However, there is some evidence to suggest that when selected chemotherapies are given at lower, continuous doses (so-called metronomic dosing), there can be significant anti-angiogenic and immunomodulatory effects resulting in anti-tumoral activity that would not be realized with standard dosing. It is well accepted that RCC is a highly antiangiogenic tumor and therefore might be receptive to such a treatment strategy. Furthermore, it has been demonstrated that RCC overexpresses cyclooxygenase 2 (COX-2) and that inhibitors of COX-2, such as celecoxib, have demonstrated significant anti-tumoral activity in preclinical models. These same preclinical models have demonstrated synergy between cyclophosphamide, given at metronomic or low continuous dosing, in combination with celecoxib. Here, Krzyzanowska and colleagues examine the activity of low dose oral cyclophosphamide in combination with celecoxib in the treatment of metastatic RCC.

In this phase II clinical trial conducted at two institutions in Canada, 36 patients were treated orally with Celecoxib 400 mg BID and 50 mg cyclophosphamide per day. Of these, 32 were evaluable for response. Median age was 62 years, 8 patients had received prior therapy, and 11 patients had a prior nephrectomy. One patient had a partial response and 3 patients had stable disease for > 6 months. The median progression free survival was 3.5 months and the median overall survival was 14.5 months. Overall, the treatment was well tolerated with minimal toxicity.

While based on sound biology and evidence of efficacy in the preclinical setting, the combination of low dose cyclophosphamide and celecoxib has little activity in metastatic renal cell carcinoma.

Monika K. Krzyzanowska, Ian F. Tannock, Gina Lockwood, Jennifer Knox, Malcolm Moore and Georg A. Bjarnason

Cancer Chemotherapy and Pharmacology (ePub) Sept.2006

Written by Christopher G. Wood, MD, a Contributing Editor with UroToday.

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