Consensus Conference. Adjuvant therapy for patients with colon and rectal cancer. JAMA. 1990;264(11):1444-1450.
2. Haller DG, Catalano PJ, Macdonald JS, et al. Phase III study of fluorouracil, leucovorin, and levamisole in high-risk stage II and III colon cancer: Final report of Intergroup 0089. J Clin Oncol. 2005;23(34):8671-8678.
3. O’Connell MJ, Laurie JA, Kahn M, et al. Prospectively randomized trial of postoperative adjuvant chemotherapy in patients with high-risk colon cancer. J Clin Oncol. 1998;16(1):295-300.
4. Dencausse Y, Hartung G, Sturm J, et al. Adjuvant chemotherapy in stage III colon cancer with 5-fluorouracil and levamisole versus 5-fluorouracil and leucovorin. Onkologie. 2002;25(5):426-430.
5. Kuebler JP, Wieand HS, O’Connell MJ, et al. Oxaliplatin combined with weekly bolus fluorouracil and leucovorin as surgical adjuvant chemotherapy for stage II and III colon cancer: Results from NSABP C-07. J Clin Oncol. 2007;25(16):2198-2204.
6. André T, Boni C, Mounedji-Boudiaf L, et al. Multicenter international study of oxaliplatin/5-fluorouracil/leucovorin in the adjuvant treatment of colon cancer (MOSAIC) investigators. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med. 2004;350(23):2343-2351.
7. Haller DG, Tabernero J, Maroun J, et al. Capecitabine plus oxaliplatin compared with fluorouracil and folinic acid as adjuvant therapy for stage III colon cancer. J Clin Oncol. 2011;29(11):1465-1471.
8. Grothey A, Sobrero AF, Shields AF, et al. Duration of adjuvant chemotherapy for stage III colon cancer. N Engl J Med. 2018;378:1177-1188.
9. Cassidy J, Clarke S, Díaz-Rubio E, et al. Randomized phase III study of capecitabine plus oxaliplatin compared with fluorouracil/folinic acid plus oxaliplatin as first-line therapy for metastatic colorectal cancer. J Clin Oncol. 2008;26(12):2006-2012.