Combined inhibition of BRAF and MEK in melanoma patients
The treatment of metastatic colorectal cancer has improved markedly during the past 15 years. With the development of irinotecan, oxaliplatin, anti-EGFR antibodies, and anti-VEGF treatment, patients with stage IV colon cancer live on average for 2 years after diagnosis, and 20% of patients can expect to live for 5 years or longer.1 However, of these recent additions to fluorouracil, only oxaliplatin has been useful in the adjuvant setting for patients with stage III colon cancer.
Taieb and colleagues present the latest adjuvant clinical trial testing one of these new agents, cetuximab. The PETACC-8 study was a multi-institutional study in which 2559 patients with stage III colon cancer were randomly assigned to receive either oxaliplatin, fluorouracil, and leucovorin chemotherapy (FOLFOX4) plus cetuximab or FOLFOX4 without cetuximab. The primary endpoint was to assess disease-free survival in the 1602 patients with KRAS wild-type tumours. The investigators reported no difference in disease-free survival or overall survival between the two groups. The study had no major flaws, robust methods, well-balanced groups, and no major design issues. Although CT scanning was not part of the eligibility criteria, 90% of patients received CT scans and investigators recorded no harmful effects.
Unfortunately, these results are similar to the findings of the N0147 trial in the USA, which was a similarly designed study that found no positive effect of the addition of cetuximab to the modified sixth version of FOLFOX (FOLFOX6) in the adjuvant setting. In view of the recent findings of the PRIME and OPUS studies that showed that additional RAS mutations affected outcomes of patients with metastatic disease, a more exhaustive look at RAS mutations might yield better results. However, the results from the subset analysis of N0147 make this highly unlikely. Mismatch repair status could have affected the outcome of this study, but again, lessons from N0147 make this situation unlikely. When taken together, N0147 and PETACC-8 essentially cement the findings of each study.
In view of the effectiveness of anti-EGFR antibody treatment in patients with stage IV colon cancer who do not have mutations of the RAS pathway, the question is why does a strategy that works reasonably well in the metastatic setting have no effect in the adjuvant setting? Two main areas of investigation might give answers to this question. First, the mechanism of development of metastases in colon cancer is probably distinct from the mechanism of worsening metastatic disease. Findings of the study by Taieb and colleagues showed that cetuximab does not affect the metastasis cascade for colon cancer. The beneficial effect in patients with T4N2 disease seen on subset analysis was probably due to the efficacy of this regimen on subclinical metastases as the rapidity of recurrence suggests. Perhaps investigators were lucky with fluorouracil; the drug's efficacy in the metastatic setting might have nothing to do with its efficacy in the adjuvant setting. An interesting area of study might be to establish what aspects of the metastatic cascade in colon cancer are affected by fluorouracil that cetuximab, bevacizumab, and irinotecan do not.
The second area of investigation includes the heterogeneity of colon cancer. Clinicians divide colon cancer on the basis of molecular genetics. Findings of studies have shown these differences might be apparent from gene expression profiles, but the mechanistic underpinnings and biological function of these transcriptional footprints remain an active area of investigation. Together, these data suggest that molecular changes associated with the metastatic phenotype are not solely defined by genetic mutations and the pathways linked with dissemination are likely to be distinct from those enriched in primary tumours and established metastases.
In view of the paucity of new drugs on the horizon for colon cancer, perhaps we have an opportunity. The recent finding that aspirin might preferentially prevent metastatic disease in PI3K-mutant colon cancers. Efforts within the cooperative groups and major academic programs should be renewed to build on scientific findings regarding the metastatic cascade and attempt to inhibit it by looking at putative inhibitors of specific pathways. The present intergroup adjuvant colon cancer study (CALGB-SWOG 80702) attempts to do this with celecoxib. To find a cure, the present framework of drug development in the adjuvant setting needs to change.
The wide gulf between stage III and stage IV colon cancer. The Lancet Oncology. 2014.15(8):785-786