- Email: [email protected]
Editorial Comment on: Combination of Bevacizumab and Docetaxel in Docetaxel-Pretreated Hormone-Refractory Prostate Cancer: A Phase 2 Study
1094
european urology 54 (2008) 1089–1096
decline of 50%) and a high response in measurable disease (59%) [15]. Table 5 describes ongoing trials with bevacizumab in HRPC. The CALGB 90401, for example, is coordinating a phase 3, placebo-controlled trial of docetaxel plus prednisone with or without bevacizumab. The originality of our report relies on several important key points: (1) There are no published articles using this regimen in pretreated patients with HRPC so far; (2) all patients had received docetaxel as first-line therapy, progressed with this drug alone, and showed an important response after the combination with bevacizumab; (3) all patients were highly pretreated, so the observed PSA decline is surprising and encouraging; (4) we did not find irreversible grade 4 toxicity; and (5) the PSA decline could be theorized as a major activity of the bevacizumab–docetaxel in a first-line setting.
5.
Conclusions
Findings from the present paper are worthy of attention, because they clearly demonstrate that the combination of bevacizumab–docetaxel deserves further assessment. In this respect, a randomized phase 2 study comparing docetaxel alone versus the combination in this set of patients is warranted. Financial disclosures: None. Acknowledgement statement: We thank BoldFace Editors for linguistic revision.
References [1] Jamal A, Siegel R, Ward E, et al. Cancer statistics 2007. CA Cancer J Clin 2007;57:43–66. [2] Di Lorenzo G, Autorino R, Figg WD, De Placido S. Hormone refractory prostate cancer. Where are we going? Drugs 2007;67:1109–24. [3] Tannock IF, de Wit R, Berry W, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 2004;351:1502–12.
Editorial Comment on: Combination of Bevacizumab and Docetaxel in Docetaxel-Pretreated Hormone-Refractory Prostate Cancer: A Phase 2 Study Ste´phane Oudard Georges Pompidou European Hospital, Medical Oncology Department, Paris Cedex 15, France [email protected]
[4] Petrylak DP, Tangen CM, Hussain MH, et al. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med 2004;351:1513–20. [5] Gerber HP, Ferrara N. Pharmacology and pharmacodynamics of bevacizumab as monotherapy or in combination with cytotoxic therapy in preclinical studies. Cancer Res 2005;65:671–80. [6] Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil and leucovorin for metastatic colorectal cancer. N Engl J Med 2004;350:2335–42. [7] Kabbinavar FF, Hambleton J, Mass RD, et al. Combined analysis of efficacy: the addition of bevacizumab to fluorouracil/leucovorin improves survival for patients with metastatic colorectal cancer. J Clin Oncol 2005;23: 3706–12. [8] Sweeney CJ, Miller KD, Sisson SE, et al. The angiogenic property of docetaxel is synergistic with a recombinant humanized monoclonal antibody against vascular endothelial growth factor or 2-methoxyestradiol but antagonized by endothelial growth factors. Cancer Res 2001;61:3369–72. [9] Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Institute of Canada. J Natl Cancer Inst 2000;92:205–16. [10] Di Lorenzo G, Autorino R. Re: Calabro` F, Sternberg CN. Current indications for chemotherapy in prostate cancer patients. Eur Urol 2007;51:17–26. Eur Urol 2007;52:613–4. [11] Sciarra A, Salciccia S. New treatment strategies in the management of hormone refractory prostate cancer (HRPC): only chemotherapy? Eur Urol 2007;52:945–7. [12] Calabro` F, Sternberg CN. Current indications for chemotherapy in prostate cancer patients. Eur Urol 2007;51: 17–26. [13] Tombal B. Docetaxel and beyond. Eur Urol 2007;51:1159–61. [14] Picus J, Halabi S, Rini B, et al. The use of bevacizumab with docetaxel and estramustine in hormone refractory prostate cancer: initial results of CALGB 90006. Proc Am Soc Clin Oncol 2003;22:393 (abstract no. 1578). [15] Ning YM, Arlen P, Gulley J, et al. A phase II trial of thalidomide, bevacizumab, and docetaxel in patients (pts) with metastatic androgen-independent prostate cancer (AIPC). 2007 ASCO Annual Meeting Proceedings. J Clin Oncol Suppl 2007;25 (abstract no. 5114).
Currently, patients with metastatic hormonerefractory prostate cancer (HRPC) still present a progressive and morbid disease with few therapeutic options and a poor outcome. At this stage, all current treatments remain palliative. Two recent and simultaneously published phase 3 studies (TAX 327 and SWOG 9916) showed a small but significant overall survival, palliation of symp-
european urology 54 (2008) 1089–1096
toms, and improvement in quality of life for men with HRPC treated with chemotherapy (docetaxel with or without estramustine phosphate) [1,2]. Since May 2004, docetaxel given every 3 wk and prednisone are the front-line therapies for patients with symptomatic or asymptomatic metastatic HRPC. However, patients will have relapses and second-line chemotherapy may be necessary. Due to the poor benefit of mitoxantrone as second-line therapy, treatment with docetaxel either alone or associated with targeted drugs may be an option after first-line response to docetaxel. The plasma level of vascular endothelial growth factor (VEGF) is an independent predictor of survival in HRPC [3]. Bevacizumab (Avastin1) is a monoclonal antibody that links to VEGF and inhibits angiogenesis. Bevacizumab has shown significant benefit in patients with metastatic colorectal, breast, and non–small-cell lung carcinomas as well as in clear cell renal carcinoma. Bevacizumab has been tested either alone or in association with chemotherapy in HRPC. No prostate-specific antigen (PSA) response was observed in monotherapy, whereas 65% biologic PSA response was demonstrated in combination with docetaxel and estramustine in the Cancer and Leukemia Group B study [4]. According to these results, a large phase 3 study has been initiated in North America comparing docetaxel with or without bevacizumab in the first-line setting. Other ongoing studies evaluating bevacizumab are reported in the Table 5 of the present article. In this article [5], the authors are reporting the results of a phase 2 study that evaluated the combination of bevacizumab and docetaxel in docetaxel-pretreated HRPC patients. They demonstrate, in a limited number of patients (n = 20), a 55% PSA response rate and a median progressionfree survival (PFS) of 4 mo (95% confidence interval [CI], 2–6 mo). These results do not seem different from a retrospective analysis performed by Eymard and colleagues on 148 patients who were initially responders to docetaxel first-line chemotherapy [6]. From these patients, 54 of 148 (36%) had received a docetaxel-based regimen as second-line therapy. A PSA decrease 50% was observed in 11 of 26 (42%) evaluable patients treated with docetaxel alone at relapse. This study showed that reintroduction of docetaxel after a drug-free interval is feasible and effective in docetaxel-pretreated patients. Whether or not bevacizumab should be associated with docetaxel in docetaxel-pretreated patients is an open question.
1095
Nevertheless, the results seem interesting because most of the patients were highly previously treated. It seems that bevacizumab reverses resistance to docetaxel in patients who were previously non-responders to docetaxel (n = 4). These results are preliminary and the authors are planning to conduct a phase 2 study comparing docetaxel alone versus the combination in patients with HRPC pretreated with docetaxel. In addition to bevacizumab, other anti-VEGF inhibitors, either monoclonal antibodies or smallmolecule compounds, are evaluated in HRPC patients. Thalidomide is an antiangiogenic drug that inhibits synthesis of tumor necrosis factor a (TNF-a), a member of the cytokine family involved in neoangiogenesis. Thalidomide has been tested in 63 HRPC patients in monotherapy, with low dose (200 mg/d) or high dose (up to 1 200 mg/d). The biologic response rate was 18% (only in low-dose arm) [7]. A phase 2 randomized study has been performed, comparing docetaxel (30 mg/m2/3 wk out of 4 with or without thalidomide, 200 mg/d continuously) in metastatic HRPC patients [8]. The biologic response rate (decrease PSA 50%) was 53% in the combination arm versus 37% for docetaxel alone. PFS was 5.9 versus 3.7 mo and overall survival was 28.9 versus 14.7 mo in favor of the combination [9]. In the docetaxel-thalidomide arm, thromboembolic and cardiovascular incidents were more frequent before systematic prophylactic anticoagulation treatment. Despite the nonsignificant statistical differences, the results using this docetaxel and antiangiogenic drug combination are promising. Sorafenib (Nexavar), is a multitarget antiangiogenic active on VEGF receptor (VEGFR), plateletderived growth factor receptor (PDGFR), c-Kit, and Flt3. It has been tested on 22 patients with HRPC. No biologic response has been observed while on treatment, and surprisingly, a PSA decrease has been observed in five patients when treatment was stopped. In addition, two patients have presented a major bone response despite absence of biologic response [10]. VEGF-Trap (Sanofi-Aventis) is a monoclonal antibody (its terminal binding site with ligand corresponding to VEGFR2 and VEGFR3 receptors) currently developed in metastatic HRPC. An international phase 3 study comparing docetaxel with or without VEGF-Trap, coordinated by SanofiAventis, is currently ongoing. In conclusion, antiangiogenic drugs in combination with chemotherapy seem extremely interesting and should be evaluated in men with HRPC.
1096
european urology 54 (2008) 1089–1096
Interpretations of the results are complicated by discordant radiographic and PSA responses. PFS or overall survival should be the primary end point. Toxicity must be carefully monitored in this elderly population. Exploration of docetaxel resistance by antiangiogenic drugs and, in particular, by bevacizumab must be prospectively evaluated.
References [1] Petrylak DP, Tangen CM, Hussain MH, et al. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med 2004;351:1513–20. [2] Tannock IF, de Wit R, Berry WR, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 2004;351:1502–12. [3] George DJ, Halabi S, Shepard TF, et al. Prognostic significance of plasma vascular endothelial growth factor levels in patients with hormone-refractory prostate cancer treated on Cancer and Leukemia Group B 9480. Clin Cancer Res 2001;7:1932–6. [4] Picus J, Halabi S, Rini B, et al. The use of bevacizumab with docetaxel and estramustine in hormone refractory prostate cancer: initial results of CALGB 90006. Proc Am Soc Clin Oncol 2003;22:393 (abstract no. 1578).
[5] Di Lorenzo G, Figg WD, Fossa SD, et al. Combination of bevacizumab and docetaxel in docetaxel-pretreated hormone-refractory prostate cancer: a phase 2 study. Eur Urol 2008;54:1089–96. [6] Eymard J, Oudard S, Gravis G, et al. Second-line chemotherapy with docetaxel (D) in men treated with docetaxel-based regimen for metastatic hormonerefractory prostate cancer (mHRPC). Multidisciplinary Prostate Cancer Symposium 22, 2007. [7] Figg WD, Dahut W, Duray P, et al. A randomized phase II trial of thalidomide, an angiogenesis inhibitor, in patients with androgen-independent prostate cancer. Clin Cancer Res 2001;7:1888–93. [8] Dahut WL, Gulley JL, Arlen PM, et al. Randomized phase II trial of docetaxel plus thalidomide in androgen-independent prostate cancer. J Clin Oncol 2004;22:2532–9. [9] Retter A, Arlen P, Gulley J, et al. A phase II trial of docetaxel, estramustine and thalidomide in patients with metastatic androgen-independent prostate cancer. Multidisciplinary Prostate Cancer Symposium, 2005. [10] Dahut WL, Scripture C, Posadas E, et al. A phase II clinical trial of sorafenib in androgen-independent prostate cancer. Clin Cancer Res 2008;14:209–14.
DOI: 10.1016/j.eururo.2008.01.083 DOI of original article: 10.1016/j.eururo.2008.01.082
european urology 54 (2008) 1089–1096
decline of 50%) and a high response in measurable disease (59%) [15]. Table 5 describes ongoing trials with bevacizumab in HRPC. The CALGB 90401, for example, is coordinating a phase 3, placebo-controlled trial of docetaxel plus prednisone with or without bevacizumab. The originality of our report relies on several important key points: (1) There are no published articles using this regimen in pretreated patients with HRPC so far; (2) all patients had received docetaxel as first-line therapy, progressed with this drug alone, and showed an important response after the combination with bevacizumab; (3) all patients were highly pretreated, so the observed PSA decline is surprising and encouraging; (4) we did not find irreversible grade 4 toxicity; and (5) the PSA decline could be theorized as a major activity of the bevacizumab–docetaxel in a first-line setting.
5.
Conclusions
Findings from the present paper are worthy of attention, because they clearly demonstrate that the combination of bevacizumab–docetaxel deserves further assessment. In this respect, a randomized phase 2 study comparing docetaxel alone versus the combination in this set of patients is warranted. Financial disclosures: None. Acknowledgement statement: We thank BoldFace Editors for linguistic revision.
References [1] Jamal A, Siegel R, Ward E, et al. Cancer statistics 2007. CA Cancer J Clin 2007;57:43–66. [2] Di Lorenzo G, Autorino R, Figg WD, De Placido S. Hormone refractory prostate cancer. Where are we going? Drugs 2007;67:1109–24. [3] Tannock IF, de Wit R, Berry W, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 2004;351:1502–12.
Editorial Comment on: Combination of Bevacizumab and Docetaxel in Docetaxel-Pretreated Hormone-Refractory Prostate Cancer: A Phase 2 Study Ste´phane Oudard Georges Pompidou European Hospital, Medical Oncology Department, Paris Cedex 15, France [email protected]
[4] Petrylak DP, Tangen CM, Hussain MH, et al. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med 2004;351:1513–20. [5] Gerber HP, Ferrara N. Pharmacology and pharmacodynamics of bevacizumab as monotherapy or in combination with cytotoxic therapy in preclinical studies. Cancer Res 2005;65:671–80. [6] Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil and leucovorin for metastatic colorectal cancer. N Engl J Med 2004;350:2335–42. [7] Kabbinavar FF, Hambleton J, Mass RD, et al. Combined analysis of efficacy: the addition of bevacizumab to fluorouracil/leucovorin improves survival for patients with metastatic colorectal cancer. J Clin Oncol 2005;23: 3706–12. [8] Sweeney CJ, Miller KD, Sisson SE, et al. The angiogenic property of docetaxel is synergistic with a recombinant humanized monoclonal antibody against vascular endothelial growth factor or 2-methoxyestradiol but antagonized by endothelial growth factors. Cancer Res 2001;61:3369–72. [9] Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Institute of Canada. J Natl Cancer Inst 2000;92:205–16. [10] Di Lorenzo G, Autorino R. Re: Calabro` F, Sternberg CN. Current indications for chemotherapy in prostate cancer patients. Eur Urol 2007;51:17–26. Eur Urol 2007;52:613–4. [11] Sciarra A, Salciccia S. New treatment strategies in the management of hormone refractory prostate cancer (HRPC): only chemotherapy? Eur Urol 2007;52:945–7. [12] Calabro` F, Sternberg CN. Current indications for chemotherapy in prostate cancer patients. Eur Urol 2007;51: 17–26. [13] Tombal B. Docetaxel and beyond. Eur Urol 2007;51:1159–61. [14] Picus J, Halabi S, Rini B, et al. The use of bevacizumab with docetaxel and estramustine in hormone refractory prostate cancer: initial results of CALGB 90006. Proc Am Soc Clin Oncol 2003;22:393 (abstract no. 1578). [15] Ning YM, Arlen P, Gulley J, et al. A phase II trial of thalidomide, bevacizumab, and docetaxel in patients (pts) with metastatic androgen-independent prostate cancer (AIPC). 2007 ASCO Annual Meeting Proceedings. J Clin Oncol Suppl 2007;25 (abstract no. 5114).
Currently, patients with metastatic hormonerefractory prostate cancer (HRPC) still present a progressive and morbid disease with few therapeutic options and a poor outcome. At this stage, all current treatments remain palliative. Two recent and simultaneously published phase 3 studies (TAX 327 and SWOG 9916) showed a small but significant overall survival, palliation of symp-
european urology 54 (2008) 1089–1096
toms, and improvement in quality of life for men with HRPC treated with chemotherapy (docetaxel with or without estramustine phosphate) [1,2]. Since May 2004, docetaxel given every 3 wk and prednisone are the front-line therapies for patients with symptomatic or asymptomatic metastatic HRPC. However, patients will have relapses and second-line chemotherapy may be necessary. Due to the poor benefit of mitoxantrone as second-line therapy, treatment with docetaxel either alone or associated with targeted drugs may be an option after first-line response to docetaxel. The plasma level of vascular endothelial growth factor (VEGF) is an independent predictor of survival in HRPC [3]. Bevacizumab (Avastin1) is a monoclonal antibody that links to VEGF and inhibits angiogenesis. Bevacizumab has shown significant benefit in patients with metastatic colorectal, breast, and non–small-cell lung carcinomas as well as in clear cell renal carcinoma. Bevacizumab has been tested either alone or in association with chemotherapy in HRPC. No prostate-specific antigen (PSA) response was observed in monotherapy, whereas 65% biologic PSA response was demonstrated in combination with docetaxel and estramustine in the Cancer and Leukemia Group B study [4]. According to these results, a large phase 3 study has been initiated in North America comparing docetaxel with or without bevacizumab in the first-line setting. Other ongoing studies evaluating bevacizumab are reported in the Table 5 of the present article. In this article [5], the authors are reporting the results of a phase 2 study that evaluated the combination of bevacizumab and docetaxel in docetaxel-pretreated HRPC patients. They demonstrate, in a limited number of patients (n = 20), a 55% PSA response rate and a median progressionfree survival (PFS) of 4 mo (95% confidence interval [CI], 2–6 mo). These results do not seem different from a retrospective analysis performed by Eymard and colleagues on 148 patients who were initially responders to docetaxel first-line chemotherapy [6]. From these patients, 54 of 148 (36%) had received a docetaxel-based regimen as second-line therapy. A PSA decrease 50% was observed in 11 of 26 (42%) evaluable patients treated with docetaxel alone at relapse. This study showed that reintroduction of docetaxel after a drug-free interval is feasible and effective in docetaxel-pretreated patients. Whether or not bevacizumab should be associated with docetaxel in docetaxel-pretreated patients is an open question.
1095
Nevertheless, the results seem interesting because most of the patients were highly previously treated. It seems that bevacizumab reverses resistance to docetaxel in patients who were previously non-responders to docetaxel (n = 4). These results are preliminary and the authors are planning to conduct a phase 2 study comparing docetaxel alone versus the combination in patients with HRPC pretreated with docetaxel. In addition to bevacizumab, other anti-VEGF inhibitors, either monoclonal antibodies or smallmolecule compounds, are evaluated in HRPC patients. Thalidomide is an antiangiogenic drug that inhibits synthesis of tumor necrosis factor a (TNF-a), a member of the cytokine family involved in neoangiogenesis. Thalidomide has been tested in 63 HRPC patients in monotherapy, with low dose (200 mg/d) or high dose (up to 1 200 mg/d). The biologic response rate was 18% (only in low-dose arm) [7]. A phase 2 randomized study has been performed, comparing docetaxel (30 mg/m2/3 wk out of 4 with or without thalidomide, 200 mg/d continuously) in metastatic HRPC patients [8]. The biologic response rate (decrease PSA 50%) was 53% in the combination arm versus 37% for docetaxel alone. PFS was 5.9 versus 3.7 mo and overall survival was 28.9 versus 14.7 mo in favor of the combination [9]. In the docetaxel-thalidomide arm, thromboembolic and cardiovascular incidents were more frequent before systematic prophylactic anticoagulation treatment. Despite the nonsignificant statistical differences, the results using this docetaxel and antiangiogenic drug combination are promising. Sorafenib (Nexavar), is a multitarget antiangiogenic active on VEGF receptor (VEGFR), plateletderived growth factor receptor (PDGFR), c-Kit, and Flt3. It has been tested on 22 patients with HRPC. No biologic response has been observed while on treatment, and surprisingly, a PSA decrease has been observed in five patients when treatment was stopped. In addition, two patients have presented a major bone response despite absence of biologic response [10]. VEGF-Trap (Sanofi-Aventis) is a monoclonal antibody (its terminal binding site with ligand corresponding to VEGFR2 and VEGFR3 receptors) currently developed in metastatic HRPC. An international phase 3 study comparing docetaxel with or without VEGF-Trap, coordinated by SanofiAventis, is currently ongoing. In conclusion, antiangiogenic drugs in combination with chemotherapy seem extremely interesting and should be evaluated in men with HRPC.
1096
european urology 54 (2008) 1089–1096
Interpretations of the results are complicated by discordant radiographic and PSA responses. PFS or overall survival should be the primary end point. Toxicity must be carefully monitored in this elderly population. Exploration of docetaxel resistance by antiangiogenic drugs and, in particular, by bevacizumab must be prospectively evaluated.
References [1] Petrylak DP, Tangen CM, Hussain MH, et al. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med 2004;351:1513–20. [2] Tannock IF, de Wit R, Berry WR, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 2004;351:1502–12. [3] George DJ, Halabi S, Shepard TF, et al. Prognostic significance of plasma vascular endothelial growth factor levels in patients with hormone-refractory prostate cancer treated on Cancer and Leukemia Group B 9480. Clin Cancer Res 2001;7:1932–6. [4] Picus J, Halabi S, Rini B, et al. The use of bevacizumab with docetaxel and estramustine in hormone refractory prostate cancer: initial results of CALGB 90006. Proc Am Soc Clin Oncol 2003;22:393 (abstract no. 1578).
[5] Di Lorenzo G, Figg WD, Fossa SD, et al. Combination of bevacizumab and docetaxel in docetaxel-pretreated hormone-refractory prostate cancer: a phase 2 study. Eur Urol 2008;54:1089–96. [6] Eymard J, Oudard S, Gravis G, et al. Second-line chemotherapy with docetaxel (D) in men treated with docetaxel-based regimen for metastatic hormonerefractory prostate cancer (mHRPC). Multidisciplinary Prostate Cancer Symposium 22, 2007. [7] Figg WD, Dahut W, Duray P, et al. A randomized phase II trial of thalidomide, an angiogenesis inhibitor, in patients with androgen-independent prostate cancer. Clin Cancer Res 2001;7:1888–93. [8] Dahut WL, Gulley JL, Arlen PM, et al. Randomized phase II trial of docetaxel plus thalidomide in androgen-independent prostate cancer. J Clin Oncol 2004;22:2532–9. [9] Retter A, Arlen P, Gulley J, et al. A phase II trial of docetaxel, estramustine and thalidomide in patients with metastatic androgen-independent prostate cancer. Multidisciplinary Prostate Cancer Symposium, 2005. [10] Dahut WL, Scripture C, Posadas E, et al. A phase II clinical trial of sorafenib in androgen-independent prostate cancer. Clin Cancer Res 2008;14:209–14.
DOI: 10.1016/j.eururo.2008.01.083 DOI of original article: 10.1016/j.eururo.2008.01.082