Letters to the Editor Re: Crawford et al.: Long-term Tolerability and Efficacy of Degarelix: 5-Year Results From a Phase III Extension Trial With a 1-Arm Crossover From Leuprolide to Degarelix (Urology 2014;83: 1122-1128) TO THE EDITOR:
I read with great interest this recent article by Crawford et al,1 which analyzed long-term tolerability and efficacy of degarelix on patients diagnosed with advanced prostate cancer and treated with degarelix and also on patients who had been previously treated with leuprolide and crossed over to degarelix. The authors stated that the prostate-specific antigen progression-free survival hazard rate for patients crossing over from leuprolide to degarelix significantly decreased from 0.20 during the first year to 0.09 during the extension phase. The authors attributed this difference in progressionfree survival to testosterone microsurges, which may result from agonist readministration. In addition, they also suggested that degarelix, an luteinizing hormone-releasing hormone (LHRH) antagonist, causes rapid and sustained testosterone suppression.1 Abundant expression of follicle stimulating hormone (FSH) receptors in the vascular endothelial cells of various endocrine tumors, especially in patients with prostate cancer, was previously reported by Radu et al.2 The mechanism of induction of these FSH receptors is still unknown. However, FSH has been shown to induce hypoxia-inducible factor-1 in ovary, which in turn leads to the upregulation of vascular endothelial factor.3 Therefore, we may speculate that FSH receptors expressed in growing tumors mediate a similar stimulation of angiogenesis. In previous studies, FSH receptor expression has been detected in hormone-refractory prostate cancer.4 Abundance of FSH receptors in blood vessels of prostate cancer may have a major and direct clinical relevance to endocrine treatment of this malignancy. Degarelix (a gonadotropin releasing-hormone [GnRH] antagonist) provides permanent suppression of FSH and luteinizing hormone.5 With GnRH agonist therapy, FSH secretion rebounds after initial suppression to pretreatment levels6 and further being another mechanism explaining the superiority of LHRH antagonists over agonists. Further clinical and pathophysiological studies are warranted to explain the mechanism of disease control with LHRH antagonists in prostate cancer. 1250
ª 2014 Elsevier Inc. All Rights Reserved
Mustafa Sofikerim, M.D. Department of Urology Acıbadem University School of Medicine _ Istanbul, Turkey References 1. Crawford ED, Shore ND, Moul JW, et al. Long-term tolerability and efficacy of degarelix: 5-year results from a phase III extension trial with a 1-arm crossover from leuprolide to degarelix. Urology. 2014; 83:1122-1128. 2. Radu A, Pichon C, Camparo P, et al. Expression of folliclestimulating hormone receptor in tumor blood vessels. N Engl J Med. 2010;363:1621-1630. 3. Alam H, Weck J, Maizels E, et al. Role of the phosphatidylinositol-3kinase and extracellular regulated kinase pathways in the induction of hypoxia-inducible factor (HIF)-1 activity and the HIF-1 target vascular endothelial growth factor in ovarian granulosa cells in response to follicle-stimulating hormone. Endocrinology. 2009;150: 915-928. 4. Dirnhofer S, Berger C, Hermann M, et al. Coexpression of gonadotropic hormones and their corresponding FSH- and LH/CG-receptors in the human prostate. Prostate. 1998;35: 212-220. 5. Crawford ED, Tombal B, Miller K, et al. A phase III extension trial with a 1-arm crossover from leuprolide to degarelix: comparison of gonadotropin-releasing hormone agonist and antagonist effect on prostate cancer. J Urol. 2011;186:889-897. 6. Huhtaniemi IT, Dahl KD, Rannikko S, Hsueh AJ. Serum bioactive and immunoreactive follicle-stimulating hormone in prostatic cancer patients during gonadotropin-releasing hormone agonist treatment and after orchidectomy. J Clin Endocrinol Metab. 1988;66: 308-313.
Reply by the Authors TO THE EDITOR:
We thank Sofikerim1 for his comments regarding our recently published study2 which demonstrated the longterm tolerability and efficacy of the gonadotropinreleasing hormone antagonist, degarelix. We agree that there may be more than 1 mechanism to explain the reduction in prostate-specific antigen progression-free survival hazard rate after the crossover from degarelix to leuprolide, and the possibility of a role for folliclestimulating hormone (FSH) is intriguing. The interaction between FSH and vascular endothelial growth factor (VEGF) may indeed play a role. Higher levels of VEGF in plasma, serum, or tumor tissue were associated with more advanced prostate cancers in several clinical trials. Patients who progress to metastatic disease or develop castrate-resistant disease have the highest 0090-4295/14
VEGF levels, followed by those with locally confined disease; healthy controls have the lowest levels.3 Bilateral orchiectomy is an effective therapy for advanced prostate cancer, despite the fact that it results in high serum levels of both luteinizing hormone (LH) and FSH. Whether this is because of the downregulation of FSH receptors by high serum levels of FSH, or whether the overwhelming effect of androgen ablation on prostate cancer diminishes the impact of the FSH-VEGF interaction, or another mechanism is involved, is unknown. There are no data comparing the long-term effectiveness of orchiectomy to an LH-releasing hormone antagonist with respect to disease control. In our report, FSH (and LH) was only measured for the first 3 months of the extension phase (15 months in total). Although this suppression coincided with the reduction in the prostate-specific antigen progression-free survival hazard rate, no relationship between these events has been established. Also, the long-term suppression of FSH and LH with degarelix beyond 15 months has not yet been confirmed. Further studies will be required to define the benefit of sustained FSH suppression with gonadotropin-releasing hormone antagonists in prostate cancer.
UROLOGY 84 (5), 2014
E. David Crawford, M.D. Department of Urologic Oncology School of Medicine University of Colorado Denver Aurora, CO Bo-Eric Persson, M.D. Ferring Pharmaceuticals Saint-Prex, Switzerland Laurence Klotz, M.D. Division of Urology University of Toronto Ontario, Canada
References 1. Sofikerim M. Re: Long-term tolerability and efficacy of degarelix: 5year results from a phase III extension trial with a 1-arm crossover from leuprolide to degarelix. Urology. 2014;84:1250. 2. Crawford ED, Shore ND, Moul JW, et al. Long-term tolerability and efficacy of degarelix: 5-year results from a phase III extension trial with a 1arm crossover from leuprolide to degarelix. Urology. 2014;83:1122-1128. 3. Peyromaure M, Goulvestre C, Fulla Y, et al. Serum levels of vascular endothelial growth factor in patients undergoing prostate biopsy for suspicion of prostate cancer. Urology. 2005;66:687-691.
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I read with great interest this recent article by Crawford et al,1 which analyzed long-term tolerability and efficacy of degarelix on patients diagnosed with advanced prostate cancer and treated with degarelix and also on patients who had been previously treated with leuprolide and crossed over to degarelix. The authors stated that the prostate-specific antigen progression-free survival hazard rate for patients crossing over from leuprolide to degarelix significantly decreased from 0.20 during the first year to 0.09 during the extension phase. The authors attributed this difference in progressionfree survival to testosterone microsurges, which may result from agonist readministration. In addition, they also suggested that degarelix, an luteinizing hormone-releasing hormone (LHRH) antagonist, causes rapid and sustained testosterone suppression.1 Abundant expression of follicle stimulating hormone (FSH) receptors in the vascular endothelial cells of various endocrine tumors, especially in patients with prostate cancer, was previously reported by Radu et al.2 The mechanism of induction of these FSH receptors is still unknown. However, FSH has been shown to induce hypoxia-inducible factor-1 in ovary, which in turn leads to the upregulation of vascular endothelial factor.3 Therefore, we may speculate that FSH receptors expressed in growing tumors mediate a similar stimulation of angiogenesis. In previous studies, FSH receptor expression has been detected in hormone-refractory prostate cancer.4 Abundance of FSH receptors in blood vessels of prostate cancer may have a major and direct clinical relevance to endocrine treatment of this malignancy. Degarelix (a gonadotropin releasing-hormone [GnRH] antagonist) provides permanent suppression of FSH and luteinizing hormone.5 With GnRH agonist therapy, FSH secretion rebounds after initial suppression to pretreatment levels6 and further being another mechanism explaining the superiority of LHRH antagonists over agonists. Further clinical and pathophysiological studies are warranted to explain the mechanism of disease control with LHRH antagonists in prostate cancer. 1250
ª 2014 Elsevier Inc. All Rights Reserved
Mustafa Sofikerim, M.D. Department of Urology Acıbadem University School of Medicine _ Istanbul, Turkey References 1. Crawford ED, Shore ND, Moul JW, et al. Long-term tolerability and efficacy of degarelix: 5-year results from a phase III extension trial with a 1-arm crossover from leuprolide to degarelix. Urology. 2014; 83:1122-1128. 2. Radu A, Pichon C, Camparo P, et al. Expression of folliclestimulating hormone receptor in tumor blood vessels. N Engl J Med. 2010;363:1621-1630. 3. Alam H, Weck J, Maizels E, et al. Role of the phosphatidylinositol-3kinase and extracellular regulated kinase pathways in the induction of hypoxia-inducible factor (HIF)-1 activity and the HIF-1 target vascular endothelial growth factor in ovarian granulosa cells in response to follicle-stimulating hormone. Endocrinology. 2009;150: 915-928. 4. Dirnhofer S, Berger C, Hermann M, et al. Coexpression of gonadotropic hormones and their corresponding FSH- and LH/CG-receptors in the human prostate. Prostate. 1998;35: 212-220. 5. Crawford ED, Tombal B, Miller K, et al. A phase III extension trial with a 1-arm crossover from leuprolide to degarelix: comparison of gonadotropin-releasing hormone agonist and antagonist effect on prostate cancer. J Urol. 2011;186:889-897. 6. Huhtaniemi IT, Dahl KD, Rannikko S, Hsueh AJ. Serum bioactive and immunoreactive follicle-stimulating hormone in prostatic cancer patients during gonadotropin-releasing hormone agonist treatment and after orchidectomy. J Clin Endocrinol Metab. 1988;66: 308-313.
Reply by the Authors TO THE EDITOR:
We thank Sofikerim1 for his comments regarding our recently published study2 which demonstrated the longterm tolerability and efficacy of the gonadotropinreleasing hormone antagonist, degarelix. We agree that there may be more than 1 mechanism to explain the reduction in prostate-specific antigen progression-free survival hazard rate after the crossover from degarelix to leuprolide, and the possibility of a role for folliclestimulating hormone (FSH) is intriguing. The interaction between FSH and vascular endothelial growth factor (VEGF) may indeed play a role. Higher levels of VEGF in plasma, serum, or tumor tissue were associated with more advanced prostate cancers in several clinical trials. Patients who progress to metastatic disease or develop castrate-resistant disease have the highest 0090-4295/14
VEGF levels, followed by those with locally confined disease; healthy controls have the lowest levels.3 Bilateral orchiectomy is an effective therapy for advanced prostate cancer, despite the fact that it results in high serum levels of both luteinizing hormone (LH) and FSH. Whether this is because of the downregulation of FSH receptors by high serum levels of FSH, or whether the overwhelming effect of androgen ablation on prostate cancer diminishes the impact of the FSH-VEGF interaction, or another mechanism is involved, is unknown. There are no data comparing the long-term effectiveness of orchiectomy to an LH-releasing hormone antagonist with respect to disease control. In our report, FSH (and LH) was only measured for the first 3 months of the extension phase (15 months in total). Although this suppression coincided with the reduction in the prostate-specific antigen progression-free survival hazard rate, no relationship between these events has been established. Also, the long-term suppression of FSH and LH with degarelix beyond 15 months has not yet been confirmed. Further studies will be required to define the benefit of sustained FSH suppression with gonadotropin-releasing hormone antagonists in prostate cancer.
UROLOGY 84 (5), 2014
E. David Crawford, M.D. Department of Urologic Oncology School of Medicine University of Colorado Denver Aurora, CO Bo-Eric Persson, M.D. Ferring Pharmaceuticals Saint-Prex, Switzerland Laurence Klotz, M.D. Division of Urology University of Toronto Ontario, Canada
References 1. Sofikerim M. Re: Long-term tolerability and efficacy of degarelix: 5year results from a phase III extension trial with a 1-arm crossover from leuprolide to degarelix. Urology. 2014;84:1250. 2. Crawford ED, Shore ND, Moul JW, et al. Long-term tolerability and efficacy of degarelix: 5-year results from a phase III extension trial with a 1arm crossover from leuprolide to degarelix. Urology. 2014;83:1122-1128. 3. Peyromaure M, Goulvestre C, Fulla Y, et al. Serum levels of vascular endothelial growth factor in patients undergoing prostate biopsy for suspicion of prostate cancer. Urology. 2005;66:687-691.
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