Annals of Oncology Advance Access originally published online on August 5, 2008
Annals of Oncology 2008 19(10):1813-1814; doi:10.1093/annonc/mdn549
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letters to the editor |
Reply to the letter "About sorafenib in castration-resistant prostate cancer" by G. Colloca, F. Checcaglini and A. Venturino
We appreciate the interest of Colloca et al. in our recently published phase II study of sorafenib in patients with castration-resistant prostate cancer (CRPC). As is pointed out in their letter, from the time of this study's inception there has been an increased awareness of the pitfalls of phase II trial design for studies involving patients with CRPC and changes in the recommended trial conduct and end points, especially with respect to prostate-specific antigen (PSA). To specifically address the questions raised by Colloca et al.: first, as indicated in the original report, the study population all had rising PSA despite castration therapy and nonsteroidal antiandrogen withdrawal with the sites of spread listed in Table 1. Secondly, as the study was not originally designed to evaluate for a post-sorafenib withdrawal effect it is not possible to reliably specify how many of the post-sorafenib PSA declines were PSA ‘responses’ per se as only the per-protocol 4 week post-study follow-up was consistently carried out. Thirdly, there were seven patients with response evaluation criteria in solid tumors criteria for objective progression at time of discontinuation of protocol therapy: five had a PSA decline after discontinuing sorafenib, one patient had a continued PSA rise and one patient had no follow-up PSA recorded. Finally, all patients maintained castration therapy as is standard for such a study population. The postulate that sorafenib restores or amplifies androgen sensitivity is still valid given the mechanisms of post-castration progression through androgen receptor amplification [1], persistent tissue levels of androgens and androgen-regulated gene expression despite castrate levels of testosterone [2], and recent findings that patients with CRPC can still respond to more potent inhibitors of androgen production [3] or androgen receptor [4]. This postulate opens a number of possible sorafenib combination strategies. Given the observation of several patients with PSA declines and long-term disease stability and the limitations of the original study plan, we feel that further study with sorafenib in patients with CRPC is still potentially warranted provided an appropriate trial design, selection of patients and incorporation of correlative studies and novel end points [5].
1 Department of Clinical Trials, University of British Columbia, Vancouver
2 National Cancer Institute of Canada–Clinical Trials Group, Queen's University, Kingston, Canada
* (E-mail: kchi{at}bccancer.bc.ca)
References
1. Chen CD, Welsbie DS, Tran C, et al. Molecular determinants of resistance to antiandrogen therapy. Nat Med (2004) 10:33–39.[CrossRef][Web of Science][Medline]
2. Mostaghel EA, Page ST, Lin DW, et al. Intraprostatic androgens and androgen-regulated gene expression persist after testosterone suppression: therapeutic implications for castration-resistant prostate cancer. Cancer Res (2007) 67:5033–5041.
3. De Bono JS, Attard G, Reid AH, et al. Anti-tumor activity of abiraterone acetate (AA), a CYP17 inhibitor of androgen synthesis, in chemotherapy naive and docetaxel pre-treated castration resistant prostate cancer (CRPC). J Clin Oncol (2008) 26:251s. Abstr 5005.
4. Scher HI, Beer TM, Higano CS, et al. Phase I/II study of MDV3100 in patients (pts) with progressive castration-resistant prostate cancer (CRPC). J Clin Oncol (2008) 26:251s. Abstr 5006.
5. Moreno J, DeBono JS, Shaffer D, et al. Multi-center study evaluating circulating tumor cells (CTCs) as a surrogate for survival in men treated for castration refractory prostate cancer (CRPC). J Clin Oncol (2007) 25:239s. Abstr 5016.[CrossRef]
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