Treatment decisions in metastatic colorectal cancer – Beyond first and second line combination therapies

Abstract

Median overall survival (OS) of patients with metastatic colorectal cancer (mCRC) has reached up to 30months in recent clinical trials of first line therapies. Following disease progression after the standard in both, 1st and 2nd line, combination chemotherapy with monoclonal antibodies, many patients maintain a good performance status and a significant proportion is motivated to undergo further therapy. Choices of treatment beyond the second line setting for mCRC are therefore becoming increasingly important. New options have entered the therapeutic field recently: Regorafenib is a multikinase inhibitor approved for mCRC patients who have progressed on chemotherapy (including fluoropyrimidines, irinotecan, and oxaliplatin), plus VEGF inhibitor(s) and - if RAS wild-type - an anti-EGFR inhibitor. Regorafenib significantly improved OS, compared to placebo, in two phase III trials (CORRECT and CONCUR) in mCRC patients. Trifluridine/Tipiracil, an oral fluoropyrimidine, also resulted in significantly improved OS when compared to placebo in the phase III RECOURSE trial, which was conducted in a similar patient population to CORRECT. Reintroduction of previously administered therapy is another valid and commonly used approach, especially for those regimens which were discontinued before progression, e.g. if associated with cumulative toxicities, such as peripheral neuropathy or due to treatment breaks. Re-challenge of drugs to which patients developed resistance is also feasible although evidence for this strategy is limited.

Population-based SEER analysis of survival in colorectal cancer patients with or without resection of lung and liver metastases

“…These therapeutic concepts are well approved in large randomized trials in the first line as well second line settings [11,28]. As refractory patients will be seen more frequently in sequential treatment of mCRC re-challenge concepts have been investigated with promising results [29,30].…”

Review of metastatic colorectal cancer treatment pathways and early clinical experience of trifluridine/tipiracil in the UK named patient programme

“…Targeted biologic treatments, such as the anti-epidermal growth factor receptor (EGFR) treatments, cetuximab and panitumumab, are also recommended for first-line treatment of RAS wild-type mCRC [5]. A range of potential post-second-line agents exist, including EGFR inhibitors (cetuximab/panitumumab), bevacizumab, regorafenib and trifluridine/tipiracil [6,7]; however, EGFR inhibitors are not currently recommended by NICE beyond first line, and therefore are not reimbursed in the UK [8], whilst regorafenib and bevacizumab are not currently available for use in mCRC within the UK irrespective of treatment line.…”

Real‐world treatment patterns and outcomes in refractory metastatic colorectal cancer

“…Adding targeted agents, which include vascular endothelial growth factor (VEGF)‐targeting or epidermal growth factor receptor (EGFR)‐targeting agents, to the chemotherapy regimen can further improve clinical outcomes . After second disease progression (PD2), many patients may still have adequate performance status and be eager to receive further treatment . Active treatment options were limited until the recent introduction of the oral multikinase inhibitor regorafenib and novel oral thymidine‐based nucleic acid analogue trifluridine/tipiracil (TAS‐102).…”