Proefschrift

insecticides selected for increased resistance mechanisms in the moth itself and secondly, the insecticides killed all of the parasitoids of the diamondback moth, resulting in what is known as “competitive release,” an ecological phenomenon whereby removing all competitors for physical space and/or resources allows unconstrained proliferation of a previously constrained population (Connell, 1961). In the coming decades, the agriculture industry and the pesticide manufacturers themselves responded by developing and enforcing guidelines to slow or curtail the widespread evolution of resistance to pesticides (Sparks and Nauen, 2015). These guidelines, known as integrated pest management (IPM), do not attempt eradication of pests, but instead strive to maintain pests, even with the presence of resistant strains, at a level that does not cause economic damage to the crops (Stern et al., 1959). Since then, IPM practices have achieved dramatic success, both as a means of slowing or preventing evolution of resistance of pests to pesticides and in decreasing pesticide use while maintaining high crop yields (Siegfried and Hellmich, 2012; Midingoyi et al., 2019; Woltz et al., 2012; Fernandez-Cornejo, 1998; Tabashnik et al., 2013). Ironically, the large scale implementation of IPM became national policy within a year of the initiation of the “war on cancer.” Unfortunately, this “war on cancer” has waged without the same sort of forethought, cooperation, and practicality regarding evolution of resistance. Now, over 40 years later, cancer is finally being redefined as a process of both ecological and evolutionary dynamics that suffers the same “resistance crisis” to available therapeutic strategies (Crespi and Summers, 2005; Ujvari et al., 2017; Korolev et al., 2014; Merlo et al., 2006; Gatenby and Brown, 2018). In IPM, the system consists of pests, crops, environment, and control methods. Correspondingly, in cancer, the system consists of cancerous cells, normal cells, the patient, and the various drugs available. Interestingly, while the mechanisms of resistance employed by cancer cells are numerous and generally considered impossible to control, many of the same resistance mechanisms are mirrored in agricultural pests (Whelan and Cunningham, 2020). By recognizing the many parallels between clinical oncology and agricultural pest management, we may ask a truly interesting and compelling question: Until truly curative therapies for metastatic disease are developed, can clinical oncology benefit from lessons learned in pest management? 1.5 Integrated Metastatic Management The ultimate goal of intervention in a patient with cancer is to keep the patient alive. This is not synonymous with eradicating all tumor cells in the body. Schipper et al. in their prescient 1995 editorial proposed to abandon the “killing paradigm” and instead focus on attaining a “functional cure” (Schipper et al., 1995). Much like with the treatment for HIV and AIDS, is it possible to live with a cancer burden that does not affect the patient’s quality of life and can this patient eventually succumb to another cause of death? While psychologically difficult to contemplate, it is not medically unreasonable to maintain a substantial cancer burden while also maintaining a high quality of life. In a study of 1105 autopsy cases, 20% had undiagnosed cancer upon death from an unrelated cause. Of these, 54% showed metastatic disease (Burton et al., 1998). 9