SUMMARY: ColoRectal Cancer (CRC) is the third most common cancer diagnosed in both men and women in the United States. The American Cancer Society estimates that approximately 140,250 new cases of ColoRectal Cancer will be diagnosed in the United States in 2018 and over 50,630 patients are expected to die of the disease. Adjuvant chemotherapy for patients with resected, locally advanced, node-positive (stage III) colon cancer, has been the standard of care since the 1990s. Adjuvant treatment with an ELOXATIN® (Oxaliplatin) based chemotherapy regimen has been considered standard intervention since 2004, for patients with stage III colon cancer, following surgical resection, and has been proven to decrease the chance of recurrent disease. Chemotherapy regimens have included (FOLFOX – Leucovorin, 5-FluoroUracil, ELOXATIN®) or CAPOX/XELOX (XELODA®/Capecitabine and ELOXATIN®), given over a period of 6 months. ELOXATIN® can however be associated with neuropathy which can be long lasting or permanent, depending on the duration of therapy. Additional toxicities with longer duration of chemotherapy include diarrhea, fatigue as well as more office visits.
The IDEA Collaboration is a prospective, pre-planned pooled analysis of 6 concurrently conducted randomized phase III trials, which included 12,834 patients from 12 countries. The goal of this study was to determine if 3 months of adjuvant chemotherapy would be as effective as 6 months of therapy and would be non-inferior. Of the enrolled patients with stage III disease, 13% had T1-2 disease, 66% had T3 tumors and 21% had T4 tumors. Seventy one percent (71%) had N1 disease and 28% of the patients had N2 disease. Approximately 60% had low-risk disease (T1-3, N1) and 40% had high-risk (T4 or N2). Overall, about 40% of patients received CAPOX regimen and 60% received FOLFOX regimen. The primary endpoint was Disease Free Survival (DFS).
At a median follow up of 41.8 months, although non-inferiority of 3 months of therapy as compared with 6 months of therapy could not be confirmed in the overall treatment population, clinically relevant findings according to treatment were noted, in prespecified subgroups of patients. Among those patients who received FOLFOX regimen, 6 months of adjuvant therapy was superior to 3 months (HR=1.16; P=0.001 for superiority of 6-month therapy). However, among those patients who received CAPOX, the Disease Free Survival for 3 months versus 6 months was non-inferior (HR=0.95; P=0.006), and this was highly significant.
In an exploratory analysis, it was noted that among the patient group with low-risk cancers (T1-3, N1 cancers), 3 months of therapy was non-inferior to 6 months of therapy (HR= 1.01) with 3-year disease-free survival of 83.1% and 83.3%, respectively. However, among the patients with high-risk cancers (T4, N2, or both), 6 months of adjuvant therapy was superior to 3 months (HR= 1.12; P=0.01 for superiority).
When subgroup analysis was performed according to treatment and risk group, among the patients with low-risk tumors, 3 months of adjuvant therapy with CAPOX was non-inferior to 6 months of therapy. Outcomes after 3 months of adjuvant FOLFOX therapy were worse than those after 6 months, independent of risk group. For patients with high-risk tumors, 6 months of adjuvant therapy with FOLFOX was superior to 3 months, with a 3-year disease-free survival of 64.7% versus 61.5%. It has been hypothesized that the protracted delivery of a Fluoropyrimidine with CAPOX might have been more effective than the twice-monthly 5-FUinfusions with FOLFOX as an adjuvant therapy. Grade 2 or more neurotoxicity was significantly lower for patients who received 3 months of adjuvant therapy versus 6 months (P <0.0001), regardless of the treatment regimen (17% vs 48% for FOLFOX and 15% vs 45% for CAPOX/XELOX, respectively).
It was concluded by the IDEA collaboration that, a risk-based approach has to be taken when making adjuvant chemotherapy recommendations for patients with stage III colon cancer, taking into consideration choice of treatment regimen and duration of therapy. In patients treated with adjuvant CAPOX/XELOX regimen, 3 months of therapy was as effective as 6 months, particularly in the low risk subgroup. In patients treated with FOLFOX, 6 months of adjuvant therapy compared to 3 months, resulted in a higher rate of Disease Free Survival, particularly in the high-risk subgroup. Duration of Adjuvant Chemotherapy for Stage III Colon Cancer. Grothey A, Sobrero AF, Shields AF, et al. N Engl J Med 2018; 378:1177-1188