Predictive Implications Of Bone Turnover Markers After Treatment In Hormone-Refractory Prostate Cancer Patients With Painful Osseous Metastases
Since emerging evidence suggests that biomarkers of bone turnover carry notable potential to become useful tools for monitoring patients with metastatic bone disease, we measured a panel of bone formation and bone resorption markers in a relatively homogenous group of patients with hormone-refractory prostatic carcinoma (HRPC) and bone only metastases, immediately before 186Rhenium-l,l-hydroxyethylidene diphosphonate (186Re-HEDP) therapy and strictly after 3 months. This practice corresponds to the time of completion of a typical clinical follow-up after palliative radionuclide treatment and also matches the 3-month schedule of others concerning measurement of various bone markers after hormonal or zoledronic acid treatment in HRPC patients. Furthermore, according to a previous observation that when there is a change in the rate of bone remodelling resorption, markers fall faster than formation markers (2-12 weeks vs. 3-6 months, respectively) and in view of the expenses and discomfort implied in serial marker measurement, the 3 month time-point supports the rationale of a properly timed conjunction of both processes in a single blood sampling.
According to our results, pre-treatment values of single bone markers could not predict response to treatment with 186Re-HEDP. On the contrary, several marker ratios as well as the percentile drop of some markers actually did correlate with pain response. Concerning both good and durable response, the best marker-derived predictors of response proved post-therapy drop of NTx > or = 20% and pre-therapy NTx/PINP > or = 1.2. The former index presumably reflects the key role of inhibition of osteolysis after 186Re-HEDP treatment for achievement of improved response. Regarding the latter ratio, the observation that a high resorption to formation rate correlates positively to palliative response might seem to be counterintuitive, since it might be expected that patients with increased bone formation, and correspondingly decreased bone resorption, would have the most optimal outcomes. This "paradoxical" observation may have been due to a breakdown in homeostatic mechanisms in bone microenvironment that surrounds a metastatic lesion, wherein the tight coupling of resorption and formation has been disrupted.
In the present study osteocalcin could not predict clinical response, mainly due to methodological heterogeneity and easy loss of the molecule's immunological activity. Accordingly, the absence of predictive power of another traditional bone marker, namely BALP, may also be attributed to the fact that serum levels of it also increase to balance localized or systemic increases in osteolytic activity or as an indication of bone formation to repair bone lesions that have responded to treatment. Most interestingly, PSA levels also could not predict response to 186Re-HEDP therapies, in accordance with the results of previous prospective trials regarding survival correlations. One possible explanation for this might be that the value of the standard deviation of PSA values in both responders and non-responders, either pre- or post-therapy with 186Re-HEDP was found to be quite wide, a drawback further amplified by the relative small patient cohort. Besides, serum PSA levels do not reflect the whole tumour burden, especially in advanced-stage tumours consisting of high-grade cancer cells which release proportionally less PSA into the blood. Finally, the discrepancy we observed between PSA and bone marker alterations presumably suggests that the decrease in bone metabolism provided by bone markers decline is not enough to lead to an objective anti-tumour effect measured by PSA alterations.
The main limitation of this study is that the cohort of the evaluable patients was relatively small, thus introducing a degree of uncertainness concerning particularly the specificity and sensitivity of the tested variables. Another limitation is that since the aforementioned analytical and biological variability of bone markers render it difficult to determine precise cut-off values for individual patients, at present results for most markers of bone turnover cannot be compared among laboratories without previous cross-calibration. Accordingly, when bone remodelling rates are changing as was the case herein, a combination of markers such as one resorption and one formation marker might appear more informative than a single marker, whilst duplicate measurements, as we also performed, can be used to minimize the effect of intra-individual variation. Even so, the influence of 186Re-HEDP therapy on changes in bone turnover markers needs to be further examined including more time points, so as to correlate the course of the metabolic response to the long-term clinical outcome.
Written by Athanasios Zafeirakis, MD, PhD as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations, etc., of their research by referencing the published abstract.
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