Frontline Treatment Selection in RAS Wild-Type mCRC

Chemotherapy is typically initiated for patients with metastatic colorectal cancer (mCRC) who present with symptoms and a good performance status, states Howard S. Hochster, MD. Treatment strategies include the chemotherapy regimens FOLFOX (leucovorin, fluorouracil, and oxaliplatin), FOLFIRI (leucovorin, fluorouracil, and irinotecan), or FOLFOXIRI (leucovorin, fluorouracil, oxaliplatin, and irinotecan), and possibility the addition of an EGFR or angiogenesis inhibitor.

Full RAS testing should be completed before beginning treatment with a biologic agent, since those with an alteration do not benefit from EGFR inhibition, notes Hochster. A biopsy of the primary tumor should be obtained at diagnosis and will usually suffice for initial treatment decisions, says Richard L. Goldberg, MD. Full molecular testing may be needed later in the course of a patient’s disease treatment, adds Goldberg.

Studies have compared frontline treatment with chemotherapy plus cetuximab or bevacizumab in patients with RAS wild-type mCRC, notably the 80405 and FIRE-3 trials. The results from these analyses have been largely unclear, in terms of identifying one optimal frontline therapy.

In 80405, patients with RAS wild-type mCRC experienced a median overall survival (OS) of 31.2 months with bevacizumab versus 32.0 months with cetuximab. Progression-free survival (PFS) did not differ significantly between the two arms (11.3 vs 11.4 months for bevacizumab and cetuximab, respectively). In FIRE-3, the median OS was 33.1 months with cetuximab versus 25.6 months with bevacizumab; however, there was no difference in PFS, which raised several questions.

The discordance between these studies could have been caused by numerous events, such as second-line therapy, testing strategies, aspirin use, and vitamin D levels. The battery of tests an individual undergoes, such as colonoscopy and liver biopsy, may be performed in separate laboratories, notes Fadi Braiteh, MD. Since the samples can be sent to different locations, it is important for each pathologist to receive a complete picture of what has already been done.

Studies have shown that individuals with higher vitamin D levels fare better than those with lower levels, comments Goldberg. It is important to distinguish this observation from the statement that therapeutic vitamin D supplements will improve outcomes, says Hochster, who notes a need for a prospective trial to investigate that claim.