Highlights
- •Optimal sequencing of cytotoxic/targeted agents in metastatic colorectal cancer remains unclear.
- •First-line choice of therapy is critical as it affects treatment decisions in later lines.
- •Molecular profiling has established new targets that may impact sequencing.
- •Recent knowledge of tumour evolution also has clinical implications for sequencing.
Abstract
Metastatic colorectal cancer (mCRC) remains incurable in most cases, but survival
has improved with advances in cytotoxic chemotherapy and targeted agents. However,
the optimal use and sequencing of these agents across multiple lines of treatment
is unclear. Here, we review current treatment approaches and optimal treatment sequencing
across the first-, second- and third-line settings in mCRC, including biological aspects
affecting sequencing and rechallenge. Effective first-line therapy is a key determinant
of treatment outcomes and should be selected after considering both clinical factors
and biological markers, notably RAS and BRAF. The second-line regimen choice depends on the systemic therapies given in first-line.
Anti-angiogenic agents (e.g. bevacizumab, ramucirumab and aflibercept) are indicated
for most patients, whereas epidermal growth factor receptor (EGFR) inhibitors do not
improve survival in the second-line setting. Molecular profiling is important in third-line
treatment, with options in RAS wild-type patients including EGFR inhibitors (cetuximab or panitumumab), regorafenib
and trifluridine/tipiracil. Immunotherapy with pembrolizumab or nivolumab ± ipilimumab
may be considered for patients with high microsatellite instability disease. Targeting
HER2/neu amplification shows promise for the subset of CRC tumours displaying this abnormality.
Sequencing decisions are complicated by the potential for any treatment break or de-escalation
to evoke a distinct clinical progression type. Ongoing trials are investigating the
optimal sequencing and timing of therapies for mCRC. Molecular profiling has established
new targets, and increasing knowledge of tumour evolution under drug pressure will
possibly impact on sequencing.
Keywords
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Article info
Publication history
Published online: January 25, 2019
Accepted:
December 18,
2018
Received:
November 25,
2018
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© 2018 Elsevier Ltd. All rights reserved.
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- More rationale for optimal sequencing of therapeutic monoclonal antibodies in metastatic colorectal cancerEuropean Journal of CancerVol. 117
- PreviewLarge recent multicentric randomised studies highlight the opportunities offered by a multiple treatment strategy in RAS wild-type metastatic colorectal cancer (mCRC). A review in the European Journal of Cancer [1] revealed that the optimal use and sequencing of cytotoxic chemotherapy and targeted agents across multiple lines of treatment for mCRC remain unclear. However, from the recently published randomised phase 2 PRODIGE 18 clinical trial, it appears that continuation of bevacizumab with second-line chemotherapy after progression confers a survival advantage (both overall survival [OS] and progression-free survival [PFS]) as compared with the alternative strategy of switching both the chemotherapy regimen and the targeted therapy [2].
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