Proefschrift

Figure 1.2: Example PSA blood serum dynamics of a patient at Moffitt Cancer Center. While each individual therapy initially provides some clinical benefit, as shown in the decrease of measured PSA indicating a decrease in cancer cells in the body, evolution of resistance is seen with each new drug. Eventually disease relapse occurs to all available drugs and the patient succumbs to the disease. scheme continues until 2 of the 3 patients experience dose limiting toxicities and the phase II trial dose is defined as the dosage just below this toxic dose level (Le Tourneau et al., 2009). In this way, at least 33% of patients will experience toxicity issues known as adverse events during MTD dosed therapy (Begg and Carbone, 1983). These adverse events are any unfavorable sign, symptom, or disease associated with treatment (Trotti et al., 2003). Adverse events are graded on a scale from 1 - 5 with grades greater than 3 generally considered dose limiting warranting a change in therapy. Even with the widespread understanding that there is a balance to be maintained between the efficacy and toxicity of drugs, MTD continues to be the drug dose of choice, often overemphasizing the efficacy at the cost of inflicting harm directly with the therapy (Niraula et al., 2012). For an alarming example, in a recent audit of mortality within 30 days of chemotherapy, 7.5% of deaths of 1976 patients were directly caused by the chemotherapy itself (O’Brien et al., 2006). In metastatic prostate cancer, consider, for example, two of the most common drugs, leuprolide and abiraterone which provide a 13.9 month and 5.6 month progression free survival, respectively, until disease relapse is detected either using bone scans or PSA blood measurements (De Bono et al., 2011; Crawford et al., 1989). The toxicities of these drugs include, but are not limited to, general pain, hot flashes and sweats, gastrointestinal and urinary tract disorders, edema, diarrhea, vomiting, respiratory infections, and anemia. Furthermore, leuprolide costs $1,500/month and abiraterone costs more than $9,000/month. The continued use of MTD in spite of the physical and financial toxicities is justified because the goal of giving MTD is to eradicate every cancerous cell in the body to ultimately result in a cure. In light of the invariable failure of these drugs to provide cure, these physical and financial toxicities caused by MTD are indefensible. This failure is rooted in the very design of MTD which precipitates a “resistance crisis.” 7