Over the past decade, prostatebrachytherapy has been usedincreasingly as definitivetreatment for early-stage carcinomaof the prostate gland, with the majorityof the literature on brachytherapyreporting biochemical results as favorableas those in the most positiveradical prostatectomy and externalbeamradiation therapy series.[1-4]Because of a lack of definitive evidencesupporting the efficacy of onelocal treatment approach over another,quality-of-life (QOL) parametershave assumed greater importance. Ithas been widely asserted that preservationof potency is more likely followingbrachytherapy, but longerfollow-up has raised substantialdoubts about brachytherapy’s potency-sparing advantage.[5,6] In addition,brachytherapy results in amyriad of previously unrecognizedeffects on sexual function.[7,8]
Erectile dysfunction is associated with brachytherapy, conformal radiation, or radical surgery (perineal or retropubic) for the control of localized prostate cancer. The article by Merrick, Wallner, and Butler focuses specifically on the effect of brachytherapy on erectile dysfunction and impotency.
Over the past decade, investigators have defined the neuroanatomy and biochemical pathways that regulate erectile function. Specifically, our growing knowledge of the pathophysiology and biochemical role of nitrous oxide (a potent biologic mediator of vascular smooth muscle relaxation) and the function of testosterone has resulted in new approaches for the pharmacologic manipulation of erectile dysfunction.[ 1] In addition, enhanced transdermal and systemic delivery of drugs portends improved therapeutic management in the future.
Elucidation of the functional genomics associated with erectile dysfunction also heralds the introduction of new therapeutic modalities. Treatment is facilitated because sexual dysfunction is no longer a "closed closet" topic, especially given mass media advertising for drugs such as sildenafil (Viagra). Mass media communication has also boosted the dialog between sexual partners and their physicians. This has improved marital relations and the treatment of patients in the earlier stages of erectile dysfunction.
Nevertheless, because all treatment modalities for the control of localized prostate cancer are nearly equal in efficacy, a cardinal question for most patients centers on the risk of impotency and other quality-oflife (QOL) issues following treatment with the various modalities. Discussion of these issues by Merrick et al is timely.
The historical development of brachytherapy reflects multiple technical advances. Gold brachytherapy for the management of prostate cancer was pioneered by Flocks at the University of Iowa and Carlton at Baylor College of Medicine in Houston. Suprapubic and transperineal brachytherapy with iodine-125 seeds were later reinvestigated by Whitmore in the 1970s.
In recent years, precise ultrasound seed placement and the science of radiation physics have yielded therapeutic results similar to those achieved with surgery for localized prostate cancer in small glands, when results are compared at 13 years in nonrandomized studies. Conformal radiation alone or in combination with external-beam irradiation, and quality control with the B-mode Acquired Target (BAT) ultrasound system, offer another alternative alone or in combination with adjunctive hormonal ablation. Thus, precise evaluation of erectile function and other QOL issues such as rectal bleeding, incontinence, and response to pharmacologic enhancement following therapy are needed to compare the results of all treatment modalities alone or in combination.
From a surgical perspective, nervesparing radical prostatectomy reflects an improved understanding of the male neuroanatomy facilitated by the landmark efforts of Lepor and others, who clearly delineated the anatomy of the neurovascular bundle. The neurovascular bundle runs parallel to the urethra and decussates along the prostate capsule and the lateral aspects of the gland. Consequently, prostate cancer arising at the apex or periphery of the gland in proximity to the neurovascular bundle requires sacrifice of the erectile nerves to attain local cancer control in some cases. If both nerves are transected, impotency is certain. If one nerve is spared, the potency is 46% at 5 years, and if both nerves are spared, this increases to 61%.
Development of an Erection
Treatment of patients postsurgically has improved erectile function. For example, sildenafil, a type 5 phosphodiesterase inhibitor, indirectly potentiates the effects of nitrous oxide on sinusoidal smooth muscle by causing increased intracellular cyclic guanosine monophosphate (GMP) in the corpora cavernosal bodies, resulting in smooth muscle relaxation and penile tumescence (see Figure 1).
However, more precise methods are needed to determine whether nerve-sparing surgery is indicated for one or both nerves. It is frequently difficult to determine the proximity of the neoplasm to the capsule, and pathologic assessment is not always accurate because of surgical trauma. Robotically controlled laparoscopy provides improved optical resolution and decreases surgical trauma but eliminates tactile clues-a potential advantage of open surgery.
Two-Dimensional Image of a Prostate
Advances in computer analysis of contrast-enhanced transrectal color Doppler ultrasonography (TRCDUS) for prostate neovascularity may assist in defining the limits of the tumor prior to deciding whether to sacrifice one or both nerves during the preoperative evaluation and serve as a guide for biopsy and rebiopsy in the future.[ 5,6] Based on the images shown in Figure 2, the three-dimensional image in Figure 3 was reconstructed via neural net analysis of radiofrequency waves generated by conventional ultrasound machines. Eventually, real-time imaging and collection of data such as this should be possible.
Reconstructed Three-Dimensional Image
A clear logical advantage of conformal radiation or seed implants is the anatomic preservation of the neurovascular bundle without the need for nerve resection and sural nerve grafting. However, if surgery is selected and a unilateral or bilateral nerve resection is required, the option of a sural nerve graft (a small nerve near the ankle) performed by the urologist and plastic surgeon facilitates nerve regeneration and erectile function. The autonomic nerves are easily identified using an electric nerve probe, and the ends are carefully marked at the base of the penis and adjacent to the bladder. Usually, the sural nerve graft is 5 to 7 cm in length, depending on the gap left following resection of the nerve. Once harvested, the graft is rotated 180o to promote nerve regeneration, and the nerve is sewn in place without tension. Nerve regeneration occurs in 6 to 12 months and, thus, requires long-term QOL assessment and supportive erections to maintain the health of the erectile tissues.
This article illustrates that there is a need to evaluate each of the treatment modalities and their effect on erectile dysfunction, both early and late in course of the prescribed therapy. Once evaluated, pharmacologic manipulation with drugs such as sildenafil or newer agents such as vardenafil and cialis potentiate the effect of nitric oxide-activated GMP by inhibiting breakdown of the enzyme. The newer inhibitors on the horizon have more rapid activation, longer duration, and potentially fewer side effects.
From a basic science perspective, it remains to be determined if there are growth factors that might improve nerve regeneration in patients reenervated with sacral nerve grafts, or in those receiving radiation therapy or chemotherapy. The molecular aspects of peripheral nerve regeneration with growth factors is an active area of research, involving both in vitro and in vivo experiments to evaluate nerve regeneration and erectile function.
Improved physical properties of radiation therapy and more precise methods of delivery (such as BAT) continue to enhance this modality. Ultrasound imaging has enabled more precise placement of iodine-125 and palladium-103 seeds as well as better control of conformal radiation, reducing intratreatment error and subjecting adjacent organs such as the rectum to less radiation. Radiation therapy provides the distinct advantage of leaving the neurovascular bundle intact with the potential for additional pharmacologic manipulation and improved quality of life with preserved erectile function. All treatment modalities have early and late undesirable effects on erectile dysfunction. The critical issue, however, is the long-term outcome following the initial 6- to 9-month evaluation.
Validation of erectile dysfunction with QOL questionnaires will assist in delineating the best multimodality approach for preserving erectile function and for minimizing the morbidity associated with the treatment of prostate cancer. Further basic science related to nerve regeneration may improve all treatment outcomes that currently result in decreased erectile dysfunction.
However, because current estimates of therapeutic effectiveness are similar for each of the various treatment options, larger controlled clinical trials will be necessary to clearly establish the best primary treatment for the control of the disease and the preservation of erectile function. Unfortunately, controlled trials comparing radiation to surgery have been difficult to complete and have neither incorporated QOL issues nor standardized surgical techniques or the delivery of radiation therapy.
Articles such as this one by Merrick et al put these issues in perspective and are likely to affect the design and completion of future clinical trials.
Financial Disclosure: The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
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