madman
Super Moderator
Abstract
Introduction: Erectile dysfunction (ED) following prostate cancer treatment is not uncommon and penile rehabilitation is considered the standard of care in prostate cancer survivorship (PCS), where both patient and his partner desire to maintain and/or recover pre-treatment erectile function (EF). There is clinical interest in the role of regenerative therapy to restore EF since existing ED treatments do not always achieve adequate results.
Aim: To review regenerative therapies for the treatment of ED in the context of PCS.
Materials and Methods: A review of the existing PubMed literature on low-intensity extracorporeal shockwave therapy (LIESWT), stem cell therapy (SCT), platelet-rich plasma (PRP), gene therapy, and nerve graft/neurorrhaphy in the treatment of ED and penile rehabilitation was undertaken.
Results: IESWT promotes neovascularization and neuroprotection in men with ED. While several systematic reviews and meta-analyses showed positive benefits, there is limited published clinical data in men following radical prostatectomy. Cellular-based technology such as SCT and PRP promotes cellular proliferation and the secretion of various growth factors to repair damaged tissues, especially in preclinical studies. However, longer-term clinical outcomes and concerns regarding bioethical and regulatory frameworks need to be addressed. Data on gene therapy in post-prostatectomy ED men are lacking; further clinical studies are required to investigate the optimal use of growth factors and the safest vector delivery system. Conceptually interpositional cavernous nerve grafting and penile reinnervation technique using a somatic-to-autonomic neurorrhaphy are attractive, but issues relating to surgical technique and potential for neural ‘regeneration’ are questionable.
Conclusion: In contrast to the existing treatment regime, regenerative ED technology aspires to promote endothelial revascularization and neuro-regeneration. Nevertheless, there remain considerable issues related to these regenerative technologies and techniques, with limited data on longer-term efficacy and safety records. Further research is necessary to define the role of these alternative therapies in the treatment of ED in the context of penile rehabilitation and PCS.
Introduction
Scientific advances in prostate cancer (PC) treatment have resulted in a better survival rate in men with clinically localized PC.1 However, this has led to greater demands for better patient health-related quality-of-life domains under the concept of prostate cancer survivorship (PCS), where both the patient and his partner desire to maintain and/ or recover pre-treatment physical functioning, including sexual function.2 Contemporary literature shows that erectile dysfunction (ED) remains as high as 60% following robotic radical prostatectomy.3 In those who receive radiation therapy, ED tends to occur later and is generally more severe in the external beam radiation group compared with those who received brachytherapy.4 Men who receive androgen deprivation therapy and those who have undergone salvage therapies are more likely to experience significant ED.2 Furthermore, the recovery of sexual function can vary from one individual to another, including the response to various sexual therapies.
Penile rehabilitation is accepted as the standard of care in men who received surgery or radiation therapy for PC. While oral phosphodiesterase type 5 inhibitor (PDE5i) remains the first-line therapy and current standard in penile rehabilitation, the evidence supporting its clinical efficacy in restoring natural spontaneous erection is far from convincing.5–7 Intracavernosal therapy is more likely to be effective, especially in the setting of neuropraxia, while penile prosthesis implantation provides a permanent mechanical solution.8,9
Over the past decade, there has been considerable interest in the role of regenerative therapy to restore erectile function (EF) without the need for dependency on medical therapy. Although there is substantial preliminary research undertaken on the role of various regenerative strategies for ED, there is a paucity of high-quality human data to support their use as a standard of care in clinical practice; particularly in the setting of penile rehabilitation in PCS. The following article explores our evolving understanding of the topic, with an overview of the basic science on regenerative technology and its role in EF recovery and penile rehabilitation in the setting of PC treatment and PCS (Table 1).
*Low-intensity extracorporeal shockwave therapy (LIESWT)
There is great interest among clinicians and patients regarding the use of LIESWT for ED since this technology has been shown to improve EF through the release of various angiogenic factors such as vascular endothelial growth factor (VEGF) and endothelial nitric oxide synthase (eNOS), which are responsible for tissue neovascularization and alteration in cellular apoptosis.21,22
*Cellular-based therapy
Stem cell therapy (SCT)
SCT has emerged as a promising regenerative approach due to its ability to drive cellular proliferation and multi-differentiation to repair damaged tissues.34
Platelet-rich plasma (PRP)
The PRP is an autologous product obtained from whole blood with more than four times normal human physiological serum platelet concentration. PRP contains many growth factors (e.g. VEGF, platelet-derived growth factor [PDGF], and fibroblast growth factor [FGF]) responsible for regenerative functions, including the recruitment of stem cells, the modulation of inflammatory responses, and the stimulation of angiogenesis and neuronal regeneration.43–45
Gene therapy
In the era of personalized medicine, gene therapy is very attractive since it offers several clinical advantages. These include single-dose therapy to restore erectile function for the long term and the ability to be combined with other therapies to optimize dose requirements and minimize side effects, and also the opportunity to develop patient-specific treatment approaches.51 Current gene therapies in ED could be categorized into activators of the nitrergic-neural system, endothelial growth factors promoters, and modulators of ion channels in smooth muscle cells. These act on various molecular targets including eNOS, neurotrophic and angiogenic factors, potassium channels, prostacyclin I2 synthase, and peptides.51,52
Interposition nerve graft and nerve transfer (neurorrhaphy)
From the identification of the cavernous neurovascular bundles to subsequent refinements in nerve-sparing radical prostatectomy, there have been considerable advances made to preserve EF in men undergoing radical prostatectomy.58 The use of an intraoperative tool to facilitate the identification of cavernous nerves, such as the CaverMap® surgical aid (UroMed, Boston, MA) has permitted various interpositional nerve grafts to be placed onto the surgical bed to repair these critical nerves. The goal is to restore the neural conduit for the preservation of EF postoperatively.
Conclusions
The potential of regenerative medicine in restoring EF following radical prostatectomy is exciting and highly innovative. In contrast to the existing treatment regime, regenerative ED technology aspires to promote endothelial revascularization and neuro-regeneration. The use of various novel agents, micro-energy applications, and novel neural ‘reconstruction’ will continue to push boundaries and perhaps promote symbiotic therapy with existing penile rehabilitation protocols. Despite this enthusiasm, there remain considerable issues related to these regenerative technologies and techniques; due in part to the limited data on longer-term efficacy and safety records.
Defining true success using regenerative therapy to restore EF is likely to be dependent on many factors, including sexual desire, penile size and shape, the ability to successfully have penetrative intercourse, and sexual practice, as well as ejaculatory and orgasmic dysfunctions. In addition, there are many interplaying factors such as changes in psychosexual, body image, and relationship dynamics, and the presence of coexisting urinary or bowel disturbances that may exacerbate the sense of loss of masculinity and sexual distress.2 The need for adjuvant or salvage radiation or hormonal therapy will adversely affect EF recovery and worsen ED. These factors underscore the limitations in current and future treatment strategies to restore EF, as well as highlight the need for a more holistic approach to male sexuality beyond achieving just an erect penis.
Introduction: Erectile dysfunction (ED) following prostate cancer treatment is not uncommon and penile rehabilitation is considered the standard of care in prostate cancer survivorship (PCS), where both patient and his partner desire to maintain and/or recover pre-treatment erectile function (EF). There is clinical interest in the role of regenerative therapy to restore EF since existing ED treatments do not always achieve adequate results.
Aim: To review regenerative therapies for the treatment of ED in the context of PCS.
Materials and Methods: A review of the existing PubMed literature on low-intensity extracorporeal shockwave therapy (LIESWT), stem cell therapy (SCT), platelet-rich plasma (PRP), gene therapy, and nerve graft/neurorrhaphy in the treatment of ED and penile rehabilitation was undertaken.
Results: IESWT promotes neovascularization and neuroprotection in men with ED. While several systematic reviews and meta-analyses showed positive benefits, there is limited published clinical data in men following radical prostatectomy. Cellular-based technology such as SCT and PRP promotes cellular proliferation and the secretion of various growth factors to repair damaged tissues, especially in preclinical studies. However, longer-term clinical outcomes and concerns regarding bioethical and regulatory frameworks need to be addressed. Data on gene therapy in post-prostatectomy ED men are lacking; further clinical studies are required to investigate the optimal use of growth factors and the safest vector delivery system. Conceptually interpositional cavernous nerve grafting and penile reinnervation technique using a somatic-to-autonomic neurorrhaphy are attractive, but issues relating to surgical technique and potential for neural ‘regeneration’ are questionable.
Conclusion: In contrast to the existing treatment regime, regenerative ED technology aspires to promote endothelial revascularization and neuro-regeneration. Nevertheless, there remain considerable issues related to these regenerative technologies and techniques, with limited data on longer-term efficacy and safety records. Further research is necessary to define the role of these alternative therapies in the treatment of ED in the context of penile rehabilitation and PCS.
Introduction
Scientific advances in prostate cancer (PC) treatment have resulted in a better survival rate in men with clinically localized PC.1 However, this has led to greater demands for better patient health-related quality-of-life domains under the concept of prostate cancer survivorship (PCS), where both the patient and his partner desire to maintain and/ or recover pre-treatment physical functioning, including sexual function.2 Contemporary literature shows that erectile dysfunction (ED) remains as high as 60% following robotic radical prostatectomy.3 In those who receive radiation therapy, ED tends to occur later and is generally more severe in the external beam radiation group compared with those who received brachytherapy.4 Men who receive androgen deprivation therapy and those who have undergone salvage therapies are more likely to experience significant ED.2 Furthermore, the recovery of sexual function can vary from one individual to another, including the response to various sexual therapies.
Penile rehabilitation is accepted as the standard of care in men who received surgery or radiation therapy for PC. While oral phosphodiesterase type 5 inhibitor (PDE5i) remains the first-line therapy and current standard in penile rehabilitation, the evidence supporting its clinical efficacy in restoring natural spontaneous erection is far from convincing.5–7 Intracavernosal therapy is more likely to be effective, especially in the setting of neuropraxia, while penile prosthesis implantation provides a permanent mechanical solution.8,9
Over the past decade, there has been considerable interest in the role of regenerative therapy to restore erectile function (EF) without the need for dependency on medical therapy. Although there is substantial preliminary research undertaken on the role of various regenerative strategies for ED, there is a paucity of high-quality human data to support their use as a standard of care in clinical practice; particularly in the setting of penile rehabilitation in PCS. The following article explores our evolving understanding of the topic, with an overview of the basic science on regenerative technology and its role in EF recovery and penile rehabilitation in the setting of PC treatment and PCS (Table 1).
*Low-intensity extracorporeal shockwave therapy (LIESWT)
There is great interest among clinicians and patients regarding the use of LIESWT for ED since this technology has been shown to improve EF through the release of various angiogenic factors such as vascular endothelial growth factor (VEGF) and endothelial nitric oxide synthase (eNOS), which are responsible for tissue neovascularization and alteration in cellular apoptosis.21,22
*Cellular-based therapy
Stem cell therapy (SCT)
SCT has emerged as a promising regenerative approach due to its ability to drive cellular proliferation and multi-differentiation to repair damaged tissues.34
Platelet-rich plasma (PRP)
The PRP is an autologous product obtained from whole blood with more than four times normal human physiological serum platelet concentration. PRP contains many growth factors (e.g. VEGF, platelet-derived growth factor [PDGF], and fibroblast growth factor [FGF]) responsible for regenerative functions, including the recruitment of stem cells, the modulation of inflammatory responses, and the stimulation of angiogenesis and neuronal regeneration.43–45
Gene therapy
In the era of personalized medicine, gene therapy is very attractive since it offers several clinical advantages. These include single-dose therapy to restore erectile function for the long term and the ability to be combined with other therapies to optimize dose requirements and minimize side effects, and also the opportunity to develop patient-specific treatment approaches.51 Current gene therapies in ED could be categorized into activators of the nitrergic-neural system, endothelial growth factors promoters, and modulators of ion channels in smooth muscle cells. These act on various molecular targets including eNOS, neurotrophic and angiogenic factors, potassium channels, prostacyclin I2 synthase, and peptides.51,52
Interposition nerve graft and nerve transfer (neurorrhaphy)
From the identification of the cavernous neurovascular bundles to subsequent refinements in nerve-sparing radical prostatectomy, there have been considerable advances made to preserve EF in men undergoing radical prostatectomy.58 The use of an intraoperative tool to facilitate the identification of cavernous nerves, such as the CaverMap® surgical aid (UroMed, Boston, MA) has permitted various interpositional nerve grafts to be placed onto the surgical bed to repair these critical nerves. The goal is to restore the neural conduit for the preservation of EF postoperatively.
Conclusions
The potential of regenerative medicine in restoring EF following radical prostatectomy is exciting and highly innovative. In contrast to the existing treatment regime, regenerative ED technology aspires to promote endothelial revascularization and neuro-regeneration. The use of various novel agents, micro-energy applications, and novel neural ‘reconstruction’ will continue to push boundaries and perhaps promote symbiotic therapy with existing penile rehabilitation protocols. Despite this enthusiasm, there remain considerable issues related to these regenerative technologies and techniques; due in part to the limited data on longer-term efficacy and safety records.
Defining true success using regenerative therapy to restore EF is likely to be dependent on many factors, including sexual desire, penile size and shape, the ability to successfully have penetrative intercourse, and sexual practice, as well as ejaculatory and orgasmic dysfunctions. In addition, there are many interplaying factors such as changes in psychosexual, body image, and relationship dynamics, and the presence of coexisting urinary or bowel disturbances that may exacerbate the sense of loss of masculinity and sexual distress.2 The need for adjuvant or salvage radiation or hormonal therapy will adversely affect EF recovery and worsen ED. These factors underscore the limitations in current and future treatment strategies to restore EF, as well as highlight the need for a more holistic approach to male sexuality beyond achieving just an erect penis.
