Proefschrift

CHAPTER 1. INTRODUCTION Treatment FDA Approval Leuprolide acetate 1985 Goserelin acetate 1987 Flutamide 1989 Docetaxel 1995 Bicalutamide 1995 Nilutamide 1996 Mitoxantrone hydrochloride 2000 Degarelix 2008 Cabazitaxel 2010 Sipuleucel-T 2010 Abiraterone acetate 2011 Enzalutamide 2012 Radium 223 dichloride 2013 Apalutamide 2018 Darolutamide 2019 Table 1.1: Available treatments approved and year of approval by the FDA for prostate cancer. cells that are already resistant or can quickly evolve resistance to the treatment due to their evolutionary history. In this way, when treatment is applied, a strong initial response is generally observed, as the treatment is effective against the abundant sensitive cells (Figure 1.2). Just as antibiotics kill 99.99% of bacteria (Davies and Davies, 2010), this initial therapy may kill 99.99% of the cancer cells, resulting in a clinical remission of disease. Unfortunately, as therapy is continued, the resistant cells initially present, or cells that evolved a novel resistance mechanism in direct response to therapy, can continue to proliferate. Eventually this resistant cell population will grow large enough to be clinically detected in what is known as disease relapse. Under the lens of Darwinian evolution, treatment failure due to evolution of resistance in cancer is almost unsurprising considering the deep understanding of treatment failure in bacterial and viral infections due to evolutionary processes (Fair and Tor, 2014; Irwin et al., 2016). 1.3 The Folly of Maximum Tolerated Dose Even with this new understanding of cancer as a Darwinian disease the consequences of evolutionary principles are generally not considered in the clinical treatment of metastatic disease. Instead, the conventional treatment strategy used universally in the clinic is known as maximum tolerated dose (MTD). The MTD of a new drug is determined in the phase I trial using what is known as a dose escalation method. A cohort of 3 patients are given a safe starting dose determined by animal toxicological studies. If none of these patients experience dose-limiting toxicity such as neutropenia, sepsis, nausea, vomiting, etc., another three patient cohort is given an incrementally higher dosage. This escalation 6