Change in markers of bone metabolism with chemotherapy for advanced prostate cancer: interleukin-6 response is a potential early indicator of response to therapy

Abstract

Men with androgen-independent prostate cancer (AIPC) frequently have bone metastasis. The effects of chemotherapy on markers of bone metabolism have not been well characterized. We conducted a prospective study of patients with AIPC randomized in the first cycle to receive either docetaxel/estramustine or zoledronic acid, a bisphosphonate, to inhibit osteoclastic activity. Here we report the effects of therapy on markers of bone metabolism in these patients following the first cycle of therapy. Serum levels of several indices of bone remodeling were evaluated using commercial enzyme-linked immunosorbent assays. Changes in markers of bone metabolism were compared in patients receiving initial chemotherapy versus bisphosphonate. There was no significant difference in median change in any of the measured bone markers in patients given zoledronic acid when compared to chemotherapy. When comparing responders to nonresponders, overall interleukin-6 (IL-6) decreased by 35% in prostate-specific antigen responders; whereas, IL-6 levels increased by 76% in nonresponders (p = 0.03). Elevated IL-6 levels and reductions in IL-6 levels early in treatment may reflect ultimate clinical response to docetaxel-based regimens.

FIG. 1.

Changes in serum IL-6 levels predict response to therapy. Bone scan positive patients with prostate cancer were given either zoledronic acid (Z) alone or the combination of docetaxel and estramustine (DE) for an initial cycle followed by two additional treatment cycles of all three drugs. Serum IL-6 levels were measured pretreatment and postinitial cycle. Prostate-specific antigen (PSA) was measured pretreatment and at each cycle. A ≥50% decline in PSA without evidence of progression by bone or CT scan was considered a responder. Results are reported as relative change from the baseline (pretreatment) value. Data are shown as a whisker-box plots based on response. The bottom of the box is the 25th percentile, the line through the box is the median, the top of the box is the 75th percentile, the top whisker cross bar is the maximum value in the upper quartile range, the bottom whisker cross bar is the minimum value in the lower quartile range, x = mean, + = outlier and ^#p = 0.03 versus nonresponders.

FIG. 2.

The extent of bone metastatic disease correlates with serum IL-6 expression. Patients were classified into the categories indicated for their extent of disease based on bone scans. Baseline (pretreatment) serum IL-6 levels were measured. Results are reported as median IL-6 level (pg/mL). Data are shown as a whisker-box plots based on response. The bottom of the box is the 25th percentile, the line through the box is the median, the top of the box is the 75th percentile, the top whisker cross bar is the maximum value in the upper quartile range, the bottom whisker cross bar is the minimum value in the lower quartile range, x = mean, + = outlier and ^#p = 0.04 versus ≤5.