Introduction: the role of systemic therapies in non-resectable metastatic disease
The last 10 to 15 years have seen major advances in the treatment of metastatic colorectal cancer. The average median survival duration is now approaching 3 years, and 5-year survival rates as high as 20% are reported in some trials of patients treated with chemotherapy alone. These improvements have been mainly driven by the availability of new active agents, which include conventional cytotoxic agents other than 5-fluorouracil (5FU), and biologic agents targeting angiogenesis and the epidermal growth factor receptor (EGFR).
There are now eight different classes of drugs with antitumour activity in metastatic colorectal cancer:
- 5FU – usually given intravenously (IV) with leucovorin (LV)
- capecitabine (oral pyrimidine analogue)
- S-1 (orally active combination of tegafur, 5-chloro-2, 4-dihydroxypyridine and potassium oxonate). S-1 is not registered in Australia by the Therapeutic Goods Administration (TGA)i
- tegafur plus uracil (oral). This combination is not registered in Australia by the TGAi
- raltitrexed - a folate analogue and thymidylate synthase inhibitor
- monoclonal antibodies targeting EGFR:
- monoclonal antibodies targeting vascular endothelial growth factor (VEGF):
- bevacizumab – recombinant humanised anti-VEGF monoclonal antibody
- ramucirumab – recombinant monoclonal antibody that binds to and blocks activation of VEGF receptor 2 (VEGFR-2)
- aflibercept – an intravenous recombinant fusion protein that functions as a decoy receptor that prevents intravascular and extravascular VEGF-A, VEGF-B, and placenta growth factor (PlGF) from binding to their receptors.
- regorafenib – an orally active inhibitor of angiogenic tyrosine kinases (including the VEGF receptors 1 to 3), as well as other membrane and intracellular kinases.
- trifluridine-tipiracil (Lonsurf ®) – an oral cytotoxic agent that consists of the nucleoside analogue trifluridine (a cytotoxic antimetabolite that inhibits thymidylate synthase and, after modification within tumour cells, is incorporated into DNA, causing strand breaks) and tipiracil (a potent thymidine phosphorylase inhibitor, which inhibits trifluridine metabolism and also has antiangiogenic properties).
Despite the pace of clinical research, the best way to combine and sequence all of these drugs to optimise treatment is not yet established. In general, exposure to all active drugs, as appropriate, is more important than the specific sequence of administration.
Chapter subsections[edit source]
Please see sections:
- Molecular pathology and biomarkers – implications for systemic therapy
- Systemic chemotherapy treatment options for first-line treatment
- Role of biological agents in first-line treatment of metastatic colorectal cancer
- Subsequent treatment and the continuum-of-care model
- Systemic options for second-line treatment
- Systemic options for third-line treatment
- Supportive care options
- Heinemann V, von Weikersthal LF, Decker T, Kiani A, Vehling-Kaiser U, Al-Batran SE, et al. FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trial. Lancet Oncol 2014 Sep;15(10):1065-75 Available from: http://www.ncbi.nlm.nih.gov/pubmed/25088940.