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Radiation Dose–Volume Effects and the Penile Bulb

      The dose, volume, and clinical outcome data for penile bulb are reviewed for patients treated with external-beam radiotherapy. Most, but not all, studies find an association between impotence and dosimetric parameters (e.g., threshold doses) and clinical factors (e.g., age, comorbid diseases). According to the data available, it is prudent to keep the mean dose to 95% of the penile bulb volume to <50 Gy. It may also be prudent to limit the D70 and D90 to 70 Gy and 50 Gy, respectively, but coverage of the planning target volume should not be compromised. It is acknowledged that the penile bulb may not be the critical component of the erectile apparatus, but it seems to be a surrogate for yet to be determined structure(s) critical for erectile function for at least some techniques.

      1. Clinical Significance

      Erectile dysfunction (ED), the consistent inability to attain or maintain an erection of sufficient quality to permit satisfactory sexual intercourse, is a common complication resulting from radiotherapy (RT) for prostate cancer (
      • Sanda M.G.
      • Dunn R.L.
      • Michalski J.
      • et al.
      Quality of life and satisfaction with outcome among prostate-cancer survivors.
      ). Many patients choose RT for their clinically localized prostate cancer because they believe there may be a lower risk of ED compared with radical prostatectomy (RP); however, this remains controversial. Posttreatment ED rates have been reported to be approximately 24% (brachytherapy alone), 40% (brachytherapy plus external RT), 45% (external RT alone), 66% (nerve-sparing RP), 75% (non–nerve-sparing RP), and 87% for cryosurgery, but physician-reported rates are known to be less reliable than patient-reported outcomes, so the optimal comparison studies have yet to be done (
      • Robinson J.W.
      • Moritz S.
      • Fung T.
      Meta-analysis of rates of erectile function after treatment of localized prostate carcinoma.
      ).

      2. Endpoints

      The time course for RT-associated ED is variable (reported as days to years) and often evolves gradually. Ascribing ED to RT alone is difficult because men lose some erectile function with age, and other common diseases (e.g., diabetes, hypertension) may contribute. Various self-administered questionnaires have been used to assess erectile function in clinical studies (e.g., the International Index of Erectile Function [IIEF]) (
      • Rosen R.C.
      • Riley A.
      • Wagner G.
      • et al.
      The international index of erectile function (IIEF): A multidimensional scale for assessment of erectile dysfunction.
      ). Additional objective diagnostic tests can be performed (e.g., nocturnal penile tumescence, somatosensory evoked potentials, bulbocavernous reflex latency, penile electromyography, color duplex Doppler ultrasound, dynamic infusion cavernosometry, and pharmacotesting), but these are generally applied to establish the etiology of ED (
      • Broderick G.A.
      Evidence based assessment of erectile dysfunction.
      ).

      3. Challenges Defining Volume

      The anatomy of the pelvic floor is challenging to visualize on CT or MRI, and hence definition of the penile bulb (PB) varies. This may contribute to inconsistent reports (
      • Brown M.W.
      • Brooks J.P.
      • Albert P.S.
      • et al.
      An analysis of erectile function after intensity modulated radiation therapy for localized prostate carcinoma.
      ,
      • Cahlon O.
      • Zelefsky M.J.
      • Shippy A.
      • et al.
      Ultra-high dose (86.4 Gy) IMRT for localized prostate cancer: Toxicity and biochemical outcomes.
      ,
      • Fisch B.M.
      • Pickett B.
      • Weinberg V.
      • et al.
      Dose of radiation received by the bulb of the penis correlates with risk of impotence after three-dimensional conformal radiotherapy for prostate cancer.
      ,
      • Mangar S.A.
      • Sydes M.R.
      • Tucker H.L.
      • et al.
      Evaluating the relationship between erectile dysfunction and dose received by the penile bulb: Using data from a randomised controlled trial of conformal radiotherapy in prostate cancer (MRC RT01, ISRCTN47772397).
      ,
      • Pinkawa M.
      • Gagel B.
      • Piroth M.D.
      • et al.
      Erectile dysfunction after external beam radiotherapy for prostate cancer.
      ,
      • Roach M.
      • Winter K.
      • Michalski J.M.
      • et al.
      Penile bulb dose and impotence after three-dimensional conformal radiotherapy for prostate cancer on RTOG 9406: Findings from a prospective, multi-institutional, phase I/II dose-escalation study.
      ,
      • Selek U.
      • Cheung R.
      • Lii M.
      • et al.
      Erectile dysfunction and radiation dose to penile base structures: A lack of correlation.
      ,
      • Skala M.
      • Rosewall T.
      • Dawson L.
      • et al.
      Patient-assessed late toxicity rates and principal component analysis after image-guided radiation therapy for prostate cancer.
      ,
      • van der Wielen G.J.
      • Hoogeman M.S.
      • Dohle G.R.
      • et al.
      Dose-volume parameters of the corpora cavernosa do not correlate with erectile dysfunction after external beam radiotherapy for prostate cancer: Results from a dose-escalation trial.
      ,
      • Wernicke A.G.
      • Valicenti R.
      • DiEva K.
      • et al.
      Radiation dose delivered to the proximal penis as a predictor of the risk of erectile dysfunction after three-dimensional conformal radiotherapy for localized prostate cancer.
      ,
      • Zelefsky M.J.
      • Chan H.
      • Hunt M.
      • et al.
      Long-term outcome of high dose intensity modulated radiation therapy for patients with clinically localized prostate cancer.
      ). The PB appears as an oval-shaped, hyperintense midline structure on T2-weighted MR images; on axial CT imaging it is bounded by the crura, corpora spongiosum, and the levator ani muscle (Fig. 1; see ref.
      • Wallner K.E.
      • Merrick G.S.
      • Benson M.L.
      • et al.
      Penile bulb imaging.
      for details). At University of California-San Francisco, the bulb is defined as the most proximal portion of the penis sitting immediately caudal to the prostate. We also recognize that the bulb itself is not part of the erectile apparatus but consider it an anatomic surrogate for periprostatic tissue likely to receive high doses of RT.
      Figure thumbnail gr1
      Fig. 1Penile and erectile tissue anatomy with CT (A) and MR (B–D) images of the penile bulb (). Adapted from Wallner et al.
      (
      • Wallner K.E.
      • Merrick G.S.
      • Benson M.L.
      • et al.
      Penile bulb imaging.
      )
      .

      4. Review of Dose–Volume Data

      Published studies assessing the correlations between the dose of external-beam RT, the PB volume irradiated, clinical factors, and ED are summarized in Table 1. Figure 2 shows a summary of PB dose–volume data vs. rates of ED. Studies that reported an association between RT dose and ED suggested that a dose of approximately 50 Gy to essentially the entire PB was a threshold dose for an increased risk of ED. However, several studies did not identify an association between RT dose and ED (
      • Brown M.W.
      • Brooks J.P.
      • Albert P.S.
      • et al.
      An analysis of erectile function after intensity modulated radiation therapy for localized prostate carcinoma.
      ,
      • Selek U.
      • Cheung R.
      • Lii M.
      • et al.
      Erectile dysfunction and radiation dose to penile base structures: A lack of correlation.
      ,
      • van der Wielen G.J.
      • Hoogeman M.S.
      • Dohle G.R.
      • et al.
      Dose-volume parameters of the corpora cavernosa do not correlate with erectile dysfunction after external beam radiotherapy for prostate cancer: Results from a dose-escalation trial.
      ).
      Table 1Erectile dysfunction after external-beam radiotherapy and correlated parameters
      First author, year (reference)NAssessment method
      All assessments are patient-reported, based on questionnaires or morbidity scoring scales (e.g., RTOG, NCI), as noted.
      Prescribed dose, treatmentOAR definitionSevere ED rate (%)Correlated parameters
      Dose–volumeClinical
      Fisch, 2001
      • Fisch B.M.
      • Pickett B.
      • Weinberg V.
      • et al.
      Dose of radiation received by the bulb of the penis correlates with risk of impotence after three-dimensional conformal radiotherapy for prostate cancer.
      21Questionnaire
      All questionnaires are self-administered.
      65–72 Gy, 3DPenile bulb33
      Potency scale declined ≥2.
      D70 ≥70 Gy
      Dx is dose delivered to the x% penile bulb volume.
      No other endpoints analyzed
      Roach, 2004
      • Roach M.
      • Winter K.
      • Michalski J.M.
      • et al.
      Penile bulb dose and impotence after three-dimensional conformal radiotherapy for prostate cancer on RTOG 9406: Findings from a prospective, multi-institutional, phase I/II dose-escalation study.
      158Patient report,

      (RTOG)
      RTOG radiation morbidity scoring scale.
      68.4 Gy, 73.8 Gy, 3DPenile bulb
      Penile bulb was defined as proximal portion of the penis.
      41Median penile bulb dose ≥52.5 Gy
      Penile bulb was defined as proximal portion of the penis.
      No other endpoints analyzed
      Wernicke, 2004
      • Wernicke A.G.
      • Valicenti R.
      • DiEva K.
      • et al.
      Radiation dose delivered to the proximal penis as a predictor of the risk of erectile dysfunction after three-dimensional conformal radiotherapy for localized prostate cancer.
      29Questionnaire
      All questionnaires are self-administered.
      66.6– 79.2 Gy, 3DPenile bulb
      The penile bulb is here specifically defined as proximal enlargement of the corpus spongiosum that is secured to the urogenital diaphragm and covered by the bulbospongiosus muscle.
      NSD30 ≥67 Gy
      Penile bulb was defined as proximal portion of the penis.


      D45 ≥63 Gy
      Penile bulb was defined as proximal portion of the penis.


      D60 ≥42 Gy
      Penile bulb was defined as proximal portion of the penis.


      D75 ≥20 Gy
      Penile bulb was defined as proximal portion of the penis.
      Alcohol and smoking not significant, dose and volume significant
      Selek, 2004
      • Selek U.
      • Cheung R.
      • Lii M.
      • et al.
      Erectile dysfunction and radiation dose to penile base structures: A lack of correlation.
      28Questionnaire
      All questionnaires are self-administered.
      78 Gy, 3DPenile bulb
      The penile bulb is here specifically defined as proximal enlargement of the corpus spongiosum that is secured to the urogenital diaphragm and covered by the bulbospongiosus muscle.
      35.7% at 2 yMean dose to penile structure 38.2 Gy, no dose–volume effect was found#Up to 68% may have had ED posttreatment? ED correlated with hypertension
      Mangar, 2006
      • Mangar S.A.
      • Sydes M.R.
      • Tucker H.L.
      • et al.
      Evaluating the relationship between erectile dysfunction and dose received by the penile bulb: Using data from a randomised controlled trial of conformal radiotherapy in prostate cancer (MRC RT01, ISRCTN47772397).
      51Questionnaire
      All questionnaires are self-administered.
      64 Gy, 74 Gy, 3DPenile bulb, crura and cavernosum
      The penile bulb was here defined as a structure, whereas the crura and the cavernosum as a separate one.
      24D15, D30, D50, D90 of penile bulb
      Penile bulb was defined as proximal portion of the penis.
      Adjusted for age, bulb volume, hypertension, and previous pelvic surgery
      Zelefsky, 2006
      • Zelefsky M.J.
      • Chan H.
      • Hunt M.
      • et al.
      Long-term outcome of high dose intensity modulated radiation therapy for patients with clinically localized prostate cancer.
      561Patient report

      (NCI)
      NCI common toxicity criteria for adverse events.
      81 Gy, IMRT
      Penile bulb not defined as a specific structure.
      49Not evaluatedHormone therapy
      Brown, 2007
      • Brown M.W.
      • Brooks J.P.
      • Albert P.S.
      • et al.
      An analysis of erectile function after intensity modulated radiation therapy for localized prostate carcinoma.
      32Questionnaire
      All questionnaires are self-administered.
      NS, IMRTPenile bulb34No relationship notedHypertension,

      pre-RT erectile function
      Cahlon, 2008
      • Cahlon O.
      • Zelefsky M.J.
      • Shippy A.
      • et al.
      Ultra-high dose (86.4 Gy) IMRT for localized prostate cancer: Toxicity and biochemical outcomes.
      478Patient report

      (NCI)
      NCI common toxicity criteria for adverse events.
      86.4 Gy, IMRT
      Penile bulb not defined as a specific structure.
      30Not evaluatedAge >70 y, diabetes, hormone therapy
      van der Wielen, 2008
      • van der Wielen G.J.
      • Hoogeman M.S.
      • Dohle G.R.
      • et al.
      Dose-volume parameters of the corpora cavernosa do not correlate with erectile dysfunction after external beam radiotherapy for prostate cancer: Results from a dose-escalation trial.
      70Questionnaire
      All questionnaires are self-administered.
      68 vs. 78 GyPenile bulb36No correlations between ED and dose–volume of crura, or the penile bulb#Adjusted for diabetes and history of cardiovascular disease
      Pinkawa, 2009
      • Pinkawa M.
      • Gagel B.
      • Piroth M.D.
      • et al.
      Erectile dysfunction after external beam radiotherapy for prostate cancer.
      123Questionnaire
      All questionnaires are self-administered.
      70.2–72 Gy, 3DNS73
      No erections firm enough for sexual intercourse.
      Not evaluatedAge, diabetes
      Abbreviations: OAR = organs at risk; ED = erectile dysfunction; RTOG = Radiation Therapy Oncology Group; NCI =National Cancer Institute; NS = not significant.
      All assessments are patient-reported, based on questionnaires or morbidity scoring scales (e.g., RTOG, NCI), as noted.
      All questionnaires are self-administered.
      Potency scale declined ≥2.
      § Dx is dose delivered to the x% penile bulb volume.
      RTOG radiation morbidity scoring scale.
      Penile bulb was defined as proximal portion of the penis.
      # The penile bulb is here specifically defined as proximal enlargement of the corpus spongiosum that is secured to the urogenital diaphragm and covered by the bulbospongiosus muscle.
      ∗∗ The penile bulb was here defined as a structure, whereas the crura and the cavernosum as a separate one.
      †† NCI common toxicity criteria for adverse events.
      ‡‡ Penile bulb not defined as a specific structure.
      §§ No erections firm enough for sexual intercourse.
      Figure thumbnail gr2
      Fig. 2Incidence of erectile dysfunction according to the radiation dose to the penile bulb. The x axis values are estimated according to the range of doses reported. The data for Fisch et al.
      (
      • Fisch B.M.
      • Pickett B.
      • Weinberg V.
      • et al.
      Dose of radiation received by the bulb of the penis correlates with risk of impotence after three-dimensional conformal radiotherapy for prostate cancer.
      )
      at 20, 55, and 80 Gy represent the reported rates of erectile dysfunction at <40, 40–70, and >70 Gy, respectively. Similarly, for Wernicke et al.
      (
      • Wernicke A.G.
      • Valicenti R.
      • DiEva K.
      • et al.
      Radiation dose delivered to the proximal penis as a predictor of the risk of erectile dysfunction after three-dimensional conformal radiotherapy for localized prostate cancer.
      )
      and Roach et al.
      (
      • Roach M.
      • Winter K.
      • Michalski J.M.
      • et al.
      Penile bulb dose and impotence after three-dimensional conformal radiotherapy for prostate cancer on RTOG 9406: Findings from a prospective, multi-institutional, phase I/II dose-escalation study.
      )
      , each symbol represents the rates of erectile dysfunction at ≤42 vs. >42 and <52.5 vs. ≥52.5 Gy, respectively. The dashed horizontal lines reflect the dose ranges ascribed to each data point. The upper x-axis range of the highest data point for Fisch et al.
      (
      • Fisch B.M.
      • Pickett B.
      • Weinberg V.
      • et al.
      Dose of radiation received by the bulb of the penis correlates with risk of impotence after three-dimensional conformal radiotherapy for prostate cancer.
      )
      and Roach et al.
      (
      • Roach M.
      • Winter K.
      • Michalski J.M.
      • et al.
      Penile bulb dose and impotence after three-dimensional conformal radiotherapy for prostate cancer on RTOG 9406: Findings from a prospective, multi-institutional, phase I/II dose-escalation study.
      )
      are unknown. The mean doses of van der Wielen et al.
      (
      • van der Wielen G.J.
      • Hoogeman M.S.
      • Dohle G.R.
      • et al.
      Dose-volume parameters of the corpora cavernosa do not correlate with erectile dysfunction after external beam radiotherapy for prostate cancer: Results from a dose-escalation trial.
      )
      and Mangar et al.
      (
      • Mangar S.A.
      • Sydes M.R.
      • Tucker H.L.
      • et al.
      Evaluating the relationship between erectile dysfunction and dose received by the penile bulb: Using data from a randomised controlled trial of conformal radiotherapy in prostate cancer (MRC RT01, ISRCTN47772397).
      )
      are estimated from the subgroup data. The x-axis values for Wernicke et al.
      (
      • Wernicke A.G.
      • Valicenti R.
      • DiEva K.
      • et al.
      Radiation dose delivered to the proximal penis as a predictor of the risk of erectile dysfunction after three-dimensional conformal radiotherapy for localized prostate cancer.
      )
      are D60 and for Fisch et al.
      (
      • Fisch B.M.
      • Pickett B.
      • Weinberg V.
      • et al.
      Dose of radiation received by the bulb of the penis correlates with risk of impotence after three-dimensional conformal radiotherapy for prostate cancer.
      )
      are D70 (i.e., minimum dose received by 60% or 70% volume of the penile bulb). A thick solid line represents the fitted model with sample size correction, with 95% confidence intervals (dotted curves).
      In general, it is difficult to extract a definite conclusion from these results, owing to relatively small numbers of patients, different anatomic definitions and endpoints for defining ED, and some potential methodologic problems. For example, Selek et al.(
      • Selek U.
      • Cheung R.
      • Lii M.
      • et al.
      Erectile dysfunction and radiation dose to penile base structures: A lack of correlation.
      ) reported that 10 of 28 patients were completely impotent after RT (zero function on a 5-point scale) but that most of these were hypertensive. Furthermore, their choice of 0 on their scale to define an event may not be appropriately sensitive. The most widely accepted scale for evaluating sexual function is the IIEF (which spans from 0 to 25). The original IIEF, described by Rosen et al.(
      • Rosen R.C.
      • Riley A.
      • Wagner G.
      • et al.
      The international index of erectile function (IIEF): A multidimensional scale for assessment of erectile dysfunction.
      ), included 15 items and five domains. They subsequently developed an abridged version of the questionnaire that contained five questions, and the scores ranged from 5 to 25 (
      • Rosen R.C.
      • Cappelleri J.C.
      • Smith M.D.
      • et al.
      Development and evaluation of an abridged, 5-item version of the International Index of Erectile Function (IIEF-5) as a diagnostic tool for erectile dysfunction.
      ). In the 1999 report the authors found that 21 was the optimal cutoff score. Thus, whenever possible investigators are encouraged to use this cutoff to define ED instead of the mild, moderate, and severe categories (unless independently validated). Thus for example, in the case of the report by Selek et al.(
      • Selek U.
      • Cheung R.
      • Lii M.
      • et al.
      Erectile dysfunction and radiation dose to penile base structures: A lack of correlation.
      ) it is likely than only assigning patients with a score “0” as being impotent underestimated the true baseline level of ED in their study population (see recommendations in “Toxicity Scoring”).
      In addition, several of these studies included a sizable fraction of patients who received phosphodiesterase type 5 inhibitors that might attenuate the effects of RT on sexual function (
      • Weber D.C.
      • Bieri S.
      • Kurtz J.M.
      • et al.
      Prospective pilot study of sildenafil for treatment of postradiotherapy erectile dysfunction in patients with prostate cancer.
      ,
      • Zelefsky M.J.
      • McKee A.B.
      • Lee H.
      • et al.
      Efficacy of oral sildenafil in patients with erectile dysfunction after radiotherapy for carcinoma of the prostate.
      ). Earlier studies were less likely to be contaminated by this issue because these agents were not available when most of these patients were treated (
      • Fisch B.M.
      • Pickett B.
      • Weinberg V.
      • et al.
      Dose of radiation received by the bulb of the penis correlates with risk of impotence after three-dimensional conformal radiotherapy for prostate cancer.
      ,
      • Roach M.
      • Winter K.
      • Michalski J.M.
      • et al.
      Penile bulb dose and impotence after three-dimensional conformal radiotherapy for prostate cancer on RTOG 9406: Findings from a prospective, multi-institutional, phase I/II dose-escalation study.
      ).
      Brown et al.(
      • Brown M.W.
      • Brooks J.P.
      • Albert P.S.
      • et al.
      An analysis of erectile function after intensity modulated radiation therapy for localized prostate carcinoma.
      ) studied 32 patients and noted no dose–response association for ED. However, they used intensity-modulated RT and attempted to spare the PB, resulting in a mean dose to the bulb of only 25 Gy. Thus, their data do not explicitly refute the presence of a dose–response association at higher doses.
      Several studies reported a significant dose–volume effect correlated with risk of ED using the metrics of Dx (i.e., the minimum dose received by x% volume of the PB). For example, Fisch et al.(
      • Fisch B.M.
      • Pickett B.
      • Weinberg V.
      • et al.
      Dose of radiation received by the bulb of the penis correlates with risk of impotence after three-dimensional conformal radiotherapy for prostate cancer.
      ) noted ED in 0, 80%, or 100% of patients with a D70 of 0–40, 40–70, and >70 Gy, respectively. Similarly, Mangar et al.(
      • Mangar S.A.
      • Sydes M.R.
      • Tucker H.L.
      • et al.
      Evaluating the relationship between erectile dysfunction and dose received by the penile bulb: Using data from a randomised controlled trial of conformal radiotherapy in prostate cancer (MRC RT01, ISRCTN47772397).
      ) reported that a D90 ≥50 Gy is associated with a significant risk of ED. Wernicke et al.(
      • Wernicke A.G.
      • Valicenti R.
      • DiEva K.
      • et al.
      Radiation dose delivered to the proximal penis as a predictor of the risk of erectile dysfunction after three-dimensional conformal radiotherapy for localized prostate cancer.
      ) reported that D30, D45, D60, and D75 correlated with an increased risk of ED. Roach et al.(
      • Roach M.
      • Winter K.
      • Michalski J.M.
      • et al.
      Penile bulb dose and impotence after three-dimensional conformal radiotherapy for prostate cancer on RTOG 9406: Findings from a prospective, multi-institutional, phase I/II dose-escalation study.
      ) reported a significant correlation between a median PB dose of 52.5 Gy and an increase in ED.
      Brachytherapy studies are mixed in their support for an association between PB doses and ED. Merrick et al.(
      • Merrick G.S.
      • Butler W.M.
      • Wallner K.E.
      • et al.
      The importance of radiation doses to the penile bulb vs. crura in the development of postbrachytherapy erectile dysfunction.
      ) used a matched-pair study of ED after brachytherapy and related PB dose–volume metrics to patient-reported questionnaire data. The rate of ED was associated with doses to the PB (particularly median dose [D50]) and to a lesser degree the crura. On the other hand, the Macdonald et al.(
      • Macdonald A.G.
      • Keyes M.
      • Kruk A.
      • et al.
      Predictive factors for erectile dysfunction in men with prostate cancer after brachytherapy: Is dose to the penile bulb important?.
      ) review of 342 patients after brachytherapy failed to show an association between median PB dose and ED.

      5. Factors Affecting Risk

      Patient-related factors for ED have not been emphasized, except for a few reports. Post-RT ED rates have been reported to be higher with baseline pretreatment ED, diabetes, smoking history, or a history of hypertension (
      • Brown M.W.
      • Brooks J.P.
      • Albert P.S.
      • et al.
      An analysis of erectile function after intensity modulated radiation therapy for localized prostate carcinoma.
      ,
      • Fisch B.M.
      • Pickett B.
      • Weinberg V.
      • et al.
      Dose of radiation received by the bulb of the penis correlates with risk of impotence after three-dimensional conformal radiotherapy for prostate cancer.
      ,
      • Merrick G.S.
      • Butler W.M.
      • Wallner K.E.
      • et al.
      The importance of radiation doses to the penile bulb vs. crura in the development of postbrachytherapy erectile dysfunction.
      ,
      • Goldstein I.
      • Feldman M.I.
      • Deckers P.J.
      • et al.
      Radiation-associated impotence. A clinical study of its mechanism.
      ). The data, however, are somewhat conflicting (Table 1).

      6. Mathematic/Biologic Models

      Penile bulb dose–volume parameters may be associated with the incidence of ED, although the results are conflicting to prove a clear correlation between those parameters (Fig. 2). For example, van der Wielen et al.(
      • van der Wielen G.J.
      • van Putten W.L.J.
      • Incrocci L.
      Sexual function after three-dimensional conformal radiotherapy for prostate cancer: Results from a dose-escalation trial.
      ) reviewed the literature and concluded that “sparing of the penile bulb to improve potency-preservation is not sufficiently supported by the current literature…” and questioned whether the potential “oncological risk” was justified given the uncertainty of potency sparing. It is possible that the key anatomic structures involved in ED pathophysiology have not been defined. Moreover, dosimetric accuracy of the true accumulated dose distribution has seldom been examined in detail. The data are sparse. Overall, the data plotted in Fig. 2 may be consistent with either a causal or surrogate relationship.

      7. Special Situations

      Hormonal therapy itself is associated with the ED. Several studies reported the deleterious impact of hormonal therapy on erectile function (
      • Rosen R.C.
      • Riley A.
      • Wagner G.
      • et al.
      The international index of erectile function (IIEF): A multidimensional scale for assessment of erectile dysfunction.
      ,
      • Rosen R.C.
      • Cappelleri J.C.
      • Smith M.D.
      • et al.
      Development and evaluation of an abridged, 5-item version of the International Index of Erectile Function (IIEF-5) as a diagnostic tool for erectile dysfunction.
      ,
      • van der Wielen G.J.
      • van Putten W.L.J.
      • Incrocci L.
      Sexual function after three-dimensional conformal radiotherapy for prostate cancer: Results from a dose-escalation trial.
      ,
      • Chen C.T.
      • Valicenti R.K.
      • Lu J.
      • et al.
      Does hormonal therapy influence sexual function in men receiving 3D conformal radiation therapy for prostate cancer?.
      ,
      • D'Amico A.V.
      • Manola J.
      • Loffredo M.
      • et al.
      6-month androgen suppression plus radiation therapy vs. radiation therapy alone for patients with clinically localized prostate cancer: A randomized controlled trial.
      ,
      • Kratzik C.W.
      • Schatzl G.
      • Lunglmayr G.
      • et al.
      The impact of age, body mass index and testosterone on erectile dysfunction.
      ,
      • Rosenberg M.T.
      Diagnosis and management of erectile dysfunction in the primary care setting.
      ). However, the association of hormonal therapy with RT dose/volume of the PB is unknown.

      8. Recommended Dose/Volume Limits

      On the basis of the data available, it is prudent to keep the mean dose to 95% of the PB volume to <50 Gy. It may also be prudent to limit the D70 and D90 to 70 Gy and 50 Gy, respectively. It is acknowledged that the PB may not be the critical component of the erectile apparatus, but it seems to be a surrogate for yet to be determined structure(s) critical for erectile function for at least some techniques.

      9. Future Toxicity Studies

      Standard methods to define the PB and associated critical structures should become more widely used. A standard method to score ED should be more widely adopted. Systematic prospective clinical trials that attempt to relate the three-dimensional dose–volume parameters from all of the potentially critical structures to clinical outcomes should be considered. Such studies may help to identify which pelvic structures are critical for ED. Dosimetric/imaging studies estimating uncertainties in the overall accumulated “true dose distribution” should be considered. This may be a key cause of inconsistencies between reported results. Anatomic studies to better define the critical anatomic sites for RT-associated ED may be helpful. Well-characterized data (including full dose distribution and imaging information) should be pooled from multiple studies where possible.

      10. Toxicity Scoring

      We recommend that patients undergo pre- and post-RT assessment of ED using the IIEF. Patients can be grouped into five groups according to their scores; for example, in none (
      • D'Amico A.V.
      • Manola J.
      • Loffredo M.
      • et al.
      6-month androgen suppression plus radiation therapy vs. radiation therapy alone for patients with clinically localized prostate cancer: A randomized controlled trial.
      ), mild (
      • Macdonald A.G.
      • Keyes M.
      • Kruk A.
      • et al.
      Predictive factors for erectile dysfunction in men with prostate cancer after brachytherapy: Is dose to the penile bulb important?.
      ), mild to moderate (
      • Wallner K.E.
      • Merrick G.S.
      • Benson M.L.
      • et al.
      Penile bulb imaging.
      ), moderate (
      • Selek U.
      • Cheung R.
      • Lii M.
      • et al.
      Erectile dysfunction and radiation dose to penile base structures: A lack of correlation.
      ), and severe (
      • Fisch B.M.
      • Pickett B.
      • Weinberg V.
      • et al.
      Dose of radiation received by the bulb of the penis correlates with risk of impotence after three-dimensional conformal radiotherapy for prostate cancer.
      ). It is important that the evaluation of ED is performed with a detailed history including sexual, medical, and psychosocial status and other laboratory tests (
      • Rosen R.C.
      • Riley A.
      • Wagner G.
      • et al.
      The international index of erectile function (IIEF): A multidimensional scale for assessment of erectile dysfunction.
      ,
      • Rosen R.C.
      • Cappelleri J.C.
      • Smith M.D.
      • et al.
      Development and evaluation of an abridged, 5-item version of the International Index of Erectile Function (IIEF-5) as a diagnostic tool for erectile dysfunction.
      ,
      • Kratzik C.W.
      • Schatzl G.
      • Lunglmayr G.
      • et al.
      The impact of age, body mass index and testosterone on erectile dysfunction.
      ,
      • Rosenberg M.T.
      Diagnosis and management of erectile dysfunction in the primary care setting.
      ). Further clinical studies may be needed to validate the IIEF for the assessment of ED after RT.

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