Can the duration of adjuvant oxaliplatin-based chemotherapy be reduced in certain stage III colon cancer patients?

A pooled analysis, including data from 6 large clinical trials, failed to show that 3 months of oxaliplatin-based chemotherapy is non-inferior to the standard 6-month adjuvant chemotherapy in stage III colon cancer. Although negative, the study at hand, including more than 12,800 patients, did show that 3 months of chemotherapy was only minimally less effective as 6 months in patients with a relatively lower recurrence risk. Moreover, this shorter regimen caused fewer side effects, particularly when looking at neurotoxicity. As such, this trial provides a framework for further discussion on the optimal duration of adjuvant chemotherapy in this setting.

Since 2004, 6 months of oxaliplatin-based treatment (FOLFOX or CAPOX) has been the standard adjuvant therapy for stage III colon cancer. Since oxaliplatin is associated with cumulative neurotoxicity, which can result in permanent numbness, tingling, and pain, a shorter duration of adjuvant therapy could diminish patients toxicity and could lead to a substantial saving in healthcare expenditures. The presented study pooled data from 6 concurrently conducted randomized phase III trials (SCOT, TOSCA, Alliance/SWOG 80702, IDEA France [GERCOR/PRODIGE], ACHIEVE, HORG) and assessed whether 3 months of adjuvant chemotherapy was as effective as 6 months. The study was established more than 10 years ago as the IDEA collaboration (International Duration Evaluation of Adjuvant therapy). With 12,834 patients included, this is the largest collaboration of its kind in oncology. The primary objective of the study was to show that the 3-month regimen was non-inferior to the standard 6-month regimen in terms of disease free survival (DFS).

Patients were followed for a median time of 39 months. For all patients combined, the rate of disease-free survival at 3 years was slightly lower with 3 months of chemotherapy than with 6 months of chemotherapy (74.6% vs. 75.5%; HR[95%CI]:1.07[1.00-1.15]). As such, the study did not meet its primary endpoint of non-inferiority. The type of chemotherapy regimen selected affected the difference in 3-year DFS between the 3-month and 6-month treatment duration (75.9% vs. 74.8% with CAPOX and 73.6% vs. 76.0% with FOLFOX), although the difference was relatively small in both cases. In the subset of patients with lower risk colon cancer (defined as cancer spread to 1-3 lymph nodes and not completely penetrated through the bowel wall), the DFS rate at 3 years was almost identical for those who received 3 (83.1%) and 6 months of chemotherapy (83.3%). The rate of clinically meaningful (grade 2 or greater) nerve damage differed depending on the type of chemotherapy regimen received, but was consistently higher for people who received 6 months versus 3 months of chemotherapy (45% vs. 15% with FOLFOX and 48% vs. 17% with CAPOX).

In summary, the primary endpoint of non-inferiority was not proven in this trial. However, the shorter 3-month course of chemotherapy was associated with a less than 1% lower chance of being colon cancer free at 3 years compared to the standard 6-month course (74.6% vs. 75.5%). In patients considered at low risk of cancer recurrence, the difference was even smaller. Nerve damage was substantially less common in patients receiving a 3-month course of chemotherapy vs. a 6-month course. These data provide a framework for discussion on risks and benefits of individualized adjuvant therapy approaches. However, to date six months of oxaliplatin-based chemotherapy should remain the standard of care for stage III colon cancer. In reality however, few patients are able to receive all 6 months of oxaliplatin-based chemotherapy due to treatment-related adverse events. The researchers suggest that the final duration of the oxaliplatin-based therapy should be a continuous matter of discussion between the physician and the patient based on the toxicity a patient experiences.

Reference

Shi Q, Sobrero A, Shields A, et al. Prospective pooled analysis of six phase III trials investigating duration of adjuvant (adjuv) oxaliplatin-based therapy (3 vs 6 months) for patients (pts) with stage III colon cancer (CC): The IDEA (International Duration Evaluation of Adjuvant chemotherapy) collaboration. Presented at ASCO 2017, Abstract LBA1.