Proefschrift

within the first two months of treatment. These patients will then be randomized to receive therapy either through adaptive or conventional protocols. Also, a trial for adaptive targeted therapy for advanced melanoma (NCT03543969) is also currently recruiting patients for again a similar 50% cycle protocol. Although not currently in progress, an ideal candidate for the use of adaptive therapy is pancreatic cancer. Pancreatic cancer is rarely diagnosed in early stages and the majority of patients present with metastatic disease. The 5 year survival rate of pancreatic cancer patients is only 4-6% (Ellison and Wilkins, 2010; Yeole and Kumar, 2004). Interestingly, pancreatic cancer has a viable blood marker called carbohydrate antigen (CA 19-9) that could be used to guide adaptive protocols. While this marker is unhelpful in early detection due to the high rate of false positives, its dynamics have been shown to correlate with disease stage and survival in symptomatic patients (Ballehaninna and Chamberlain, 2011). The standard of care is maximum tolerated dose of gemcitabine, which provides an average of 6.8 months of overall survival. A second treatment is available for advanced pancreatic cancer known as FOLFIRINOX, a combination therapy of folinic acid, fluorouracil, irinotecan, and oxaliplatin) that yields a median overall survival of 11.1 months (Ducreux et al., 2015). An adaptive protocol for either of these treatments could potentially provide a much needed benefit to the treatment of advanced pancreatic cancer. 7.6 Concluding Remarks Redefining clinical success to focus primarily on cumulative years with good quality of life regardless of tumor burden will require the joint cooperation of many fields, including oncologists, mathematicians, computer and data scientists, funding agencies, universities, and the pharmaceutical industry. In the simplest sense, the ultimate goal of treating cancer is for the patient to remain alive. Until truly curative therapies for metastatic disease are developed, clinical oncology could greatly benefit from a shift to a long-term disease management paradigm. First and foremost, the use of maximum tolerated dose of available non curative therapies should be generally discontinued. Instead, each available therapy should be administered using a resistance management plan that prolongs the effectiveness of the drug, subsequently lengthening the overall survival of the patient. The combination of adaptive androgen deprivation therapy, adaptive enzalutamide, and adaptive abiraterone treatment has the potential to significantly lengthen the overall survival of men with metastatic prostate cancer. Based on the results from this thesis, it is not unreasonable to assume that the time a drug is effective using current methods can be at least doubled in the clinic. If the effectiveness of this series of drugs can indeed be doubled, men with metastatic prostate cancer could potentially manage their disease for well over 10 years: an extraordinary clinical achievement. 115