Maarten van der Doelen

General introduction and outline of the thesis

Alpharadin in Symptomatic Prostate Cancer Patients (ALSYMPCA) trial. (23) The OS benefit of radium-223was found to be irrespective of previous docetaxel chemotherapy, baseline opioid use and bisphosphonate use. (23, 44, 45) Radium-223 also prolonged the time to first symptomatic skeletal event and patients experienced meaningful health related quality of life improvement during treatment as compared to placebo. (46, 47) Radium-223 has a low myelosuppression incidence and tolerable side effects, and is deemed safe on the long term, with no evidence of radiation-induced hematological malignancies described so far. (23, 48-50) Radium-223 is injected intravenously at a dose of 55 kBq per kilogram bodyweight and repeated every four weeks for a maximum of six injections. (51)

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GAPS IN KNOWLEDGE Effect evaluation of targeted alpha-radionuclide therapies

Assessing treatment response during systemic therapies for mCRPC is important, as it will inform physicians and patients whether there is a therapeutic benefit. Most often, response is assessed by a combination of imaging tests, serum biochemical markers and symptom assessments. TheALSYMPCA trial didnotmandate radiological evaluationduring radium-223 therapy. Although bone progression during radium-223 therapy is rare, extraskeletal disease progression following radium-223 has been reported in up to 46% of the patients. (52) This underlines the importance of meticulous evaluation of solid lesions before therapy and effect evaluation during therapy. Standard of care during radium-223 therapy currently includes monthly biochemical tests and imaging with bone scintigraphy and computer tomography (CT) of thorax, abdomenandpelvisbeforeandafter radium-223therapy. (51)However, intheALSYMPCA trial, a 30 percent or greater reduction in prostate-specific antigen (PSA) was found in only 16% of patients after three radium-223 injections. (23) Alkaline phosphatase (ALP), a recognized marker of osteoblast activity due to bone metastases, might be a better biomarker for the effect evaluation of radium-223 therapy. (53) For evaluation of PSMA targeted RLT, both PSA and ALP might be useful response markers. Furthermore, since radiation may induce immunological changes, evaluation of immune cell subsets in patients treated with TAT may also provide information on response to therapy.

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