Weekly Neoadjuvant Ixabepilone on Surgical Feasibility and Clinical Outcomes in Locally Advanced High-Risk Prostate Cancer: A Phase II Clinical Trial

• J.L. Layton

  Brown University Alpert School of Medicine, Brown University Oncology Research Group, and Lifespan Corporation, Providence, RI, USA

• J.F. Renzulli II

  Brown University Alpert School of Medicine, Brown University Oncology Research Group, and Lifespan Corporation, Providence, RI, USA

• A.M. Taber

  Brown University Alpert School of Medicine, Brown University Oncology Research Group, and Lifespan Corporation, Providence, RI, USA

• D. Golijanin

  Brown University Alpert School of Medicine, Brown University Oncology Research Group, and Lifespan Corporation, Providence, RI, USA

• J.E. Collins

  Brown University Alpert School of Medicine, Brown University Oncology Research Group, and Lifespan Corporation, Providence, RI, USA

• H.H. Safran

  Brown University Alpert School of Medicine, Brown University Oncology Research Group, and Lifespan Corporation, Providence, RI, USA

• A.E. Mega

  Brown University Alpert School of Medicine, Brown University Oncology Research Group, and Lifespan Corporation, Providence, RI, USA

 Background:Men diagnosed with locally advanced high-risk prostate cancer have up to a 40% risk of biochemical recurrence after prostatectomy. The authors performed a phase II trial of neoadjuvant weekly ixabepilone prior to radical prostatectomy.

Methods:Enrollment criteria included patients with high-risk prostate cancer defined by D¢‚¬„¢Amico criteria or high-volume Gleason 4+3 with a palpable nodule. Patients received ixabepilone 20 mg/m²/week or 16 mg/m²/week for 3 weeks every 28 days for 4 cycles followed by surgery 2-8 weeks later.

Results:Sixteen patients were enrolled with a mean age of 56.5 years (range 43-70). PSA values decreased by a mean of 47% in 14/16 men with patients receiving a mean of 8.25 weeks of treatment (range 2-12). Nine men experienced an adverse event requiring dose modification or premature cessation of chemotherapy. Pathologic staging in 9 patients showed T3a, 5 with T3b, and 1 with T2c disease; 8 had R1 disease and 2 demonstrated nodal involvement. Mean operative time, blood loss, and hospital stay were 189 minutes, 184 mL, and 1.5 days, respectively. At median follow-up of 32 months (range 15-45), 4 patients experienced biochemical recurrence.

Conclusions: Neoadjuvant weekly ixabepilone had a good PSA response and no increased surgical morbidity; however, a higher dose is associated with significant persistent neuropathy. There were no complete pathologic responses, but biochemical recurrence rate is low. Further assessment of time to treatment failure will require continued, planned follow-up to evaluate the long-term potential clinical benefit of this study.

Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin 2013; 63(1): 11-30. http://dx.doi.org/10.3322/caac.21166

Han M, Partin AW, Piantadosi S, Epstein JI, Walsh PC. Era specific biochemical recurrence-free survival following radical prostatectomy for clinically localized prostate cancer. J Urol 2001; 166(2): 416-19. http://dx.doi.org/10.1016/S0022-5347(05)65955-1

Partin AW. Combination of Prostate-Specific Antigen, Clinical Stage, and Gleason Score to Predict Pathological Stage of Localized Prostate Cancer. A Multi-institutional Update. JAMA J Am Med Assoc 1997; 277(18): 1445. http://dx.doi.org/10.1001/jama.1997.03540420041027

Kattan MW, Eastham JA, Stapleton AMF, Wheeler TM, Scardino PT. A Preoperative Nomogram for Disease Recurrence Following Radical Prostatectomy for Prostate Cancer. JNCI J Natl Cancer Inst 1998; 90(10): 766-71. http://dx.doi.org/10.1093/jnci/90.10.766

Abbas F. Why neoadjuvant androgen deprivation prior to radical prostatectomy is unnecessary. Urol Clin North Am 1996; 23(4): 587. http://dx.doi.org/10.1016/S0094-0143(05)70338-4

Soloway MS. Neoadjuvant androgen ablation before radical prostatectomy in cT2bNxMo prostate cancer: 5-year results. J Urol 2002; 167(1): 112. http://dx.doi.org/10.1016/S0022-5347(05)65393-1

Tsai HK. Androgen deprivation therapy for localized prostate cancer and the risk of cardiovascular mortality. JNCI J Natl Cancer Inst 2007; 99(20): 1516. http://dx.doi.org/10.1093/jnci/djm168

Saigal CS. Androgen deprivation therapy increases cardiovascular morbidity in men with prostate cancer. Cancer 2007; 110(7): 1493. http://dx.doi.org/10.1002/cncr.22933

Gleave M, Chi K, Goldenberg L, et al. Multicentre phase II trial of combination neoadjuvant hormone therapy and weekly docetaxol prior to radical prostatectomy in high risk localized prostate cancer (CUOG-P01a). Proc ASCO 2004; 22(No 14S): 4635.

Febbo PG. Neoadjuvant Docetaxel before Radical Prostatectomy in Patients with High-Risk Localized Prostate Cancer. Clin Cancer Res 2005; 11(14): 5233-40. http://dx.doi.org/10.1158/1078-0432.CCR-05-0299

Magi-Galluzzi C. Neoadjuvant docetaxel treatment for locally advanced prostate cancer: a clinicopathologic study. Cancer 2007; 110(6): 1248. http://dx.doi.org/10.1002/cncr.22897

Ross RW, Galsky MD, Febbo P, et al. Phase 2 study of neoadjuvant docetaxel plus bevacizumab in patients with high-risk localized prostate cancer: A Prostate Cancer Clinical Trials Consortium trial. Cancer 2012; 118(19): 4777-84. http://dx.doi.org/10.1002/cncr.27416

Pettaway CA. Neoadjuvant chemotherapy and hormonal therapy followed by radical prostatectomy: feasibility and preliminary results. J Clin Oncol 2000; 18(5): 1050.

Höfle G, Bedorf N, Steinmetz H, Schomburg D, Gerth K, Reichenbach H. Epothilone A and B—Novel 16-Membered Macrolides with Cytotoxic Activity: Isolation, Crystal Structure, and Conformation in Solution. Angew Chem Int Ed Engl 1996; 35(13-14): 1567-69. http://dx.doi.org/10.1002/anie.199615671

Bollag DM. Epothilones, a new class of microtubule-stabilizing agents with a taxol-like mechanism of action. Cancer Res Baltim 1995; 55(11): 2325.

Kowalski RJ. Activities of the microtubule-stabilizing agents epothilones A and B with purified tubulin and in cells resistant to paclitaxel (Taxol(R)). J Biol Chem 1997; 272(4): 2534. http://dx.doi.org/10.1074/jbc.272.4.2534

Ixabepilone Investigator Brochure. Bristol-Myers Squibb. Version 8, March 2007.

Perez EA. Efficacy and safety of ixabepilone (BMS-247550) in a phase II study of patients with advanced breast cancer resistant to an anthracycline, a taxane, and capecitabine. J Clin Oncol 2007; 25(23): 3407. http://dx.doi.org/10.1200/JCO.2006.09.3849

Galsky MD. Multi-institutional randomized phase II trial of the epothilone B analog ixabepilone (BMS-247550) with or without estramustine phosphate in patients with progressive castrate metastatic prostate cancer. J Clin Oncol 2005; 23(7): 1439. http://dx.doi.org/10.1200/JCO.2005.09.042

D’Amico AV. Pretreatment nomogram for prostate-specific antigen recurrence after radical prostatectomy or external-beam radiation therapy for clinically localized prostate cancer. J Clin Oncol 1999; 17(1): 168.

Oken MM. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982; 5(6): 649. http://dx.doi.org/10.1097/00000421-198212000-00014

Sfoungaristos S, Kourmpetis V, Fokaefs E, Perimenis P. Neoadjuvant Chemotherapy prior to Radical Prostatectomy for Patients with High-Risk Prostate Cancer: A Systematic Review. Chemother Res Pr 2013; 2013: 1-7. http://dx.doi.org/10.1155/2013/386809

• PDF