Evaluierung von quervernetztem nicht-isomerisierten carboxyterminalen Telopeptid desKollagens Typ I (alpha-CTX) als neuen Marker desKnochenstoffwechsels bei Patienten mit lokalisiertem,metastasiertem und hormonrefraktärem Prostatakarzinom

The skeleton is a frequently targeted organ and constitutes the primary site affected by metastases arising from prostate cancer. The majority of patients afflicted by cancer do not succumb to the primary tumor, but rather to its metastases. Metastatic bone involvement influences, by virtue of the associated increase in morbidity as well as considerably decreased quality of life, the progression and course of the disease. Next to the numerous sequelae of bone metastases for patients suffering from prostate cancer, such as pain, pathologic fractures possibly associated with spinal cord involvement and/or hypercalcemia, the diagnosis and therapy constitute a major challenge not only to the urologist, but also to the financial resources of health care system. An early diagnosis and prompt therapeutic intervention pertaining to the treatment of bone metastases are highly desirable, but rather limited considering the currently available diagnostic tools. Established radiologic and szintigraphic procedures are not sensitive enough to detect the most tiny of metastatic foci. The humorally induced pathological bone changes are often not detected by imaging studies, but rather incidentally only in the later stages as hypercalcemia. Hence, at the time of diagnosis the metastatic spread is often quite advanced, concomitantly proving difficult and disadvantageous for pharmacological intervention. The discovery of novel specific biomarkers of bone metabolism has thus raised the question about the utility of such markers regarding the early detection of bone metastases and has become the center of oncologic research. Utilization of biomarkers is not solely of interest regarding the diagnostic aspect, but also for monitoring the course of subsequent antiosteolytic therapy. The results presented of this thesis may be summarized as follows: The biomarker urine-alpha-CTX (crosslinked non-isomerized c-telopeptide fragments of type-I collagen, alpha-CTX) showed the most significant rise in hormone refractory prostatic cancer patients (HRPCA) with metastases compared to patients without metastases. This parameter hence seems to provide useful additional information concerning tumor expansion owing to bone metastases. In addition this biomarker (detection in urine) decreased significantly in HRPCA-patients with bone metastases (+BM) undergoing chemotherapy with docetacel/zolendronate, but did not display any changes in patients without bone metastases (-BM) undergoing chemotherapy with docetaxel. These results underline the value and specificity of this novel biomarker in monitoring „bone-targeting” therapies. At the same time, alpha-CTX was the only marker that displayed independence from growth of the primary tumor in the prostate. A significant increase of this marker could only be observed after lymph node involvement (N1M0). This suggests that alpha-CTX may be a useful biomarker for patients with locally progressed prostatic cancer, who may have an increased risk of hidden micrometastases. However, in order to establish a role for this biomarker in clinical practice, it needs to be determined -in the framework of longitudinal studies- to which extent increased alpha-CTX levels in N1M0-patients (which represent a risk population) can point to metastatic lesions that have not yet been detected by conventional imaging studies. Besides, it remains to be determined by future studies whether imaging procedures, in particular szintigraphy, may be replaced by early detection of bone metastases utilizing biomarkers in patients afflicted by malignancies. Parallel monitoring of changes in biomarkers as well as imaging in a significant population of patients with prostate cancer would be necessary in order to corroborate the promising potential of alpha-CTX plus other markers of bone metabolism as a (i) diagnostic tool as well as (ii) device to monitor success of therapeutic interventions.