Maarten van der Doelen

Chapter 9

To date, the effect of radium-223 therapy is monitored using monthly biochemical tests and imaging bone scintigraphy and CT of thorax, abdomen and pelvis before and after radium-223 therapy. Although these evaluation methods provide important information about the response to therapy, new noninvasive biomarkers for effect monitoring are needed. In chapter 3 of this thesis, we describe the outcomes of an explorative prospective multicenter study that evaluated changes in circulating peripheral blood mononuclear cells of thirty mCRPC patients collected before, during, and after treatment with radium-223. We observed a substantial decrease in absolute lymphocyte counts during therapy. Simultaneously, an increase was observed in the proportion of T cells that expressed costimulatory or inhibitory checkpoint molecules. Moreover, the fraction of two immunosuppressive subsets – the regulatory T cells and the monocytic myeloid-derived suppressor cells – increased throughout treatment. The findings in this study may spark dedicated trials investigating radium-223 therapy in combination with cancer immunotherapy (in particular check point inhibitors, anti PD-L1/anti-PD-1 agents) in men with mCRPC. Bone metastases of prostate cancer may cause pain and deterioration of the quality of life. With the expansion of the number of life-prolonging therapeutic agents and the improved prognosis of metastatic prostate cancer, maintaining or improving quality of life has become increasingly important. In chapter 4 we report the outcomes of a multicenter, prospective observational cohort study that evaluated the health-related quality of life, psychological distress and fatigue in 122 mCRPC patients treated with radium-223. We found that stabilization of HR-QoL was perceived and psychological distress and fatigue remained stable in patients who completed radium-223 therapy. However, clinically meaningful and statistically significant deterioration of HR-QoL, psychological distress and fatigue over time was observed in patients who discontinued therapy. A trajectory analysis revealed that quality of life deterioration over time was more likely in patients with opioid use, low hemoglobin and high alkaline phosphatase (ALP) levels prior to the initiation of radium-223 therapy. The findings in this study underline the importance of completing radium-223 therapy, in order to achieve the quality of life benefits of this therapy. The studies in part II of this thesis explored potential prognostic parameters in mCRPC patients treated with radium-223. With the increased number of therapeutic options for patients with metastatic prostate cancer, the selection of the preferred therapy for each patient has become even more important. Knowledge of pretherapeutic prognostic factors can lead to better patient selection for each available therapy, improved treatment outcomes and might lead to a reduction of healthcare costs.

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