Proefschrift

CHAPTER 1. INTRODUCTION The human body is surprisingly adept at maintaining function in the presence of malignant growths. An example of a bone cross-section from a patient who died of metastatic prostate cancer at Johns Hopkins University (provided by Dr. Pienta) shows extensive bone infiltration yet the patient had normal marrow function at the time of death. In small cell lung cancer, there are many cases where patients have no symptoms of metastatic disease only to progress to death extremely quickly, sometimes within a week of onset of any symptom at all. For example, Figure 1.4 shows the liver of a patient with small cell lung cancer that presented with liver failure only nine days before death (Guerriero et al., 2019). The liver in this example was completely infiltrated by the lung metastatic cells, with only thin cords of hepatocytes remaining. Yet this patient had normal liver function up until 9 days before death. If we accept the psychological burden of Figure 1.4: Left: Bone cross-section from a patient who died of metastatic prostate cancer at Johns Hopkins University (provided by Dr. Pienta). The large white nodules are metastatic lesions. Right: Cross-sections showing the hepatic parenchyma completely occupied by yellowish-white nodules, with an average diameter of 3-4 mm. The liver weighed 4.25 kg where normal livers usually weight approximately 1.5 kg. tolerating metastatic disease for long periods of time, how does one go about actually achieving this clinically? In 2015, Barzman et al. formalized the eight fundamental principles of IPM that proved most successful in obtaining long-term control of pest populations (Barzman et al., 2015). These principles advocate for the judicious use of any pesticide in order to explicitly delay or prevent evolution of resistance, maximize the useful life of the toxin, and minimize toxicity to the non-target organisms. In this thesis, these concepts are discussed within the context of cancer biology, and Integrated Metastatic Management is qualitatively formalized as a framework to build and develop a long-term management paradigm for metastatic disease by integrating evolutionary dynamics into cancer therapy. Implementing facets of IPM principles into clinical oncology can result in the slowing or curtailing of widespread resistance to treatment, reducing overall drug usage, and increasing the overall survival and quality of life of cancer patients. 1.6 Adaptive Therapy Only within the last couple of decades have studies suggested incorporating IPM-like principles into clinical cancer therapy in an attempt to delay or prevent evolution of 10