Caren van Roekel

260 Chapter 10 • Irinotecan (a camptothecin analog that stabilizes the topisomerase I complex, resulting in single-strand DNA breaks and ultimately cell death (20)) • Oxaliplatin (an alkylating agent, which binds to DNA, inhibiting DNA replication and transcription, resulting in cell death) • Cetuximab and panitumumab (monoclonal antibodies, directed against the epidermal growth factor receptor) • Bevacizumab (monoclonal antibody, directed against the vascular endothelial growth factor receptor (VEGF)) • Aflibercept (a recombinant fusion protein that prevents intra- and extravascular receptor binding of VEGF-A, VEGF-B and placenta growth factor) • Regorafenib (an inhibitor of angiogenic tyrosine kinases) • Trifluridine-tipiracil (TAS-102) (this consists of the nucleoside analog trifuridine that causes DNA strand breaks, inhibiting proliferation of tumor cells, and of tipiracil that prevents breakdown of trifuridine, enabling its function) • Nivolumab, pembrolizumab (immune checkpoint inhibitors targeting the programmed death receptor PD-1) There are inconsistencies in the literature as to whether patients should be treated with sequential single agents or with initial combination chemotherapy. The use of sequential single agents could reduce overall toxicity. Two randomized trials, the FOCUS and CAIRO trials, found a similar median overall survival for sequential versus initial combination therapy. However, progression-free survival was better with combination therapy (median progression-free survival 6 versus 8 months) (21, 22). According to the Dutch guidelines, for patients in a good clinical condition, first-line treatment consists of a fluoropyrimidine combined with bevacizumab, or fluoropyrimidine only. Patients in a poor clinical condition are to receive a combination of a fluoropyrimidine with oxaliplatin or irinotecan. Further treatment lines may consist of a combination of irinotecan, oxaliplatin, a monoclonal antibody, with or without bevacizumab (23). For patients who are chemotherapy-refractory after all common treatment options, a longer overall survival (median 1.8 months) may be obtained after treatment with TAS-102 (24).