Letters

Previous Presentation: Presented in part at the Annual Meeting of the Infectious Disease Society for Obstetrics and Gynecology; August 11-13, 2011; Chicago, Illinois. 1. Morris SR, Bauer HM, Samuel MC, Gallagher D, Bolan G. Neonatal herpes morbidity and mortality in California, 1995-2003. Sex Transm Dis. 2008;35(1): 14-18. 2. Brown ZA, Wald A, Morrow RA, Selke S, Zeh J, Corey L. Effect of serologic status and cesarean delivery on transmission rates of herpes simplex virus from mother to infant. JAMA. 2003;289(2):203-209. 3. Kropp RY, Wong T, Cormier L, et al. Neonatal herpes simplex virus infections in Canada: results of a 3-year national prospective study. Pediatrics. 2006;117 (6):1955-1962. 4. Bradley H, Markowitz LE, Gibson T, McQuillan GM. Seroprevalence of herpes simplex types 1 and 2—United States, 1999-2010. J Infect Dis. 2014;209(3): 325-333. 5. Fanfair RN, Zaidi A, Taylor LD, Xu F, Gottlieb S, Markowitz L. Trends in seroprevalence of herpes simplex virus type 2 among non-Hispanic blacks and non-Hispanic whites aged 14 to 49 years—United States, 1988 to 2010. Sex Transm Dis. 2013;40(11):860-864. 6. Ashley RL. Militoni J, Lee F, Nahmias A, Corey L. Comparison of Western Blot (immunoblot) and glycoprotein G-specific immunodot enzyme assay for detecting antibodies to herpes simplex types 1 and 2 in human sera. J Clin Microbiol. 1988;26(4):622-627. .

COMMENT & RESPONSE

Tadalafil for Erectile Dysfunction Prevention After Radiotherapy for Prostate Cancer To the Editor Dr Pisansky and colleagues1 did not find any beneficial effect of daily tadalafil administration in preventing erectile dysfunction (ED) in men treated with radiotherapy for prostate cancer. Concerns about the methodology of this study parallel those raised after previous trials testing penile rehabilitation after radical prostatectomy. These include inadequate patient selection,1 short-term follow-up,2 and possibly improper tadalafil administration.3 First, selected patients with a high probability of erectile function recovery after radiotherapy were enrolled. The majority of men were free from any significant comorbidity and had no or mild ED at treatment initiation. Such a favorable baseline profile may have diluted the effect of tadalafil on erectile function recovery, given the high probability of these patients to maintain erectile function after radiotherapy with or without any medication.2 Moreover, no detailed description of cardiovascular risk factors was provided by Pisansky et al.1 This is important given the effect on recovery of erectile function after radiotherapy.2 Second, longer follow-up and longer exposure to phosphodiesterase type 5 inhibitors (PDE5-I) may be needed to evaluate the efficacy of penile rehabilitation after radiotherapy. The reason for this lies in the pathophysiology of postradiotherapy ED, which includes neurovascular damage as well as induced chronic oxidative stress. The latter seems to be the primary step in a gradual fibrotic process that takes place over several years.3 Therefore, evaluating postradiotherapy erectile function at 1 year may underestimate the cavernosal damage induced by radiotherapy, as well as the potential beneficial effect of any penile rehabilitation after radiotherapy.4 Third, whether a possible beneficial effect of PDE5-I administered prior rather than after penile neurovascular 748

damage exists needs to be tested, as shown in the setting of damage from ischemia reperfusion.5 For all these reasons, we believe that further research is needed to properly assess the effectiveness of PDE5-I use for ED after radiotherapy. Targeting the right patient and using proper administration schedules represent the main factors in the success of any penile rehabilitation protocol. Fabio Castiglione, MD Francesco Montorsi, MD Alberto Briganti, MD Author Affiliations: Division of Oncology, IRCCS Ospedale San Raffaele, Milan, Italy. Corresponding Author: Alberto Briganti, MD, Division of Oncology, IRCCS Ospedale San Raffaele, Via Olgettina 60, 20132 Milan, Italy (briganti.alberto @hsr.it). Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Montorsi reported receiving speaker honoraria from Eli Lilly. No other disclosures were reported. 1. Pisansky TM, Pugh SL, Greenberg RE, et al. Tadalafil for prevention of erectile dysfunction after radiotherapy for prostate cancer: the Radiation Therapy Oncology Group [0831] randomized clinical trial. JAMA. 2014;311(13):1300-1307. 2. Wang Y, Liu T, Rossi PJ, et al. Influence of vascular comorbidities and race on erectile dysfunction after prostate cancer radiotherapy. J Sex Med. 2013;10(8): 2108-2114. 3. Zhao W, Robbins ME. Inflammation and chronic oxidative stress in radiation-induced late normal tissue injury: therapeutic implications. Curr Med Chem. 2009;16(2):130-143. 4. Siglin J, Kubicek GJ, Leiby B, Valicenti RK. Time of decline in sexual function after external beam radiotherapy for prostate cancer. Int J Radiat Oncol Biol Phys. 2010;76(1):31-35. 5. Weiss ES, Champion HC, Williams JA, Baumgartner WA, Shah AS. Long-acting oral phosphodiesterase inhibition preconditions against reperfusion injury in an experimental lung transplantation model. J Thorac Cardiovasc Surg. 2009;137 (5):1249-1257.

In Reply Although our study did not identify a role for tadalafil to prevent radiotherapy-related ED, Dr Castiglione and colleagues urge cautious interpretation of our results based on inadequate participant inclusion criteria and follow-up duration, and on possibly improper tadalafil administration. We do not agree that our participants’ favorable baseline (erectile function) profile negatively affected the trial’s outcome. It is important to distinguish between penile rehabilitation after urological surgery (an ED preventive strategy after radiotherapy) and a therapeutic intervention for established ED. In the first, an acute vasogenic or neurogenic event (ie, radical prostatectomy) precipitates a sudden loss of function, from which recovery is sought—thus, rehabilitation. Radiotherapy-related injury to erectogenic tissue accumulates slowly and as a delayed response to treatment administered over several months—thus, a strategy seeking to prevent loss of existing function. We selected trial participants without ED because we sought to preserve spontaneous offdrug erectile function. Inclusion of participants with ED or with a significant burden of conditions contributing to its occurrence1 potentially would have confounded the results,

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Letters

lessening the opportunity to identify a treatment effect, and would have risked lack of generalization to the target population. We acknowledged previously that further follow-up of study participants may “reveal a [unexpected] lateappearing benefit to tadalafil” because a planned analysis at 24 months is a secondary end point of our trial. Other patient-reported outcomes research does not provide great optimism in this regard, however,2-4 with stability in the ED rate from 12 months to 24 months,2-4 or even up to 6 years after radiotherapy.3 Causes of ED unrelated to prostate cancer therapy (eg, advancing age, vascular disease) or use of androgen suppression subsequently are apt to lessen the effect of preventive or rehabilitative interventions in the long-term.4 We agree that many uncertainties exist about optimal PDE5-I dosing and treatment duration when this drug class is tested to prevent radiotherapy-related ED. Yet the development and conduct of our study was supported by the efficacy of tadalafil at 5-mg (vs 10-mg) once daily dosing,5 which aligned with usage approved by the US Food and Drug Administration and which was demonstrated also during the active 24week drug administration phase of our trial (Figure 2). We cannot know presently whether a longer treatment phase would yield other outcomes, but it is essential to consider the value of such an approach compared with on-demand PDE5-I use as treatment for ED. Although it may be sensible to further test the effect of PDE5-I administered prior to surgery, as proposed by Castiglione and colleagues, our study essentially did so with radiotherapy—tadalafil was started before vasogenic injury is thought to occur. We therefore cannot endorse a research strategy that would extend this hypothesis further in the context of radiotherapy. We encourage further research in this area, but cannot endorse use of a PDE5-I as a preventive measure until such an approach is found beneficial. Thomas M. Pisansky, MD Deborah W. Bruner, PhD, RN Richard E. Greenberg, MD Author Affiliations: Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota (Pisansky); Emory University, Atlanta, Georgia (Bruner); Fox Chase Cancer Center, Philadelphia, Pennsylvania (Greenberg). Corresponding Author: Thomas M. Pisansky, MD, Department of Radiation Oncology, Mayo Clinic, 200 First St SW, Rochester, MN 55905 (pisansky.thomas @mayo.edu). Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Bruner reported receiving grant funding from the National Cancer Institute and Eli Lilly & Co; and travel support from the Community Clinical Oncology Program. No other disclosures were reported. Disclaimer: The views presented herein are those solely of the Radiation Therapy Oncology Group and of the authors, who accept no liability for the consequences of any actions taken on the basis of information provided. 1. Wang Y, Liu T, Rossi PJ, et al. Influence of vascular comorbidities and race on erectile dysfunction after prostate cancer radiotherapy. J Sex Med. 2013;10 (8):2108-2114. 2. Sanda MG, Dunn RL, Michalski J, et al. Quality of life and satisfaction with outcome among prostate-cancer survivors. N Engl J Med. 2008;358(12):12501261.

3. Siglin J, Kubicek GJ, Leiby B, Valicenti RK. Time of decline in sexual function after external beam radiotherapy for prostate cancer. Int J Radiat Oncol Biol Phys. 2010;76(1):31-35. 4. Resnick MJ, Koyama T, Fan KH, et al. Long-term functional outcomes after treatment for localized prostate cancer. N Engl J Med. 2013;368(5):436-445. 5. Porst H, Giuliano F, Glina S, et al. Evaluation of the efficacy and safety of once-a-day dosing of tadalafil 5mg and 10mg in the treatment of erectile dysfunction: results of a multicenter, randomized, double-blind, placebo-controlled trial. Eur Urol. 2006;50(2):351-359.

Statins and Ischemic Stroke To the Editor The report from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study1 indicated that the new equations for predicting atherosclerotic cardiovascular risk appeared to overestimate the risk of atherosclerotic events in the participants. This study affords an opportunity to assess a possible problem with the new Pooled Cohort risk equations. The accompanying Editorial2 emphasized underascertainment of events in the observational REGARDS study as a likely reason for apparent overestimation of risk and raised the possibility that statin therapy in participants may have reduced outcomes compared with the prediction by the equations. Another possibility should be considered: it may be an error to classify all ischemic strokes as hard atherosclerotic end points. Because the REGARDS study was designed to assess differences between blacks and other racial/ethnic groups, it may be possible to investigate this issue even though data on stroke subtypes were not collected. Strokes due to large artery atherosclerosis constitute only a subset of stroke subtypes, which also include cardioembolic stroke, infarctions due to hypertensive small vessel disease (lacunar infarctions), other causes such as vasculitis, and strokes of undetermined origin. Historical data from mainly white populations suggest that strokes due to large artery atherosclerosis account for approximately 20% of strokes.3 The Greater Cincinnati/Northern Kentucky Stroke Study4 showed that black participants were nearly twice as likely as whites to have strokes due to small vessel disease. Although the overall performance of the risk equations in the REGARDS study was similar between black and white participants, there was an indication that they performed less well in blacks: the Hosmer-Lemeshow χ2 for blacks was 11.8 (P = .16) vs 14 for whites (P = .08), and the C index was lower for blacks (0.69; 95% CI, 0.65-0.74) than for whites (0.74; 95% CI, 0.710.77). The risk equations were designed to identify which individuals would qualify for statin therapy under the new cholesterol-lowering guidelines2; however, statins may be more effective in preventing large artery stroke.5 It would be of interest to reanalyze the data to compare the performance of the equations in blacks and whites in the prediction of coronary events, which represent truly atherosclerotic events, with ischemic stroke. This would give an indication of the extent to which it may be erroneous to classify all ischemic strokes as atherosclerotic end points. J. David Spence, MD, FRCPC

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Tadalafil for erectile dysfunction prevention after radiotherapy for prostate cancer.

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