Adjuvant systemic chemotherapy in colon cancer

Choices for adjuvant therapy for patients with resected, non-metastatic colon cancer depend on the stage of disease:

Patients with stage I disease do not require any adjuvant therapy.

Patients with low-risk stage II disease can be enrolled in a clinical trial, observed without adjuvant therapy, or considered for capecitabine or 5-FU/leucovorin (LV). The addition of Oxaliplatin to 5-FU based therapy is not considered appropriate adjuvant therapy in patients with stage II disease without high-risk features.

Patients with high-risk stage II disease, defined as those with poor prognostic features, including T4 tumours (stage IIB/IIC), poorly differentiated histology (exclusive of those cancers that are MSI-high [MSI-H]), lymphovascular invasion, PNI, bowel obstruction, lesions with localized perforation or close, indeterminate, or positive margins, or inadequately sampled nodes (<12 lymph nodes) can be considered for adjuvant chemotherapy with 5-FU/LV, capecitabine, FOLFOX, capecitabine/oxaliplatin (CapeOx), or bolus 5-FU/LV/oxaliplatin (FLOX). Observation without adjuvant therapy is also an option in this population. The benefit from adjuvant chemotherapy for stage II patients is a modest but significant survival benefit (83.6% vs 80% 5-year mortality, relative risk of death, 0.82; 95% CI 0.70-0.95; p=0.008).

Microsatellite Instability (MSI) is a marker of a more favorable outcome. The panel recommends that MMR testing be considered to assist decision making in patients with stage II disease.

For patients with stage III disease, the panel recommends 6 months of adjuvant chemotherapy after primary surgical treatment. The treatment options are FOLFOX (preferred) or CapeOx (preferred) FLOX or single-agent capecitabine or 5-FU/LV in patients for whom oxaliplatin therapy is believed to be inappropriate. The addition of oxaliplatin to 5-FU/LV conferred an OS benefit compared to 5-FU/LV alone at the 6 year follow up update (72.9% and 68.7%, respectively (HR 0.80; 95% CI 0.65-0.97; p=0.023). CapeOx showed an improved 3-year disease-free survival (DFS) rate compared with 5-FU/LV (70.9% vs 66.5%, HR 0.80; 95% CI 0.69-0.93; p=0.0045).1

Overall, the benefit and toxicities of 5-FU based adjuvant therapy seem to be similar in older and younger patients. In contrast, the panel cautions that a benefit for the addition of oxaliplatin to 5-FU/LV in patients aged 70 years and older has not been proven in stage II or stage III colon cancer. Individualized assessment will assist in decision making for older patients with CRC.

The panel recommends against the use of bevacizumab, cetuximab, panitumumab, or irinotecan in adjuvant therapy for non-metastatic disease.

The workgroup members unanimously support the general adoption of the NCCN guidelines.

The workgroup members unanimously support the following statements as modifications to the NCCN guidelines:

The lack of convincing benefit of adjuvant therapy in stage II colon cancer without any poor prognostic features supports observation alone as the preferred option for the majority of low risk stage II colon cancer patients. The QUASAR trial showed a modest but significant survival benefit for patients treated with 5-FU/LV compared to observation (83.6% vs 80% 5-year mortality, relative risk of death, 0.82; 95% CI 0.70-0.95; p=0.008). However, the trial also included more than 60% of patients who had <12 lymph nodes sampled, and may reflect patients with higher risk features.2Pooled analysis from SEER databases and meta-analysis showed that OS benefit from chemotherapy was statistically significant for stage III patients but not for (unselected) stage II.3,4However, it can be considered if at least 1 high risk clinical feature is present.

The MOSAIC trial did not show a benefit of the addition of oxaliplatin to 5-FU/LV (FOLFOX) for patients with stage II disease, both for DFS and OS, despite accounting for such patients with high risk features as described above (HR 0.72; 95% CI 0.50-1.02; p=0.063 and HR 0.91; 95% CI 0.61-1.36; p=0.648 respectively).1The 5 year DFS rate was 82.3% for FOLFOX vs 74.6% for 5-FU/LV, while the 6 year OS rate was 85% vs 83.3%. Similar results were seen in the C-07 study comparing FLOX to 5-FU/LV5(Absolute benefit of 2% for 5 year DFS and 0.1% for OS, both statistically not significant). Given the potential risk of long term peripheral neuropathy among other side effects, and the lack of evidence, the routine addition of oxaliplatin to 5-FU/LV is not advised in the adjuvant treatment of most patients with stage II colon cancers.

The efficacy and safety data of randomized trials comparing either FOLFOX or CapeOx to 5-FU based regimens are more convincing compared to randomized trials comparing FLOX to 5-FU based regimens. In general, FLOX should not be considered a regimen of choice.